Book

A HISTORY OF HUMAN HELMINTHOLOGY DAVID I. GROVE MD. FRACP, FRCPA, DTM&H Department of Clinical Microbiology and Infectious Diseases The Queen Elizabeth Hospital Woodville South Australia

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British Library Cataloguing in Publication Data Grove, David I A history of human helminthology 1. Man. helminthic diseases I. Title 616.962 ISBN 0-86198-689-7

Printed and bound in the UK by Bookcraft (Bath) Ltd

CONTENTS Preface

vii

Acknowledgements

viii

1. The nomenclature and classification of worms

1

2. Understanding the origin and transmission of worms

33

3. The discovery and development of anthelmintics

75

4. Fasciola hepatica and fascioliasis

103

5. Fasciolopsis buski and fasciolopsiasis

127

6. Clonorchis sinensis and clonorchiasis

141

7. Paragonimus westermani and paragonimiasis

159

8. Schistosoma haematobium and schistosomiasis haematobia

187

9. Schistosoma mansoni and schistosomiasis mansoni

233

10. Schistosoma japonicum and schistosomiasis japonica

263

11. Trematode infections of lesser importance

297

12. Echinococcus granulosus and echinococcosis or hydatid disease

319

13. Taenia solium and taeniasis solium and cysticercosis

355

14. Taenia saginata and taeniasis saginata

385

15. Diphyllobothrium latum and diphyllobothriasis

397

16. Cestode infections of lesser importance

421

17. Enterobius vermicularis and enterobiasis

439

Contents

18. Trichuris trichiura and trichuriasis

455

19. Ascaris lumbricoides and ascariasis

469

20. Anyclostoma duodenale, Necator americanus and hookworm disease

499

21. Strongyloides stercoralis and strongyloidiasis

543

22. Trichinella spiralis and trichinosis

571

23. Wuchereria bancrofti, Brugia species and filariasis

597

24. Loa loa and loiasis

641

25. Onchocerca volvulus and onchocerciasis

661

26. Dracunculus medinensis and Guinea worm disease

693

27. Nematode infections of lesser importance

721

28. Miscellanea

765

29. Biographies

783

Person index

823

Subject index

836

PREFACE In his History of Tropical Medicine published in 1939, HH Scott wrote : "Ankylostomiasis is almost the only helminthic infestation of man in the tropics which can be said to have a history, at all events a history of sufficient interest to call for any detail". Scott was wrong. Many worms a re visible to the naked eye and some have been recognized for millenia. The study of worms has been an integral component of Man's struggle to come to grips with the origin s of infectious diseases and the means by which they are transmitted from one to another. This book is an attempt to describe th e unfolding of those events which have led to our current understanding of helminth s infecting humans. They have occupied many centuries and have been undertaken b y diverse men and women in many locations and climes. The first three chapters of the book are gen eral in nature, the next eight are concerned with trematodes (flukes), the next five deal with cestodes (tapeworms and cysti c worms), the following eleven consider nematodes (roundworms) and the final chapter covers various miscellaneous items. Chapters concerned with specific worm infections follow a consistent plan, beginning with the discovery of the parasite and then its life cycle, followed by an historical treatment of how the clinical features have bee n recognized, diagnostic techniques developed, treatment evolved, the epidemiolog y understood and preventive and control measures applie d. Short biographies of the major research workers are appended at the end of the book. This work has been a labour of love from its conception some dozen years ago till the presentation of the typeset manuscript to the publisher. History is a dynamic subject, and it is my hope that others will build upon and refine all that is recounted herein.

ACKNOWLEDGEMENTS I am very grateful to the University of Western Australia for twelve months' sabbatical leave during which time much of the basic research for this book was undertaken in the United Kingdom. Special tribute must be paid to two key sources. The first is th e magnificent Tropical Medicine and Parasitology: Classic Investigations edited by BH Kean, KE Mott and AJ Russell (Cornell University Press, Ithaca, 1978) in whic h translations of many of the most important original articles are brought together. The second is the Tropical Diseases Bulletin in which the helminthological literature has been abstracted since the early part o f this century. Thanks are due to Dr CR Morris for providing a photograph of his grandfather, WH Ransom, to Dr John Walker fo r obtaining a photograph of H Dew from the University of Sydney, and to Prof J Bailenger for assistance in collecting biographical details of L Normand and C Bavay. The photographic plates were expertly put together by Mr J Hadaway and Mr C Hentschke. Publication of these plates has been made possible by a generous grant from the Pathology Advisory Fund Committee of the Queen Elizabeth Hospital, Woodville, South Australia. This book has been produced on a personal computer using Wor d Perfect 5.1 (Word Perfect Corporation, Utah) and Glyphix (SWFTE International , Delaware). Finally, and most importantly, I must express my gratitude to my wife , Marilyn, and my children, Duncan, Graham, Br onwen and Lachlan, for the patience and forbearance they have shown during the many hours that this book has taken to prepare.

Chapter 1

THE NOMENCLATURE AND CLASSIFICATIO N OF WORMS

THE NATURE OF WORMS Worms are multicellular invertebrate animals, each of which belongs to one of several phyla or classes in the animal kingdom. The name "worm" is an in definite though emotive and evocative term which conjures up in the popula r mind visions of any elongated, creeping thing that is not obviously something else. This is not at all surprising, for the word, which is derived from the Latin "vermis", has been used down the centuries as an all-embracing description to apply to all worm-like creatures, whether they be earthworms, insect larvae in fruit, in vegetables or in trees, or parasitic worms in animals 34. Indeed, Linnaeus in the eighteenth century was even more liberal and used the titl e "Vermes" in his Systema Naturae to include a wide range of multicellula r organisms which we might now classify as invertebrates 32. Since worm-like creatures have been found in many branches of the animal kingdom, variou s authorities have drawn different lines of demarcation between worm an d non-worm. Worms are now, however, commonly considered to encompass the following phyla and classes: Nematoda (roundworms), Platyhelminthes (flat worms), Acanthocephala (thorny-headed worms), Nematomorpha (hairworms or gordiid worms) and Annelida (segmented worms including earthworms and leeches). These various groups differ from each other in both externa l appearance and fundamental organization, the sal ient features being summarized briefly as follows: (1) Nematoda The worms are elongated and cylindroidal in shape with a basically bilateral symmetrical arrangement. The integument consists of a non-nucleated cuticle secreted by the underlying hypodermis. They have a pseudocoele (a body cavity which is not lined with mesothelium), a complete gastrointestinal tract, and those that are parasitic in humans are unisexual. (2) Platyhelminthes These helminths are bilaterally symmetrical and are compressed dorsoventrally to give a leaf-like or tape-like shape. The integument generally consists of a syncitial cytoplasmic covering continuous with nucleated portions of the cytoplasm situated in the parenchyma beneath the muscle layer. They lack a body cavity, with the region between the internal organs being filled with spongy, mesenchymatous cells. Flatworms of human importance fall into two classes: a.Trematoda The worms are unsegmented and the adult forms are usually endowed with suckers and an incomplete gut (one aperture only). They may be either unisexual or

1

2

A History of Human Helminthology

hermaphroditic. b. Cestoda The adult worms are usually segmented with the body being divided transversely into separate, sexually complete units called proglottids. The scolex (head) is provided with suckers + hooks. They have no gut and are hermaphroditic. (3) Acanthocephala The adult worms have a proboscis armed with hooks which is retractile into a sheath. The elongated, more or less cylindroidal worms have an integument that is perforated by canals, a large pseudocoele, no gastrointestinal tract and are unisexual. Transmission occurs through an arthropod intermediate host. (4) Nematomorpha These elongated, cylindroidal worms have a true body cavity, the mouth and anus is frequently absent, and the pharynx is degenerate. They have no excretory system and the sexes are separate. The adult forms are free-living in the soil while the juvenile stages are parasitic in arthropods. (5) Annelida These are bilaterally symmetrical, segmented creatures with a well-defined gut, body cavity and excretory, vascular and nervous systems. Earthworms (oligochaetes) and leeches (hirudines) are hermaphroditic, with the latter possessing suckers.

The early physicians and naturalists, however, regarded parasitic worms a s an homogenous but separate an d discrete group of creatures without backbones that were characterized by the possession of a soft, elongated body without any locomotor appendage or well-developed hea d, and that were found in the bodies of other animals. In the early nineteenth century, Carl Rudolphi coined a ne w word, "Entozoa", to describe such organisms; this indicated that they wer e animals living inside the bodies of other animals 39. This word, which mean s literally "animal within" was derived from the Greek words (ENTOS) meaning "within" or "inside" and (ZOON) meaning "animal". This was a particularly useful term for parasitic worms and held sway while the concept that parasitic worms were a distinct systematic group persisted until the latter half of the nineteenth century. Eventually, however, with the discovery of th e complex life cycles and migrations of many worms, it became clear that th e word was inappropriate for describing the eggs and larvae of parasitic worms that might be found in the external environment. The word is rarely met wit h nowadays and worms are generally qualified as being either free-living o r parasitic worms or helminths. The latter word, "helminth", has much the same meaning in modern parlance as does "worm". It is derived from the Greek word, µ (HELMINS) [Combining form µ - (HELMINTHO-)] which was used by the ancient Greek physicians and naturalists to denote worms found in th e intestines of animals. "Helminthology", or the study of worms, is derived from a combination of µ (HELMINTHO-) and (LOGOS) meaning "account", "reason" or "discourse". Although the word may have no exac t meaning in zoological classification, it is common in medical terminology and is still used in the same sense as it was by Sir William Ramsay, physician t o King Charles II of England, in 1668. He published a volume entitle d Elminthologia, or some Physical Considerations of the Matter, Origination,

Nomenclature and Classification

3

and Several Species of Worms Macerating and Direfully Cruciating every part of the Bodies of Mankind etc. which appears to be the first English textbook on this subject. In his book, Ramsay dealt with worms and their origin, thei r distribution within the human body, the effects of age and other factors o n susceptibility to infection, the clinical features, the prognosis, treatment an d methods of prevention of worm infections 35. Although used by some parasit ologists such Dujardin (Histoire naturelle des helminthes ou vers intestinaux , 184517) and Diesing (Systema Helminthum, 1849-1851 16), the term was not usually adopted in general pathological and medical texts until Requin (1852) in his "Élémens de pathologie médicale " argued that the term "la maladi e vermineuse" (wormy illness) was complex, clumsy and embarrassing, an d championed the use of the word "helminthiasis", derived from a combination of µ (HELMINTHIAN) meaning "to suffer from worms", and (ASIS), to denote "the condition of" suffering from a worm infection 38. There were, however, some opponents. Davaine (1877), for example, wrote that h e did not believe that medical language gained in clarity or conciseness by th e introduction of the expression 15. Nevertheless, the terms "helminth" an d "helminthiasis" found favour with many subsequent authors and are no w well-entrenched in the medical literature.

AWARENESS OF PARASITIC WORMS DOWN THE AGES The Greek and Roman physicians of the M editerranean basin before and around the time of Christ recognized two, sometimes three, worms as parasitizing the human frame. All these worms were large and inhabited the gastrointestina l tract, hence they were appreciated relatively easily. Thus, Celsus (c.30 BC-38 AD)12 and Pliny (23-79 AD) 11 spoke of tapeworms and roundworms, whereas Hippocrates (c.460-374 BC) 22, Aristotle (384-c.322 BC) 4 and Galen (129-c.200 AD)19 were familiar with tapeworms ( Taenia species), round worms ( Ascaris lumbricoides) and threadworms (Enterobius vermicularis ). Ascaris lumbricoides was called in Greek µ (HELMINS STRONGYLE), meaning "round worm", Enterobius vermicularis was termed (ASKARIS, ASCARIS - there have been two transliterations, th e former said to be closer to the original etymologically and the latte r phonetically), and the tapeworm was known as µ (HELMINS PLATEIA) meaning "flatworm" or, more rarely, a s (TAINIA, TAENIA) meaning "band" or "ribbon worm". The Romans and those who wrote in Latin translated the word µ (HELMINS) by "lumbricus". They used this expression to encompass all th e intestinal worms, and also earthworms which they believed were closel y related. Thus, the word "lumbricus" was a group term analogous to a generi c description and was modified by an adjective to indicate the type in the fol lowing manner: "lumbricus teres" ("teres" = "round, cylindrical") for Ascaris

4

A History of Human Helminthology

Table 1.1. Classification of worms infecting humans according to Linnaeus, 1758 33. (Worms found rarely or not then recognized as being pathogenic for humans have been omitted in Tables 1-14) ___________________________________________________________________ Classis Vermes CURRENT NAME Ordo Intestina Gordius medinensis Dracunculus medinensis Ascaris vermicularis Enterobius vermicularis Ascaris lumbricoides Ascaris lumbricoides Fasciola hepatica Fasciola hepatica Ordo Mollusca Ordo Testacea Ordo Lithophyta Ordo Zoophyta Taenia solium Taenia solium Taenia lata Diphyllobothrium latum ____________________________________________________________________

lumbricoides, "lumbricus latus" ("latus" = "broad, wide") for Taenia species, and "lumbricus terrenus" ("terrenus" = "earth") for the common earthworm. Following the fall of Rome in the fifth century AD, medical learning wa s largely maintained and developed throughout the Dark Ages by Persian an d Arabic physicians. These authors recognized three, four, or sometimes five , species of worms. They were all familiar with Ascaris lumbricoides and Enterobius vermicularis, but their understanding of tapeworms varied . Serapion (c. ninth century), for example, regarded the Taenia proglottids as distinct and independent worms which he called "cucurbitini" in view of their fancied resemblance to pumpkin seeds. He did not recognize Taenia itself as a worm but as a membrane formed by the intestine to hold and develop th e cucurbitini41. Avicenna (981-1037), in contrast, spoke of roundworms, threadworms, tapeworms and cucurbitini, with the last-named being considered as a distinct parasite 5. In addition, the Arabo-Persian physicians were familia r with dracunculiasis (Guinea worm infection) as a clinical entity, but th e verminous nature of the condition was a matter of debate amongst them (se e chapter 26). This was the situation which presented itself to the European physicians and naturalists of the Renaissance. The person who had the greatest and mos t profound influence on the nomenclature of helminths was the Swede, Carl von Linné (Carolus Linnaeus). This effect resulted, not from a prime consideration of helminths themselves, but as a consequence of his general treatment of al l living things. Following the classical line of thought, Linnaeus initially (1735) recognized three forms of worms as infecting humans: lumbrici (now known as Ascaris lumbricoides), ascarides (Enterobius vermicularis ) and taeniae (Taenia species and Diphyllobothrium latum )32. Linnaeus had divided th e animal world into six classes - Mammalia (mammals), Aves (birds), Amphibia

Nomenclature and Classification

5

Table 1.2. Classification of worms infecting humans according to Goeze, 1782 21 ____________________________________________________________________ Genus

CURRENT NAME

Ascaris lumbricoides Ascaris lumbricoides Ascaris vermicularis cauda subulata Enterobius vermicularis Trichocephalos Trichuris trichiura Gordius Dracunculus medinensis Planaris latiuscula Fasciola hepatica Taenia cucurbitina grandis saginata Taenia saginata Taenia cucurbitina plana pellucida Taenia solium Taenia lata Diphyllobothrium latum Taenia visceralis socialis granulosa Echinococcus granulosus ____________________________________________________________________

(frogs etc.), Pisces (fish), Insecta (arthropods and crustaceans) and Verme s (other invertebrates). He then subdivided these classes into various orders, the Class Vermes being partitioned into five orders (Table 1.1). There wer e justifiable criticisms of his class ification. For example, George Louis Leclerc de Buffon, a wealthy French count and keeper of the Jardin du Roi, wrote wit h some acerbity that no-one could imagine that a mollusc was a worm or tha t crayfish were insects. With the publication of the tenth edition of his work i n 1758 33 , Linnaeus introduced a major change in the manner of describin g animals. He had derived his concepts of genus and species from Greek logic , and in the earlier editions of his Systema Naturae had used several lines o f descriptive text to define and differentiate various species. In this edition , however, he limited the species designation to a single word in order to reduce the expenses of publication. Thus, by a combination of force of circumstances and Greek logic, binary nomenc lature was born. By 1758, he acknowledged six species of worms, which were placed in two different orders, as being capable of infecting humans (Table 1.1). The differentiation between Taenia solium and Taenia lata (now known as Diphyllobothrium) was clearly established . Fasciola hepatica, which he had at one time regarded as a leech, now found its rightful place among the helminths, and Gordius medinensis (= Dracunculus medinensis) was becoming accepted increasingly by various authorities as being of a verminous nature. In 1782, the German pastor, Johann Goeze (Göze) published a major work on the natural history of worms inhabiting the bodies of animals entitle d Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper 21. This book was written primarily for submission to the Royal Academy o f Science in Copenhagen which had set in 1780 a prize essay on the subject o f the origin of parasitic worms. Goeze argued for the spontaneous origin o f helminths and received second prize. His work, however, is a major contribution to the helminthological literature, particularly from a systematic point o f

6

A History of Human Helminthology

Table 1.3. Classification of worms infecting humans according to Gmelin, 1788-1793 20 ____________________________________________________________________ Classis Vermes CURRENT NAME Ordo Intestina Ascaris vermicularis Enterobius vermicularis Ascaris lumbricoides Ascaris lumbricoides Trichocephalus hominis Trichuris trichiura Filaria medinensis Dracunculus medinensis Fasciola hominis Fasciola hepatica Taenia solium Taenia solium Taenia vulgaris Diphyllobothrium latum Taenia visceralis Echinococcus granulosus Taenia cellulosae Taenia solium ____________________________________________________________________

view. Goeze did not follow the binary system of nomenclature and often used a number of adjectives to describe each parasite. He divided worms into te n genera: Ascaris, Trichocephalos, Gordius, Cucullanus, Strongylus, Pseudoechinorhynchus, Planaria, Fasciola, Taenia and Chaos. He recognized nine species of worms as infecting the human body reasonably commonly (Tabl e 1.2). The additions to the worms described by Linnaeus were due to th e differentiation of Taenia saginata from T. solium by Goeze, his appreciatio n that hydatid cysts (Echinococcus granulosus ) were wormy in nature when he found the characteristic taeniid heads within each cyst, and the discovery in the interim by others of Trichuris, which Goeze renamed Trichocephalos when he found that what had been identified previously as the tail was in fact the head. Between 1788 and 1793, JF Gmelin issued a revised version of Linnaeus' s work which was published as the thirteenth edition of Systema Naturae 20. Gmelin retained the basic format used by Linnaeus. The total number o f parasitic species listed by Gmelin remained the same (Table 1.3), but th e number of species which are recognized today fell by one. Gmelin failed t o maintain Goeze's distinction between Taenia solium and Taenia saginata and this separation fell into oblivion for another 60 years. On the other hand, h e recognized correctly the helminthic nature of Cysticercus cellulosae , which he called Taenia cellulosae. He was completely unaware, however, that this organism was merely a stage in the life cycle of Taenia solium, and accorded it separate specific status. In 1798, G Cuvier in his Tableau élémentaire de l'histoire naturelle de s animaux, produced a classification which divided worms into two groups - the "cavitaires" and the "parenchymateux". Worms in the first group had a distinctive digestive cavity with an anus. The second group lacked complete digestive tubes: if there was a gut at all, it was incomplete with the anus being absent 14. In 1800, the German naturalist, Johann Zeder, published what was purport-

Nomenclature and Classification

7

Table 1.4. Classification of worms infecting humans according to Zeder, 1800 43 and 180044 ____________________________________________________________________ Zeder, 1800

Zeder, 1803

CURRENT NAME

Rundwürmer Rundwürmer Fusaria lumbricoides Fusaria lumbricoides Ascaris lumbricoides Fusaria dispar Mastigodes hominis Trichuris trichiura Fusaria vermicularis Enterobius vermicularis Filaria medinensis Dracunculus medinensis Hakenwürmer Hakenwürmer Saugwürmer Saugwürmer Distoma hepaticum Distoma hepaticum Distoma hepaticum Bandwürmer Bandwürmer Halysis solium Taenia solium Halysis lata Diphyllobothrium latum Blasenwürmer Blasenwürmer Polycephalus hominis Polycephalus echinococcus Echinococcus granulosus Cysticercus finna Taenia solium (also C. pyriformis, C. albopunctatus) ___________________________________________________________________

ed to be a revision of Goeze's work (Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer mit Zusätzen und Anmerkungen herausgegeben von JGH Zeder), but was in fact so different as to be hardly recognizable as such 43. Not only did he revert to binary nomenclature and co mpletely change the generic and many of the specific names, but Zeder introduced a novel system of classifying worms which was the forerunner of the modern system of classification. H e divided the entozoa into five groups: Rundwürmer (roundworms) , Hakenwürmer (hookworms, equivalent to the modern Acanthocephala o r thorny-headed worms and not ancylostomes), Saugwürmer (sucking worms) , Bandwürmer (tapeworms) and Blasenwürmer (cystic worms) (Table 1.4). The Rundwürmer would become the modern nematodes and the Saugwürmer th e modern trematodes. The Bandwürmer and the Blasenwürmer would eventually be combined to form the cestodes, but this division by Zeder inhibite d realization that the two groups were related, and more than 50 years were t o pass before the relationship was proven with the recognition that cystic worms were intermediate stages in the life cycles of tape worms. Being a revision o f Goeze's work, this edition was n ot all-encompassing and a number of important human pathogens were omitted. In 1803, Zeder produced a new book entitled Anleitung zur Naturgeschichte der Eingeweidewürmer 44. He again used the same classification as he ha d employed three years earlier. Although he generally gave the worms different names, he recognized the same species as infecting humans as di d

8

A History of Human Helminthology

Table 1.5. Classification of worms infecting humans according to Rudolphi. 1808-1810 39 ____________________________________________________________________ Ordo Nematoideorum CURRENT NAME Filaria medinensis Dracunculus medinensis Trichocephalus dispar Trichuris trichiura Ascaris lumbricoides Ascaris lumbricoides Ascaris vermicularis Enterobius vermicularis Ordo Trematodorum Distoma hepaticum Fasciola hepatica Ordo Cestoideorum Taenia lata Diphyllobothrium latum Taenia solium Taenia solium Ordo Cysticorum Cysticercus cellulosae Taenia solium Echinococcus hominis Echinococcus granulosus (also E. simiae E. veterinorum) ___________________________________________________________________

Gmelin (Table 1.4). He divided (incorrectly) Gmelin's Taenia cellulosae into three species and placed them in a new genus named Cysticercus. The worm infecting humans he called C. finna, that infecting subhuman primates he designated C. pyriformis, and that infecting other animals he labelled C. albopunctatus. Between 1808 and 1810, the German physician, Carl Rudolphi published a massive opus totalling 1,370 pages entitled Entozoorum, sive vermium intestinalium historia naturalis meaning the natural history of entozoa or intestinal worms 39 . He took the same basic five groups as proposed by Zeder and con verted the German names into classical ones. It was from these names that the modern words nematode, trematode and cestode are derived. (1) The roundworms became t he Entozoa Nematoidea. This name was derived from a combination of the Greek words µ (NEMA) [combining for m µ - (NEMATO)] = "thread" and (ODES) = "like, of the nature of", to indicate their filiform or thread-like sh ape. He defined them as being "corpore elongato, cylindrico, tenuissime, an ulato, elastico" 39meaning that the body of the worm was elongated, cylindrical, thin, ringed and elastic. (2) the "hookworms" became the Entozoa Acanthocephala. This name was derived from a combination of the Greek words (AKANTHA, ACANTHA) = "spine" or "thorn" and (KEPHALE, CEPHALE) = "head", to indicate the characteristic hooks on the head of the worms. H e defined them as being "corpore teretiusculo, utriculari, subelastico, proboscide seriatim uncinata, retractili" 39 meaning that the body was slightly rounded , bag-shaped and partly elastic, while the probosc is or head had a row of retractile hooks. (3) The sucking worms became the Entozoa Trematoda. This name was de-

Nomenclature and Classification

9

Table 1.6. Classification of worms infecting humans according to Bremser, 1819 10 ____________________________________________________________________ Nematodeorum CURRENT NAME Ascaris lumbricoides Ascaris lumbricoides Oxyuris vermicularis Enterobius vermicularis Trichocephalus dispar Trichuris trichiura Filaria dracunculus Dracunculus medinensis Trematodorum Distoma hepaticum Fasciola hepatica Cestoideorum Taenia solium Taenia solium Bothriocephalus latus Diphyllobothrium latum Cysticorum Cysticercus cellulosae Taenia solium Echinococcus hominis Echinococcus granulosus (also E. veterinorum) ____________________________________________________________________

rived from the Greek word µ (TREMATODES) meanin g "foraminous" or "pierced with holes", to reflect the fact that they were usually provided with conspicuous suckers ( µ is a combination of µ = "hole" or "orifice" and (ODES) = "of the nature of"). Rudolphi defined them as being "corpore depresso vel teretiusculo, molli, poris suctoriis" 39 meaning that the body was flattened or slightly rounded, soft and provided with sucking holes. (4) The tapeworms became the Entozoa Cestoidea. This name was derive d from a combination of the Gre ek words (KESTOS, CESTOS) = "tape", "belt" or "ribbon" and (ODES) = "of the nature of", to indicate that they are elongated, ribbon-like organisms. He defined them as being "corpor e elongata, depresso, molli"39 meaning that the body was elongated, flattened and soft. (5) The cystic worms became the Ento zoa Cystica. This name was derived from the Greek word (KUSTIS, CYSTIS) meaning "bladder". He define d them as being "membranacei, plerumque rugosi, intus cavi, capitis coron a uncinata, cystide inclusi" 39 meaning that they had a generally wrinkle d membrane and an internal cavity containing heads crowned with hooks. The species of worms that Rudolphi recognized as being of huma n importance are indicated in Table 1.5. It can be seen that there were n o significant changes from those published by Zeder. Rudolphi gave the generic name of Echinococcus to hydatids and divided them (incorrectly) into thre e species, hominis, simiae, and veterinorum to reflect their location in human , subhuman primate, and domestic or other animal hosts. In 1819, Rudolphi produced a revision of his opus entitled Entozoorum Synopsis 40. He listed a total of 993 species of parasitic worms, 552 of whic h he considered as definite and 441 as being dubious. There were no majo r

10

A History of Human Helminthology

Table 1.7. Classification of worms infecting humans according to Dujardin, 1845 17 ____________________________________________________________________ Nématoides CURRENT NAME Trichocephalus dispar Trichuris trichiura Filaria medinensis Dracunculus medinensis Filaria oculi humani Loa loa (also F. lacrymalis) Oxyuris vermicularis Ascaris lumbricoides Trichina spiralis Trichinella spiralis Trématodes Distoma hepaticum Fasciola hepatica Cestoïdes (Cestoidea et Cystica of Rudolphi) Taenia solium Taenia solium Bothriocephalus latus Diphyllobothrium latum Cysticercus cellulosae Taenia solium Echinococcus veterinorum Echinococcus granulosus ____________________________________________________________________

changes to the parasites infecting humans in this volume, other than hi s acceptance of the separation by Bremser of Diphyllobothrium latum from the genus Taenia and his placement of it in the genus Bothriocephalus. In the same year (1819), JG Bremser, custodian of the Imperial museum in Vienna published his book entitled Ueber lebende Würmer im lebende n Menschen 10. No new worms of human importance were listed (Table 1.6), but he transferred Ascaris vermicularis to the genus Oxyuris and, as mentioned, reclassified Taenia lata as Bothriocephalus latus. He recognized two species of Echinococcus, E. hominis and E. veterinorum in other animals. In 1845, the Frenchman Felix Dujardin produced his Histoire naturelle des helminthes ou vers intestinaux 17. His classification had features of bot h Rudolphi's and Cuvier's systems. He divided the parasitic worms into two basic groups which were in turn partitioned into subclasses. The animals of the first group had a gut. This category was then subdiv ided depending upon whether the gut was complete or incomplete, and whether the worms were unisexual o r hermaphroditic. Unisexual worms with a complete gut but no spines on th e proboscis were placed in the subclass Nématoï des, while those with spines were located in the subclass Acanthothèques. Hermaphroditic worms with a n incomplete gut were in the subclass Trématodes. The second group had n o intestines or true mouth and were in turn partitioned. Those with separate sexes were placed in the subclass Acanthocéphales, while those which wer e hermaphroditic were set in the subclass C estoïdes. This last group encompassed both the Cestoidea and Cystica of Rudolphi. Two major additions to huma n helminths were listed (Table 1.7). Trichina spiralis was described in detail, and the worm now known as Loa loa was mentioned and stated as being definitely different from Dracunculus medinensis , although no details were provided.

Nomenclature and Classification

11

Table 1.8. Classification of worms infecting humans according to Diesing, 1849-1851 16 ____________________________________________________________________ Nematoidea CURRENT NAME Trichina spiralis Trichinella spiralis (also T. affinis) Ascaris vermicularis Enterobius vermicularis Ascaris lumbricoides Ascaris lumbricoides Filaria medinensis Dracunculus medinensis Trichocephalus dispar Trichuris trichiura Ankylostomum duodenale Ancylostoma duodenale Trematoda Distoma hepaticum Fasciola hepatica Cephalocotylea Echinococcus polymorphus Echinococcus granulosus Cysticercus cellulosae Taenia solium Taenia solium Taenia solium Dibothrium latum Diphyllobothrium latum ____________________________________________________________________

Soon afterwards, in 1849 and 1851, the German CM Diesing issued his two volume Systema Helminthum totalling 1,267 pages16. Human helminths fell into three orders, the Nematoidea, Myzelmintha and Cephalocotylea. The orde r Myzelmintha included two suborders, the Cercariaea and Trematoda. Th e Cercariaea contained many species of the genera Cercaria of Müller and Redia of de Filippi which were later shown to be larval stages of adult worms placed in the suborder Trematoda. In this book, another species of human importance, Anchylostomum duodenale , was now listed (Table 1.8). The labours of Goeze, Zeder, Rudolphi, Dujardin, Diesing and others ha d expanded helminthology greatly, developing it into a specialized study of th e metazoan parasites of the internal organs and structures of Man and animals. In the process, however, the relationship between these worms and non-parasitic animals was largely lost, for the parasitic helminths were generally considered to be a separate and peculiar class of animals. There were opponents of thi s view, such as CE von Baer and FS Leuckart, but this error was not correcte d finally until the middle of the nineteenth century when Carl Vogt united th e various groups of parasitic helminths with those of the free-living animals with which they were closely relate d42. Thus, Vogt classified the parasitic nematodes together with the free-living nematodes in the Nemathelminthes, and cas t parasitic cestodes and trematodes with free-living flatworms such a s turbellarians in the Platyhelminthes. While this was satisfying for the zoologist, it was not particularly relevant to the medical practitioner who was less interested in systematics and preferred to consider the helminths as a biological group. With the appearance in 1855 of Friedrich Küchenmeister's book Die in und an dem Körper des lebende n Menschen vorkommenden Parasiten 28, medical helminthology leaves th e

12

A History of Human Helminthology

Table 1.9. Classification of worms infecting humans according to Küchenmeister, 185528 ____________________________________________________________________ Nematelmia CURRENT NAME Trichocephalus dispar Trichuris trichiura Trichina spiralis Trichinella spiralis Oxyuris vermicularis Enterobius vermicularis Ancylostoma duodenale Ancylostoma duodenale Ascaris lumbricoides Ascaris lumbricoides Filaria medinensis Dracunculus medinensis Trematodea Distoma hepaticum Fasciola hepatica Distoma haematobium Schistosoma haematobium Cestoidea Bothriocephalus latus Diphyllobothrium latum Taenia solium Taenia solium Taenia mediocanellata Taenia saginata Taenia nana Hymenolepis nana Echinococcus altricipariens Echinocococcus granulosus Echinococcus scolicipariens Echincococcus granulosus ____________________________________________________________________

Table 1.10. Classification of worms infecting humans according to Cobbold, 1864 13 ____________________________________________________________________ Nematoda CURRENT NAME Ascaris lumbricoides Ascaris lumbricoides Trichocephalus dispar Trichuris trichiura Trichina spiralis Trichinella spiralis Sclerostoma duodenale Ancylostoma duodenale Oxyuris vermicularis Enterobius vermicularis Dracunculus medinensis Dracunculus medinensis Dracunculus loa Loa loa Trematoda Fasciola hepatica Fasciola hepatica Bilharzia haematobia Schistosoma haematobium Cestoda Taenia solium Taenia solium Taenia mediocanellata Taenia saginata Taenia flavopunctata Hymenolepis diminuta Taenia nana Hymenolepis nana Taenia elliptica Dipylidium caninum Taenia echinococcus Echinococcus granulosus Bothriocephalus latus Diphyllobothrium latum ____________________________________________________________________

Nomenclature and Classification

13

Table 1.11. Classification of worms infecting humans according to Davaine, 1877 15 ____________________________________________________________________ Nématodes CURRENT NAME Oxyuris vermicularis Enterobius vermicularis Ascaris lumbricoides Ascaris lumbricoides Trichocephalus dispar Trichuris trichiura Anchylostoma duodenale Ancylostoma duodenale Anguillula stercoralis Strongyloides stercoralis Anguillula intestinalis Strongyloides stercoralis Trichina spiralis Trichinella spiralis Filaria medinensis Dracunculus medinensis Filaria sanguinis hominis Wuchereria bancrofti Trématodes Distomum hepaticum Fasciola hepatica Distomum crassum Fasciolopsis buski Distomum haematobium Schistosoma haematobium Cestoïdes Taenia solium Taenia solium Taenia mediocanellata Taenia saginata Taenia nana Hymenolepis nana Taenia flavopunctata Hymenolepis flavopunctata Tania echinococcus Echinococcus granulosus Bothriocephalus latus Diphyllobothrium latum ____________________________________________________________________

major works of systematic helminthology. From Küchenmeister's time, a series of texts appeared which were devoted primarily or exclusively to human helminthology. The worms discussed by Küchenmeister are listed in Table 1.9 . Several major advances had occurred by then. Schistosoma haematobium and the common but relatively innocuous Hymenolepis nana had been discovered by Bilharz, and Küchenmeister himself had rediscovered the difference between Taenia solium and T. saginata. He blotted his copybook a little, however, by making a false subdivision of Echinococcus granulosus into E. scolicipariens and E. altricipariens. Perhaps most importantly of all, new understandings of the transmission of worms had led to alterations in the manner of classification. The publication by Steenstrup in 1842 of the Alternation of Generations in which he showed that cercariae and rediae were merely stages in th e reproduction of trematodes (see chapters 2,4), culminated in the disappearance of these genera from the list of flatworms as promulgated by Dujardin an d Diesing. Similarly, the demonstration of the relationship between cystic worms and tapeworms by Küchenmeister, von Siebold and others (see chapters 2, 12, 13), eliminated bladderworms such as Cysticercus cellulosae as separate species. The major addition by the time of Cobbold's book in 1864 13 was acceptance of Loa loa as a distinct nematode that was not uncommon in certain parts o f

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A History of Human Helminthology

Table 1.12. Classification of worms infecting humans according to Blanchard, 1885-18908 ____________________________________________________________________ Nematodes CURRENT NAME Ascaris lumbricoides Ascaris lumbricoides Oxyuris vermicularis Enterobius vermicularis Trichocephalus dispar Trichuris trichiura Ankylostoma duodenale Ancylostoma duodenale Rhabdonema intestinale Strongyloides stercoralis Filaria loa Loa loa Filaria medinensis Dracunculus medinensis Filaria sanguinis hominis Wuchereria bancrofti Trematodes Distoma hepaticum Fasciola hepatica Distoma sinense Clonorchis sinensis Distoma japonicum Clonorchis sinensis Distoma buski Fasciolopsis buski Distoma ringeri Paragonimus westermani Distoma heterophyes Heterophyes heterophyes Bilharzia haematobia Schistosoma haematobium Cestodes Taenia saginata Taenia saginata Taenia solium Taenia solium Taenia echinococcus Echinococcus granulosus Taenia nana Hymenolepis nana Taenia canina Dipylidium caninum Bothriocephalus latus Diphyllobothrium latum ____________________________________________________________________

the world (Table 1.10). In addition, the parasites now known as Hymenolepis diminuta and Dipylidium caninum were listed as infecting humans. Two new nematodes and another trematode made their appearance in Davaine's text i n 187715 (Table 1.11). Strongyloides stercoralis was discovered in the pre-ceding year, but it was not at first realized that the parasitic female worm and th e first-stage larva were different stages in the life cycle of the same parasite, and they were each given separate specific s tatus. Microfilariae had been discovered a number of years earlier by Demarquay then had been identified in the blood by Lewis in 1872, hence their designation as Filaria hominis sanguinis . Although the adult worm had be en discovered in 1876 by Bancroft, news of the find came too late to be incorporated into Davaine's book and his descriptio n was based upon the microfilaria l stage. Fasciolopsis buski had been discovered more than forty years before by Busk, but the finding of further cases in th e 1870's renewed interest in a previously obscure parasite. By the appearance of Blanchard's two volume work in 1885-1890 8, the identity of Anguillula intestinalis and A. stercoralis had been determined an d

Nomenclature and Classification

15

Table 1.13. Classification of worms infecting humans according to Braun, updated by Sambon and Theobald, 1906 ___________________________________________________________________ Nematoda CURRENT NAME Strongyloides intestinalis Strongyloides stercoralis Filaria medinensis Dracunculus medinensis Filaria bancrofti Wuchereria bancrofti Filaria diurna Loa loa Filaria perstans Mansonella perstans Filaria ozzardi Mansonella ozzardi Filaria loa Loa loa Filaria volvulus Onchocerca volvulus Trichocephalus trichiurus Trichuris trichiura Trichinella spiralis Trichinella spiralis Ankylostoma duodenale Ancylostoma duodenale Uncinaria americana Necator americanus Ascaris lumbricoides Ascaris lumbricoides Oxyuris vermicularis Enterobius vermicularis Trematoda Fasciola hepatica Fasciola hepatica Fasciolopsis buski Fasciolopsis buski Paragonimus westermani Paragonimus westermani Opisthorchis felineus Opisthorchis felineus Opisthorchis sinensis Clonorchis sinensis Schistosomum haematobium Schistosoma haematobium Schistosomum japonicum Schistosoma japonicum Cestoda Dibothriocephalus latus Diphyllobothrium latum Dipylidium caninum Diphylidium caninum Hymenolepis nana Hymenolepis nana Hymenolepis diminuta Hymenolepis diminuta Taenia solium Taenia solium Taenia saginata Taenia saginata Taenia echinococcus Echinococcus granulosus Echinococcus multilocularis Echinococcus multilocularis _________________________________________________________________________

Blanchard called the parasite Rhabdonema intestinale (Table 1.12). Two new flukes of some importance had been discovered - Clonorchis sinensis by McConnell and Paragonimus westermani in humans by Ringer and Manson . Baelz had incorrectly divided the former parasite into two species and Blan chard perpetuated the error. Mention was also made of the parasite now called Heterophyes heterophyes . By 1906, when the English version of Braun's textbook was published 9, several new nematodes had been described (Table 1.13). Manson had reported in 1893 a portion of Leuckart's description of Onchocerca volvulus from specimens sent to him from West Africa by a missionary, and Stiles had diff erentiated Necator americanus from Ancylostoma duodenale . In addition, two new filarial parasites, Filaria ozzardi and Filaria perstans had been discovered. Similarly, major fin ds had been made with the trematodes. Katsur-

16

A History of Human Helminthology

Table 1.14. Classification of worms according to Faust, 1939 18 ____________________________________________________________________ Nematodes Trematodes Cestodes Trichinella spiralis Schistosoma haematobium Diphyllobothrium latum Trichocephalus trichiurus Schistosoma mansoni Hymenolepis nana Strongyloides stercoralis Schistosoma japonicum Hymenolepis diminuta Ancylostoma duodenale Fasciola hepatica Dipylidum caninum Necator americanus Fasciolopsis buski Taenia solium Enterobius vermicularis Opisthorchis species Taenia saginata Ascaris lumbricoides Clonorchis sinensis Echinococcusgranulosus Wuchereria bancrofti Paragonimus westermani Onchocerca volvulus Acanthocheilonema perstans Mansonella ozzardi Loa loa Dracunculus medinensis microfilaria malayi _________________________________________________________________________

ada had discovered Schistosoma japonicum in 1904 and Opisthorchis felineus was now appreciated as infecting humans. Finally, a number of authors wer e beginning to accept the specificity of Echinococcus multilocularis . The second edition of Faust's text on human helminthology 18 in 1939 incorporated two major changes (Table 1.14). The specific systematic position of Schistosoma mansoni proposed in 1908 by Sambon had been proven b y transmission experiments, and Lichtenstein and Brug had appreciated tha t certain microfilariae in Southeast Asia were different from those of Wuchereria bancrofti and these had been labelled microfilaria malayi. Furthermore, infections with Opisthorchis viverrini had been recognized. These represented the last major discoveries of worms important for human medicine althoug h worms of limited geographical distribution such as Capillaria philippinensis , Brugia timori and Schistosoma mekongi would be discovered or differentiated in the next few decades. Table 1.15 lists those worms which have been des cribed in Beaver, Jung and Cupp's 1984 revision of Craig and Faust's Clinical Parasitology as infecting humans 6. These parasites range from exceedingl y common worms, such as Ascaris lumbricoides which infects nearly one billion people, to extremely rare ones which have been encountered in humans onl y once or twice.

THE RULES OF ZOOLOGICAL NOMENCLATURE It is clear from the foregoing discussion that many different names were often used to describe the same worm. This led to chaos and confusion and inhibited the flow of ideas and the generation of new discoveries, for unles s everyone possessed a common language, there was considerable uncertainty

Nomenclature and Classification

17

Table 1.15. Classification of worms according to Beaver, Jung and Cupp, 1984 6. ____________________________________________________________________ Class Nematoda Ancylostoma ceylanicum Ancylostoma duodenale* Angiostrongylus species Anisakis species Ascaris lumbricoides* Brugia malayi* Brugia timori multilocularis Capillaria species Dioctophyma renale Dirofilaria species Dracunculus medinensis* madagascariensis Enterobius vermicularis* Gnathostoma spinigerum Gongylonema pulchrum Haemonchus contortus Lagochilascaris minor Loa loa* Mammomonogamus laryngeus Mansonella ozzardi Mansonella perstans Mansonella streptocerca Metastrongylus elongatus Necator americanus* Phocanema species Oesophagostomum species Onchocerca volvulus* Phocanema species Physaloptera caucasica Strongyloides fülleborni Strongyloides stercoralis* Ternidens deminutus Thelazia species Toxocara species Trichinella spiralis* Trichuris trichiura* Wuchereria bancrofti* * common or relatively common

Class Trematoda Achillurbania species Alaria species Clonorchis sinensis* Dicrocoelium dendriticum Echinostoma species Fasciola gigantica Fasciola hepatica

Class Cestoidea Bertiella species Diphyllobothriumcordatum Diphyllobothrium latum* Diplogonoporus grandis Dipylidium caninum Echinococcusgranulosus* Echinococcus

Fasciolopsis buski Gastrodiscoides hominis Heterophyes heterophyes Metagonimus yokogawai

Echinococcus vogeli Hymenolepis diminuta Hymenolepis nana* Inermicapsifer

Opisthorchis felineus Opisthorchis viverrini Paragonimus westermani* Plagiorchis species Poikilorchis species Schistosoma haematobium* Schistosoma intercalatum Schistosoma japonicum* Schistosoma mansoni* Schistosoma margrebowiei Schistosoma mattheei Schistosoma rodhaini Spelotrema species Troglotrema salmincola Watsonius watsoni

Mesocestoides variabilis Raillietina demerariensis Sparganum species Spirometra houghtoni Taenia brauni Taenia multiceps Taenia saginata* Taenia serialis Taenia solium* Taenia taeniaeformis

____________________________________________________________________

as to what other writers were saying. This problem applied not just to medical helminthology, but was even more germane to zoologists who had to deal with more than a million animal species. In an attempt to produce uniformity and order, the Frenchman, Raphae l Blanchard, presented a Code to the First International Zoological Congress in Paris in 1889. This code was adopted by that and the subsequent Congress in 1892 but failed to receive universal support. The Third Congress in 189 5 appointed an international commission to develop a code which would be ac-

18

A History of Human Helminthology

ceptable to all zoologists. Progress reports were delivered at the Fourth (1898) and Fifth (1901) Congresses. At the Sixth Congress in 1904, the International Code of Zoological Nomenclature was p resented and the commission was made permanent. The code consisted of 36 articles supplemented with various recommend ations including a code of ethics and conditions for the suspension of the rules in certain cases. The naming of animals was based upon the binary system o f nomenclature. Article 26 provided the foundation stone upon which the whole edifice was erected for this statement confirmed that the starting point for such an arrangement began with the publication in 1758 of the tenth edition o f Linnaeus's Systema Naturae. The 36 basic articles which were adopted ar e reproduced in Table 1.16. In addition to these articles, a code of ethics was laid down in which it wa s suggested that when an author published a name of a new genus or specie s which was preoccupied, the person discovering the error should inform th e author and give him ample opportunity to propose a new name. Furthermore, a procedure was devised whereby the rules could be suspended in certai n cases. The circumstance in which this could arise would be when the com mission judged that a strict application of the rules would result in greate r confusion than uniformity. In such cases, notice of at least one year had to b e given in two or more of the following publications: Bulletin de la Société Zoologique de France, Monitore Zoologica, Nature, Science, or Zoologischer Anzeiger in order to allow debate. If the vote of the commission was no t unanimous, then the matter would be referred to the next Internationa l Congress which would appoint a special boar d of three members to make a final decision. The accumulation of knowledge over the years has in many instances necessitated the splitting of a species or the subdivision of a genus. An example of the former is the differentiation of the Taenia solium and Taenia saginata. In like manner, the genus Distoma of Retzius 1790 has been subdivided into man y genera including Clonorchis, Fasciolopsis, Paragonimus and Schistosoma. On some occasions, a name has been applied which had already been used fo r another member of the animal kingdom. Thus, Trichina spiralis of Owen 1835 was changed to Trichinella spiralis by Railliet in 1895 when it was realized that the generic name had already b een used for an insect. This is an example where a name is a homonym, i.e. where the same name has been applied to two o r more different animals. This contra sts with synonyms which are different names used for the same animal. All these eventualities were covered in the rules, but the article which gave rise to the greatest dissent and concern, particularly in the medical sphere, was Article 25 which described the law of priority. This law required that the valid name of a genus or species was the name under which it was first described , provided the principles of binary nomenclature were followed and the nam e was accompanied by an indication, definition or description of the organism .

Nomenclature and Classification

19

Table 1.16. The rules of zoological nomenclature (cited in 18) ____________________________________________________________________

"Article 1. - Zoological nomenclature is independent of botanical nomenclature in the sense that the name of an animal is not to be rejected simply because it is identical with the name of a plant. If, however, an organism is transferred from the vegetable to the animal kingdom its botanical names are to be accepted in zoological nomenclature with their original botanical status; and if an organism is transferred from the animal to the vegetable kingdom its names retain their zoological status. "Article 2. - The scientific designation of animals is uninominal for subgenera and all higher groups, binominal for species, and trinominal for subspecies. "Article 3. - The scientific names of animals must be words which are either Latin or Latinized, or considered and treated as such in case they are not of classic origin. "Article 4 - The name of a family is formed by adding the endingidae, the name of a subfamily by adding inae, to the root of the name of its type genus. "Article 5 - The name of a family or subfamily is to be changed when the name of its type genus is changed. "Article 6 - Generic and subgeneric names are subject to the same rules and recommendations, and from a nomenclatural standpoint they are coordinate, that is, they are of the same value. "Article 7 - A generic name becomes a subgeneric name, when the genus so named becomes a subgenus and vice versa "Article 8 - A generic name must consist of a single word, simple or compound, written with a capital initial letter, and employed as a substantive in the nominative singular. Examples:Canis, Perca, Ceratodus, Hymenolepis. "Article 9 - If a genus is divided into subgenera, the name of the typical subgenus must be the same as the name of the genus (see Article 25). "Article 10 - When it is desired to cite the name of a subgenus, this name is to be placed ni parenthesis between the generic and the specific names. Examples:Vanessa (Pyrameis) cardui. Article 11 - Specific and subspecific names are subject to the same rules and recommendations, and from a nomenclatural standpoint they are coordinate, that is, they are of the same value. "Article 12 - A specific name becomes a subspecific name when the species so named becomes a subspecies, and vice versa. "Article 13 - While specific substantive names derived from names of persons may be written with a capital initial letter, all other specific names are to be written with a small initial letter. Examples: Rhizostoma Cuvieri or R. cuvieri, Francolinus Lucani or F. lucani, Hypoderma Diana or H. diana, Laophonte Mohammed or L. mohammed, Oestrus ovis, Corvus corax. Article 14 - Specific names are: "(a) Adjectives, which must agree grammatically with the generic name. Example: Felis marmorata. "(b) Substantives in the nominative in apposition with the generic name. Example:Felis leo. "(c) Substantives in the genitive. Examples: rosae, sturionis, antilarum, galliae, sancti-pauli, sanctae-helenae. "If the name is given as a dedication to one or several persons, the genitive si formed in accordance with the rules of Latin declination in case the name was employed and declined in Latin. Examples: plini, aristotelis, victoris, antonii, elisabethae, petri (given name). "If the name is a modern patronymic, the genitive is always formed by adding, to the exact and complete name, an i if the person is a man, or an ae if the person is a woman, even if the name has a Latin form; it is placed in the plural if the dedication involves several persons of the same name. Examples: cuvieri, möbiusi, nuñezi, merianae, sarasinorum, bosi (not bovis), salmoni (not salmonis). "Article 15 - The use of compound proper names indicating dedication, or of compound words indicating a comparison with a simple object, does not form an exception to Article 2. In these cases the two words composing the specific name are written as one word with or without the hypen. Example: sanctae-catharinae or sanctaecatharinae, jan-mayeni or janmayeni, cornu-pastoris or cornu-pastoris, cor-angium or coranguinum, cedo-nulli or cedonulli.

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A History of Human Helminthology

Expressions like rudis palnusque are not admissible as specific names. "Article 16 - Geographical names are to be given as substantives in the genitive, or are to be placed in the adjectival form. Examples: sancti-pauli, sanctae-helenae, edwardiensis, diemensis, magellanicus, burdigalenesis, vindobonensis. Article 17 - If it is desired to cite the subspecific name, such is written immediately following the specific name, without the interposition of any mark of punctuation. Example:Rana esculenta marmorata Hallowell, but not Rana esculenta (marmorata) or Rana marmorata, Hallowell. Article 18 - The notation of hybrids may be given in several ways; in all cases the name of the male parent precedes that of the female parent, with or without the sexual signs: "(a) The names of the two parents are united by the sign of multiplication (X) Example:Capra hircus male X Ovis aries female and Capra hircus X Ovis aries are equally good formulae. "(b) Hybrids may also be cited in form of a fraction, the male parent forming the numerator and the female parent the denominator. Example: Capra hircus/Ovis aries. This second method is in so far preferable that it permits the citation of the person who first published the hybrid form as such. Example: Bernicla canadensis/Anser cygnoides Rabé. "(c) The fractional form is also preferable in case one of the parents is itself a hybrid. Example: Tetrao tetrix X Tetrao urogallus/Gallus gallus. In the latter case, however, parenthesis may be used. Example: (Tetrao tetrix X Tetrao urogallus) X Gallus gallus. "(d) When the parents of the hybrid are not known as such (parents), the hybrid takes provisionally a specific name, the same asif it were a true species, namely, as if it were not a hybrid; but the generic name is preceded by the sign of multiplication. Example: X Coregonus dolosus Fatio. "Article 19 - The original orthography of a name is to be preserved unless an error of transcription, a lapsus calami, or a typographical error is evident. "Article 20 - In forming names derived from languages in which the Latin alphabet is used, the exact original spelling, including diacritic marks, is to be retained. Examples: Selysius, Lamarckia, Köllikeria, Mülleria, Stilia, Krøyeria, Ibañesia, möbiusi, medi i, c j eki, spitzbergensis, islandicus, paraguayensis, patagonicus, barbadensis, faröensis. "Article 21 - The author of a scientific name is that person who first publishes the name ni connection with an indication, a definition or a description unless it is clear from the contents of the publication that some other person is responsible for said name and its indication, definition, or description. "Article 22 - If it is desired to cite the author's name, this should follow the scientific name without interposition of any mark of punctuation; if other citations are desirable (date, sp n., emend., sensu stricto, etc.,), these follow after the author's name, but are separated from it bya comma or by parentheses. Examples: Primates Linné, 1758, or Primates Linné (1758). "Article 23 - When a species is transferred to another than the original genus or the specific name is combined with any other generic name than that which it was originally published, the name of the author of the specific name is retained in the notation but placed in parentheses. Example: Taenia lata Linné, 1758, and Dibothriocephalus latus (Linné, 1758); Fasciola hepatica Linné, and Distoma hepaticum (Linné, 1758). If it is desired to cite the author of the new combination, his name follows the parentheses. Example: Limnatis nilotica (Savigny, 1820) Moquin-Tandon, 1826. "Article 24 - When a species is divided, the restricted species to which the original specific name of the primitive species is attributed may receive a notation indicating both the name of the original author and the name of the reviser. Example: Taenia solium Linné partim, Goeze. "Article 25 - The valid name of a genus or species can be only that name under which it was first designated on the condition: "(a) That this name was published and accompanied by an indication, or a definition, ora description; and "(b) That the author has applied the principles of binary nomenclature. "Article 26 - The tenth edition of Linné's Systema Naturae, 1758, is the work which inaugurated

Nomenclature and Classification

21

the consistent general application of the binary nomenclature in zoology. The date 1758, therefore, is accepted as the starting point of zoological nomenclature and of the law of priority. "Article 27 - The law of priority obtains and consequently the oldest available name is retained: "(a) When any part of an animal is named before the animal itself; "(b) When the larva is named before the adult; "(c) When the two sexes of an animal have been considered as distinct species or even as belonging to distinct genera; "(d) When an animal represents a regular succession of dissimilar generations which have been considered as belonging to different species or even to different genera. "Article 28 - A genus formed by the union of two or more genera or subgenera takes the oldest valid generic or subgeneric name of its components. If the names are of the same date, that selected by the first reviser shall stand. "The same rule obtained when two or more species or subspecies are united to form a single species or subspecies. "Article 29 - If a genus is divided into two or more restricted genera, its valid name must be retained for one of the restricted genera. "If a type was originally established for said genus, the generic name is retained for the restricted genus containing said type. "Article 30 - The designation of type species of genera shall be governed by the following rules (a to g), applied in the following order of precedence: "I. Cases in which the generic type is accepted solely upon the basis of the original publication: "(a) When in the original publication of a genus, one of the species is definitely designated as a type, this species shall be accepted as type, regardless of any other considerations. (Type by original designation.) "(b) If in the original publication of a genus, typicus or typus is used as a new specific name for one of the species, such use shall be construed as 'type by original designation.' "(c) A genus proposed with a single original species takes that species as its type. (Monotypical genera.) "(d) If a genus, without originally designated (see a) or indicated (see b) type, contains among its original species one possessing the generic name as its specific or subspecific name, either as valid name or synonym, that species or subspecies becomes ipso facto type of the genus. (Type by absolute tautonymy.) "II. Cases in which the generic type is accepted not solely upon basis of original publication: "(e) The following species are excluded in determining the types of genera. "Species which were not included under the generic name at the time of its original publication. "Species which were species inquirendae from the standpoint of the author of the generic name at the time of its publication. "Species which the author of the genus doubtfully referred to it. "(f) In case a generic name without originally designated type is proposed as substitute for another generic name, with or without type, the type of either, when established, becomes ipso facto the type of the other. "(g) If an author, in publishing a genus with more than one valid species, fails to designate (see a) or to indicate (see b, d) its type, any subsequent author may select the type, and such designation is not subject to change. (Type by subsequent designation.) "The meaning of the expression 'select the type' is to be rigidly construed. Mention of a species as an illustration or example of a genus does not constitute a selection of a type. "Article 31 - The division of a species into two or more restricted species is subject to the same rules as the division of a genus. But a specific name which undoubtedly rests upon an error of identification cannot be retained for the misdetermined species even if the species in question are afterward placed in different genera. Example: Taenia pectinata Goeze, 1782 = Cittotaenia pectinata (Goeze), but the species erroneously determined by Zeder, 1800, as Taenia ' pectinata Goeze' = Andrya rhopalocephala (Riehm); the latter species does not take the name Andrya pectinata (Zeder).

22

A History of Human Helminthology

"Article 32 - A generic or a specific name, once published, cannot be rejected even by its author, because of inappropriateness. Example: Names like Polyodon, Apus, albus, etc., when once published, are not to be rejected because of a claim that they indicatecharacters contradictory to those possessed by the animals in question. "Article 33 - A name is not to be rejected because of tautonymy, that is, because the specific or the specific and subspecific names are identical with he generic name. Examples:Trutta trutta, Apus apus. "Article 34 - A generic name is to be rejected as a homonym when it has previously been used for some other genus of animals. Example: Trichina Owen, 1835, nematode, is rejected as homonym of Trichina Meigen, 1830, insect. "Article 35 - A specific name is to rejected as a homonym when it has previously been used for some other species of the same genus. Example: Taenia ovilla Rivolta, 1878 (n. sp.) is rejected as homonym of T. ovilla Gmelin, 1790. "When in consequence of the union of two genera, two different animals having the same specific or subspecific name are brought into one genus, the more recent specific or subspecific name is to be rejected as a homonym. "Specific names of the same origin and meaning shall be considered homonyms if they are distinguished from each other only by the following differences: "(a) The use of ae, oe and e, as coeruleus, cereleus; ei, i and y as chiropus, cheiropus; c and k as microdon, mikrodon. "(b) The aspiration or non-aspiration of a consonant, asoxyryncus, oxyrhynchus. "(c) The presence or absence of a c before t, as autumnalis, auctumnalis. "(d) By a single or double consonant, litoralis, littoralis. "(e) By the ending ensis and iensis to a geographical name, as timorensis, timoriensis. "Article 36 - Rejected homonymscan never be again used. Rejected synonyms can again be used in case of the restoration of erroneously suppressed groups. Example: Taenia Giardi Moniez, 1879, was suppressed as a synonym of Taenia ovilla Rivolta, 1878; later it was discovered that Taenia ovilla was preoccupied (Taenia ovilla Gmelin, 1790). Taenia ovilla, 1878, is suppressed as a homonym and can never again be used, it was still-born and cannot be brough to life, even when the species is placed in another genus (Thysanosoma). Taenia Giardi, 1879, which was suppressed as a synonym, becomes valid upon the suppression of the homonymTaenia ovilla Rivolta.

____________________________________________________________________

This applied whether or not a particular name was in common or popular use. Thus, Bilharzia haematobia, a name which had been used for decades to designate the worm discovered by Bilharz, had to be altered to Schistosoma haematobium because the latter name was given to the parasite several months before Cobbold published his designation. Such occurrences led the British Medical Journal in an editorial in 1926 to complain tha t "archaeoparasitologists" or: assiduous individuals have spent their days and nights ransacking musty archives and long-forgotten tombs. From these they have extracted a galaxy of paradoxically new yet old names which they have tacked on to the familiar names of our youth. 1

Nevertheless, such changes were essential if the rules were to produce th e uniformity and stability for which they were designed. A major difficulty , however, lay in knowing who real ly said what about which worm. Not only was much of the literature inaccessible or unavailable, but there was ofte n

Nomenclature and Classification

23

considerable doubt as to the acceptability or completeness of an accompanying description which would allow the organism to be identified with certainty, or in other words, to answer the question as to what really was the name first given to any animal29. Having begun by saying that zoological nomenclature was a sore point with everybody, especially the medical profession, th e above-mentioned editorial concluded by observing that: What the mass of zoologists want is a system which will secure stability, which will obviate the necessity for antiquarian research, which, at the same time, will reject enigmatical descriptions, and will insist on the reference of all species to a central authority.1

As a result of sentiments such as as these, the International Commission o n Zoological Nomenclature appo inted a small advisory committee to consider the names of certain worms. In a series of opinions, they fixed the generic names of a number of helminths which were the subject of some contention: Opinion 66 (February 1915): Ancylostoma, type duodenale; Ascaris, type lumbricoides; Dracunculus, type medinensis; Gnathostoma, type spinigerum; Necator, type americanus; Strongyloides, type stercoralis; Trichostrongylus, type retortaeformis 24. Opinion 77 (31 January 1922): Schistosoma, type haematobium; Hymenolepis,type diminuta 25. Opinion 84 (16 December 1925): Dicrocoelium, type lanceolatum (vel dendriticum sub judice); Fasciola, type hepatica; Heterophyes, type heterophyes; Davainea, type proglottina; Dipylidium, type caninum; Echinococcus, type granulosus; Taenia, type solium 26.

Nevertheless, not everyone was satisfied. Leiper (1926), for example , declaimed against "the tyranny of nomenclatural rules in medicine." 31 He declared that alterations flowing from the rule of priority had been a source of considerable annoyance to medical men and of bitter complaint from medical students. Leiper noted that one of the requisites of this law stated that the rules of binary nomenclature had to be applied but this was often not bein g observed. For example, Taenia mediocanellata of Küchenmeister had bee n replaced by Taenia saginata of Goeze even though the latter had actually described the worm as Taenia cucurbitina, grandis, saginata . Similarly, vernacular names were sometimes being used as generic or specific names. Thus, the term "dracunculus" had been used in the vernacular sense until Cobbol d gave it generic status in 1864, by which time it had been pre-occupied as th e name for a group of reptiles. Again, specific names were sometimes abandoned without, in Leiper's opinion, sufficient justification. He regarded thi s state of affairs as intolerable and demanded that the International Com mission should use its plenary powers to suspend those rules which cause d greater confusion than conformity. Further, he believed that steps should b e taken to press for an extension of this power by allowing well-establishe d names to be placed upon the list of accepted names 29. An editorial in the British Medical Journal applauded this suggestion, remarking that "there is no reason why such a list of names should be beyond the forensic powers of ou r biological and medical legislators" 2 but added with cynical realism that "W e

24

A History of Human Helminthology

fear, however, that Professor Leiper's pl ea will bring him neither tranquillity nor peace"2. It ought to be added in parenthesis, moreover, that Leiper himself was no saint in these matters, for he sought to use the rules to his own advantag e when he attempted (unsuccessfully) to rename Dracunculus medinensis as Fuellebornius medinensis 30. Nevertheless, comments such as these did have one solid effect. In order to leave no room for uncertainty as to the features of an organism being newl y named, the International Zoological Congress which met in Budapest in 1927 added a new section (c) to the law of priority, article 25: (c) But no generic name nor specific name, published after December 31, 1930, shall have any status of availability (hence also of validity) under the Rules, unless and until it is published either 1. with a summary of characters (seu diagnosis; seu definition; seu condensed description) which differentiate or distinguish the genus from other genera or species. 2. or with a definite bibliographic reference to such summary of characters (seu diagnosis; seu definition; seu condensed description). And further 3. In the case of a generic name, with the definite unambiguous designation of the type species (seu genotype; seu autogenotype; seu orthotype). (Cited in 18).

One major change in medical te rminology occurred subsequently, not under the auspices of the International Commission on Zoological Nomenclature, but as an opinion of the committee on terminology of the American Society o f Parasitologists when it reported in December 1940 that: It was of the opinion of the Committee that under the International Rules of Zoological Nomenclature Trichuris rather than Trichocephalus is the valid generic name.37

The committee also indicated that it felt that Dioctophyma renale was the correct name for the giant kidney worm which infects humans very rarely. In July 1958, the XV International Congress of Zoology adopted a new , complete official transcript of the International Code of Zoological Nomen clature. This was published in London in 1961 with alternate pages set i n French and English and has set the seal on the nomenclature of animals 27.

PARASITISM Another word in need of definition is the term "parasite". This word was derived from the Greek word (PARASITOS) which means literally "on e who eats at the table of another" and was formed by a combination of (PARA) = "besides" and (SITOS) = "food". Küchenmeister in 185 5 defined parasites in the following manner: Parasites are independent organised beings, descended from peculiar animal or vegetable parents, which require, in order that they may be enabled to complete their development, growth, or reproduction, to take up their abode either constantly or temporarily in or upon a second animal or vegetable organism of a different kind, from which they also derive their nourishment. Human parasites are those which select the

Nomenclature and Classification

25

human body as this second organism.28

In a similar vein, Cobbold (1864) wrote that: The happiest way of studying the entozoa is to regard them as a peculiar fauna destined to occupy an equally peculiar territory i.e. the interior of the bodies of man and animals.13

while Braun (1906) penned: By the term parasites is understood living organisms which for the purposes of procuring food take up their abode, temporarily or permanently, on or within a living organism.4

The idea of a parasite was well-expressed in the lay literature in the lines o f Swift who, in response to the discovery by Leeuwenhoek when using hi s microscope that the fleas which infest man were in turn parasitized by mites , wrote: So, naturalists observe, a flea Has smaller fleas that on him prey: And these have smaller still to bite 'em. And so proceed ad infinitum

PJ van Beneden (1889) recognized that there were varying relationships be tween two animals which lived in close relationship with each other. He called them parasites, mess-mates and mutualists, and described them thus: The parasite is he whose profession it is to live at the expense of his neighbour, and whose only employment consists in taking advantage of him....He is a pauper who needs help lest he should die on the public highway....The parasite instals himself either temporarily or definitively in the house of his neighbour; either with his consent or by force, he demands from him his living, and very often his lodging. The mess-mate is he who is received at the table of his neighbour to partake with him of the produce of the day. He does not live at the expense of his host; all that he desires is a home or his friend's superfluities. Mutualists are animals which live on each other without being either parasites or mess mates.7

These concepts find modern expression in the terms parasite, where th e organism does harm, commensal, where the organism neither helps nor hinders, and symbiote or mutualist, where the two organisms assist each other in some way. Van Beneden also noted that whereas the beast of prey kills its victim in order to eat the flesh, it is generally profitable f or the parasite if it does not kill its host. With respect to the damage caused by these creatures, Küchenmeister (1855) believed that the most dangerous worms were larvae engaged in migratio n through the tissues; these were followed in turn by mature worms migrating in gut, then large encysted worms, then finally, small encysted worms 28. Braun (1906) expressed modern concepts when he remarked that the pathogenicity of helminths was largely determined by the location, numbers and movement o f worms9.

26

A History of Human Helminthology

INFECTION VERSUS INFESTATION The word "infest" has sometimes been used instead of "infect" to denote th e presence of worms in a host. "Infect" and "infection" are derived from the Latin word "infectus", the past participle of "inficere" meaning "to dip in", "put into", "taint" or "stain". Its use long antedated the knowledge of pathogeni c microorganisms and implied tainting with morbid matter, or contamination with noxious effluvia, vapours and miasmata. Thus, there was a connotation o f trouble caused by invisible, internal agents. "Infest" and "infestation" on th e other hand, are derived from the Latin word "infestus", the past participle o f "infestare", meaning "to make hostile, unsafe, disturbed or troublesome", an d referred to obvious external agents such as pirates, thieves, rats and fleas which molested or harassed the victim. These ideas were embodied in Dr. Samue l Johnson's Dictionary of 1785 whic h defined infect as to "act upon by contagion; to taint; to poison; to pollute" while to infest was "to harass; to disturb; t o plague". The same concepts are enjoined in the modern Oxford Englis h Dictionary which gives the meaning of infect as "to affect (a person, animal or part of a body) with disease" while to infest is "to trouble (a country or place) with hostile attacks....said of persons (e.g . robbers, pirate), animals (e.g. wolves, vermin, insects), diseases or other evils". Nevertheless, as pathological processes due to organisms capable o f independent multiplication within the host such as bacteria, protozoa, fungi and viruses became increasingly recognized, there was an attempt to limit the term infection to such organisms, while infestation was proposed for thos e organisms which do not (or usually do not) multiply within the host such a s helminths and insects. Further, the argument was expressed that intestina l worms are not truly within the body, though this idea has never been used t o assert that non-invasive gastrointestinal bacterial infections should be calle d infestations. In view of this confusion, the American Society of Parasitology in 193 3 appointed a committee to investigate the matter. They concluded: We believe that 'infest' and 'infestation' ought to revert to their original use in connection with external, and in most cases, visible agents. There would be retained the long established use of these terms in connection with most insects in speaking of such conditions as dogs "infested" with fleas, "infestations" of mosquitoes and the like. On the other hand, we believe the terms 'infect' and 'infection' are properly applicable wherever the parasite invades and establishes itself within the body of the host, including in this sense, the gastro-intestinal tract. This would apply then, not only to bacteria and protozoa, but also to helminths....We fail to see any reason for continuing the use of the term 'infestation' as applied to internal parasites and believe that the present confusion will disappear only as its use be discontinued. 36

This view was supported in 1960 by an editorial in the British Medical Journal which remarked that "Consistency and common sense would therefore seem to favour the use of the word infection for intestinal helminths." 3 This concept has largely held sway and most technical works now refer to helminth infection s

Nomenclature and Classification

27

rather than infestations.

REFERENCES 1. 2. 3. 4. 5.

6. 7. 8. 9.

10.

11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21. 22. 23. 24.

ANONYMOUS. Zoological nomenclature. British Medical Journal ii: 1989-1990, 1910 ANONYMOUS. The nomenclature of parasitology. British Medical Journal ii: 1129, 1926 ANONYMOUS. Infect and infest. British Medical Journal ii: 1724, 1960 ARISTOTLE. Opera omnia, graece et latine, cum indice nominum et rerum absolutissimo, F Dübner, E Heitz and UC Bussemaker (Editors), Didot, Parisiis, five volumes, 1848-1874 AVICENNA. Libri in re medica omnes, qui hactenus ad nos pervenere. Id est, libri canonis quinque, De viribus cordis, De removendis nocumentis in regimine sanitas, De sirupo acetosa et cautica, translated by JP Mongio Hydruntino et J Costaeo Laudens, V Valgrisius, Venetiis, pp 966, 1564. Original arabic "Al Canon fi al Tib" c. 1000 AD BEAVER PC, JUNG RC, CUPP EW. Clinical parasitology, ninth edition, Lea and Febiger, Philadelphia, pp 825, 1984 van BENEDEN PJ. Animal parasites and mess-mates, fourth edition, Kegan Paul, Tranch and Co., London, pp 274, 1889 BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1691, 1885-1890 BRAUN M. The animal parasites of man. A handbook for students and medical men, translated by P Falck, revised by LW Sambon and FV Theobald, John Bale, Sons and Danielsson, London, pp 453, 1906 BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst einem Anhange über Pseudo-Helminthen, Carl Schaumburg und Comp., Wien, pp 284, 1819 CAIUS PLINIUS SECUNDUS. Historia naturalis, translated by J Bostock and HT Riley, Bohn's Classical Library, London, six volumes, 1855-1857. CELSUS AC. De medicina, translated by WG Spencer, Loeb Classical Library, Heinemann, London, three volumes, 1948-1953 COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference, more particularly, to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 CUVIER JG. Tableau élémentaire de l'histoire naturelle des animaux, Paris, 1798 DAVAINE C. Traité des entozaires et des maladies vermineuses de l'homme et des animaux domestiques, second edition, J-B Baillière et fils, Paris, pp 1003, 1877 DIESING CM. Systema helminthum, Wilhelmum Braumüller, Vindobonae, two volumes, pp 1267, 1849-1851 DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairie encyclopédique de Roret, Paris, pp 652, 1845 FAUST EC. Human helminthology. A manual for physicians, sanitarians and medical zoologists, second edition, Henry Kimpton, London, pp 780, 1939 GALENUS CC. Works of, In: Medicorum Graecorum opera quae exstant, edited by KG Kühn (Greek text with Latin translation), Leipzig, 20 volumes, 1821-1833 GMELIN JF. Systema naturae per regna tria naturae, secundum classes, ordines, genera, species, cum characteribus differentiis, synonymis, locis, thirteenth edition, GE Beer, Lipsiae, 8 volumes, pp 3021-3909, 1788-1793 GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, PA Pape, Blankenburg, pp 471, 1782 HIPPOCRATES. Works of, translated by WH Jones and ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953 HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, pp 526, 1959 INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. Nematode and Gordiacea names placed in the official list of generic names (Opinion 66), Smithsonian Institution Publication 2359, Washington, DC, pp 171-176, 1915

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A History of Human Helminthology

25. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. Thirty five generic names in Protozoa, Coelenterata, Trematoda, Cestoda, Cirrepoda, Tunicata and Pisces placed in the official list of generic names (Opinion 77), Smithsonian Miscellaneous Collections, Smithsonian Institution, Washington, DC, Publication 2657, 73: 71-73, 1922 26. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. Trematode, Cestode and Acanthocephala names placed in the official list of generic names (Opinion 84), Smithsonian Miscellaneous Collections, Smithsonian Institution, Washington, DC, Publication 2830, 73: 11-12, 1925. Also, Nature 117: 414, 1926 27. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. International code of zoological nomenclature adopted by the XV International Congress of Zoology, International Trust for Zoological Nomenclature, London, pp 176, 1961 28. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group Entozoa, translated byE Lankester, The Sydenham Society, London, pp 452, 1857 29. LANE C The correct names of the helminths of man. Indian Medical Gazette 51: 165-173, 1916 30. LEIPER RT. Discussion on the validity of certain generic names at present in use in medical helminthology. Archiv für Schiffs- und Tropen-Hygiene 30: 484-491, 1926 31. LEIPER RT. Cited in, Zoological nomenclature in medical literature. British Medical Journal ii: 1122-1123, 1926 32. LINNAEUS C. Systema naturae, sive regna tria naturae systematice proposita per classes, ordines, genera et species, first edition, Theodorum Haak, Lugduni Batavorum, 1735 33. LINNAEUS C. Systema naturae per regna tria naturae, secundum classes, ordines, genera, species cum characteribus, differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 34. MOULÉ L. La parasitologie dans la littérature antique. II Les parasites du tube digestif. Archives de Parasitologie 14: 353-383, 1911 35. RAMSAY W. Elminthologia, or some physical Considerations of the Matter, Origination, and Several Species of Wormes macerating and Direfully Cruciating every part ofthe Bodies of Mankind etc., 1668 36. REPORT OF THE COMMITTEE ON TERMINOLOGY. Infection vs. infestation. Journal of Parasitology 23: 325-326, 1937 37. REPORT OF THE COMMITTEE ON NOMENCLATURE. Trichuris Roederer 1761 vs. Trichocephalus Schrank 1788. Journal of Parasitology 27: 277, 279-282, 1941 38. REQUIN AP. Élémens de pathologie médicale, Paris, volume 3, p 193, 1852 39. RUDOLPHI CA. Entozoorum, sive vermium intestinalium historia naturalis, Treuttel & Würtz, Paris, three volumes, pp 1370, 1808-1810 40. RUDOLPHI CA. Entozoorum synopsis cui accedunt mantissima duplex et indices locupletissima, Sumtibus Augusti Rücker, Berolini, pp 811, 1819 41. SERAPION (YUHANNA IBN SARA-BIYUN). Practica etc., translated, Venetiis, 1497. Cited in 23 42. VOGT C. Zoologische Briefe, Naturgeschichte der lebenden und untergegangen Thiere, Frankfurt, two volumes, 1851 43. ZEDER JG. JAE Goeze's Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer mit Zusätzen und Anmerkungen herausgegeben von Johan Georg Heinrich Zeder, Siegfried Lebrecht Crusius, Leipzig, pp 320, 1800 44. ZEDER JG. Anleitung zur Naturgeschichte der Eingeweidewürmer, Bamberg, pp 432, 1803

Chapter 2

UNDERSTANDING THE ORIGIN AND TRANSMISSION OF WORMS The finding of worms within the bodies of humans and animals inevitably led to questions concerning how those so afflicted became infected. For much o f recorded history, the most comfortable and gen erally accepted explanation given was that the parasites had arisen by a process of spontaneous generation. This was a theory not easily denied, and a critical battle raged for over a century and a half from the late seventeenth century until near the middle of the nineteenth century before the protagonists of this theory were finally silenced. There were two key factors which determined the outcome of this conflict of opinion. The first was the invention of the microscope which allowed discovery of th e presence of ova and spermatozoa and demonstration of the cellular basis o f animals, including helminths. As will be shown, this was not enough t o persuade many students of the subject, and the argument was only settled when the second factor, experiment, was introdu ced into helminthology. Nevertheless, even after it was agreed that wor ms multiplied by sexual and asexual processes, many years often elapsed before the precise details of the mode of transmission of a particular parasite were defined. How and when these various discoveries were m ade are recounted for specific worms in the various chapters that follow. In particular, the events leading to the demonstration of the phenomenon of alternation of generations in trematodes are reviewed in chapter 4 while the controversy that led to the recognition of th e relationship between cystic w orms and tapeworms is covered in chapter 12. the present chapter attempts to provide the historical sequence in which thes e disparate threads unfolded and the interpretations which they engendered in the minds of helminthologists.

FROM EARLY TIMES TO THE MIDDLE OF THE SEVENTEENT H CENTURY Belief in the spontaneous generation of certain plants and animals goes back to ancient times and probably began when man started to speculate on the origins of life. This process of "spontaneous generation", sometimes known a s "equivocal generation" or, more latterly, "abiogenesis" provided the simples t and most obvious explanation for many puzzling observations. How else could the sudden appearance of mus hrooms after a heavy rain or the plague of locusts or rodents in certain seasons be explained? As has been described in th e

29

30

A History of Human Helminthology

previous chapter, several intestinal roundworms and tapeworms have bee n recognized for millenia and these were regarded as an excellent proof of thi s doctrine, for it seemed impossible to account in any other way for the existence of such large organisms in the human intestine, as they clearly had not bee n ingested as such. Examples of such beliefs have been recorded from many regions of th e ancient world. Thus, the ancient Egyptians believed that the sacred copro phagous scarab beetles took their origin from balls of dung. Maggots an d intestinal worms were thought by them to be produced from decomposing food and putrefying wounds in the intestines, espe cially under the influence of fever 77. In the same vein, ancient Babylonian texts have been found which alleged that worms were generated from the mud of canals 118. Likewise, the Persians of old believed that bees were generated in the dead bodies of bulls 58. Concepts like these were behind the Old Testament accounts of the plagues of Egypt such as the derivation of frogs from water and insects from dust (Exodus 8). Similarly, in Judges 14: 5-9, the story is told how Samso n killed a lion with his bare hands, then on returning to the scene after a tryst with his beloved, found the carcass swarming with bees and honey. The Greeks and Romans in the centuries around the time of Christ wer e equally at home with such ideas. Hippocrates (c.460-375 BC) regarded intestinal worms as originating in excrements in the fetus before birth 76. Aristotle (384-322 BC) considered that there were four kinds of generation, includin g spontaneous generation. He claimed that many worms, insects, sponges an d coelenterates arose in this way, even if they produced offspring of a sort; these he regarded as a dead end: Among the bloodless animals....there are.... groups which, although they generate, do not generate offspring identical with their parents. Such are the creatures which come into being not as the result of the copulation of living animals, but out of putrescent soil and out of residues....(some) insects moreover are not produced out of animals at all but out of putrefying fluids (in some cases, solids). 6

Many Romans, including Virgil, Ovid, Pliny and Celsus, accepted this doctrine of spontaneous generation, particul arly as it applied to arthropods. In particular, Galen (129-c.200 AD) believed in the spontaneous generation of intestina l helminths, considering that they took their origin from the gut contents 64. Likewise, Oribasius (325-403 AD), physician to the emperor Julian th e Apostate, considered that worms arose in the humours 155. According to Aldrovandi2, Oribasius regarded Enterobius as arising in the black humour , Ascaris in the bilious humour, and tapeworms in the mucous humour. Similar ideas were found in the Orient. In India, bed bugs were thought to be derived from blood while intestinal worms were assumed to have arisen from faeces, phlegm, and blood as a result of a poor diet, insufficient exercise, bad sleeping habits, or excessive warmth 83. In China, intestinal worms wer e considered to be the result of transformation of stagnating food in the bowe l under the influence of heat, moisture, "aura", and wind 77.

Origin and Migration of Worms

31

These beliefs persisted into the Middle Ages and the Renaissance. Th e Arabians of the Dark and Middle Ages provided the prime link between th e literature of the past and the Renaissance in Europe. Avicenna (Ibn Sina ) (980-1037) was convinced that intestinal worms arose from the intestina l contents in combination with moisture and various other factors: There are four kinds of worms....They are different because of different origin and surrounding. Some are formed from moisture not divided or broken up by attraction of the liver, or excess of fermentation. Others are formed from moisture divided or broken up by the attraction of the liver and fermentation....Thirdly, some are formed by an intermediate condition.8

Moreover, Avicenna even believed that with a proper mixing of the element s and under the influence of the stars, all animal s and even man could be produced by spontaneous generation. Another Arab, Al-Qaz wini (died 1283), propounded a novel explanation for the existence of these worms. He suggested that divine wisdom determined that parasites should take their origin from putrefyin g substances so that they could absorb them as food and hence purify the air and prevent epidemic diseases 3. These concepts were accepted by a number of European writers of the Middle Ages such as Albertus Magnus (Albert von Baellstaedt, c.1193-1280) 9, Villanovanus (Arnauld de Villeneuve, c.1300) 198, Edward Wotton (1492-1555) 207 and Cardanus of Pavia (1501-1576)33 . Thus, Villanovanus considered that there were four kinds of worms: long, round worms bred from "salt Fleghm"; short, round worms in "sharp Fleghm"; long, broad worms i n "sweet Fleghm"; and short, broad worms in "natural Fleghm or Mucus" 198. Cardanus believed that slow putrefaction produced lower animals such a s worms while rapid putrefaction resulted in higher animals such as birds 33. This belief in the influence of temperature was taken up by other writers such a s Gabucinus (1547) who wrote that the lower temperature of the intestine led to the formation of tapeworms 63, while Mercurialis (1623) claimed that different temperatures influenced the formation of small and large intestinal worms 130. Paracelsus (1493-1541) had similar fantastic ideas: many things will be changed in putrefaction so that they give birth to a noble fruit, because putrefaction is a reversal and death of all things and a destruction of the original character of all natural things. From this comes rebirth and a new birth with thousandfold improvement.160

Thus, Paracelsus considered that worms were produced from "sperma" an d putrefaction, a bird could be recreated from its own ashes in horse manure , while a pigmy could be similarly produced fro m putrefied human sperm if it was kept under the correct conditions. Likewise, Ambroise Paré, one of the fathers of modern surgery, believed that intestinal worms were created by spontaneous generation in decomposing humours: The worms are formed by a thick, sticky and crude material which decomposes in the stomach and then descends into the intestines....On account of its stickiness which makes it adherent to the intestines, it cannot be discharged from the abdomen. Being retained, it undergoes still further putrefaction wherefrom worms are produced and

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take their origin by the action of the warmth.161

Spigelius (Adrian van der Spiegel) wrote in 1618 that pinworms were produced by a mixture of phlegm and ex crements at the proper temperature, roundworms were dependent upon phlegm and bile, and tapeworms arose in thick, viscous phlegm185. William Harvey (1578-1657), despite the doctrine of "omne vivum ex ovo" (all life comes out of eggs) attributed mistakenly to him by many subsequen t commentators, believed that "imperfect animals" such as worms and insect s arose by spontaneous generation. He considered that this occurred as a consequence of a special principle existing in putrescent material: Many animals, especially insects....are supposed to have arisen spontaneously, or from decomposition because their ova are nowhere to be found....For even in fortuitous semina there is an inherent motive principle of generation, which procreates from itself and of itself; and this is the same as that which is found in the semina of congenerative animals, a power to wit, of forming a living creature. 74

In fact, the words which appeared on the allegorical title-page of his De generatione animalium were "Ex ovo omnia" (all creatures come from an egg). This statement adorned an opened egg h eld by Jove from which many creatures, embryos of man, mammals, reptiles and fish were escaping. Harvey had no t seen the minute ova of viviparous creatures and he may well have been using the image figuratively 183. Moreover, he was an Aristotelian and at times use d language which is entirely consistent with a belief in spontaneous generation. In any case, Harvey was more concerned with embryological development than with the origin of generation. His postulate that in higher animals the organs are successively formed out of the indifferent matter in the egg came to be known as "epigenesis". Common threads can be discerned in these writings over the centuries. Most authors considered that intestinal worms arose in the gut contents wherea s ectoparasites were produced by perspiration and dirt, all being influenced in an undefined way by some special principle. These basic concepts wer e systematized in various theories. Certain Western and Eastern schools o f thought regarded Man as a microcosm which took its origin in the macrocosm. When the balance and harmony between microcosm and macrocosm were disturbed, disease occurred and parasites were created. Others, such as the Greeks, Democritus (c.460-360 BC) and Epicurus (341-270 BC), considered that al l matter was composed of minute un its or atoms, and that when these atoms were agglomerated and amalgamated by a special force, spontaneous generation took place. A variation upon this theme was expounded by Aristotle who proclaimed that spontaneous generation occurred when there was a disharmony of the four elements (fire, air, water, earth), the four qu alities (heat, cold, dryness, moisture) and the four humours (blood, phlegm, yellow bile, black bile), in decomposing substances, all under the influence of a vital force. This "vital force" has been given many names including "nous" (Anaxagorus), "physis" (Hippocrates) , "psyche" (Plato and Aristotle), "pneuma" (Plato and others), "virtus vivificata" (Albertus Magnus), "archaeus" (Paracelsus), "principe vital" (Theophile d e

Origin and Migration of Worms

33

Bordeu) and "Lebenskraft" (F riedrich Casimir Medicus). The way in which this invisible and imperceptible vital principle was supposed to act was described differently by the various schools of philosophy. In general, however, it wa s believed that the vital force either created living creatures directly out of its own metaphysical properties or it generated them by its action upon primordia l matter.

THE SECOND HALF OF THE SEVENTEENTH CENTURY Not everyone was happy with such ideas, however. Thus, Sir Thoma s Browne (1645) questioned "whether mice may be bred by putrefaction?" 27 Browne, however, only refuted error with error, or at least with opinions that seemed more reasonable than did the original ones. It was around this period that the doctrine of "preformation" was evolved. The central thesis of preformation was that the act of procreation merely permitted the appearance in an organized and formed state of a being that was already pre-existent . The theory first appeared in the scientific literature in Swammerdam's book on insects in 1669189, then the theme was taken up by others. Marcell o Malpighi, for example, believed that he could discern the form of an embryo in an unincubated egg126,127. This led to the supposition that a complete being lay in an egg and only a suitable stimulus was required to cause it to unfold. This view extended to the concept of "emboitement" or "syngenesis" i n which it was held that the being in the egg held, in its own ovaries, egg s which in turn held secondary ova and so on. Thus, Eve was considered to contain within her gonads the forms of all the men and women that wer e ever to be. Thus, de Malebranche in 1673, in propounding his "principle of plenitude" wrote: all the bodies of men and beasts, which shall be born or produced till the end of the world, were possibly created from the beginning of it. 125

This concept of preformation was then applied to the origin of worms, but this led to all sorts of philosophical and theological difficulties, particularly in th e first half of the eighteenth century, as will be described later. It was at this stage that two events of epochal importance occurred: (1) Redi began to experiment on the origin of invertebrate animals and (2) th e microscope was invented then its use in microbiology popularized b y Leeuwenhoek. Both of these fac tors were ultimately to have immense effects on the acceptance of the theory of spontaneous generation. Francisco Redi, court physician to the Duke of Tuscany, published in 1668 his monumental work, Esperienze intorno alla generazione degl'insett i (Experiments on the generation of insects )169. Redi could not accept the view that "worms" were produced in dead animals or plants but postulated that they were generated by insemination in putrefying matter, the latter merely serving

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as a suitable nest in which animals could deposit their eggs and in which th e resultant offspring could find nourishment. In contrast to his predecessors , however, Redi undertook a large number of experiments in order to test thi s view. First, he killed three snakes and placed them in an open box to decay . Soon afterwards, he found that they were covered with maggots (which he called worms). Once all the meat had been consumed, however, the maggot s disappeared. In order to determine what had become of them, he repeated the experiment but, on this occasion, he covered ev ery exit from the box. He noticed that some of the worms became quiet, appeared to shrink and assumed a shape similar to an egg. Furthermore, he recognized that there was a variety of shapes amongst these pupae, so he separated them into different glass container s covered with paper. After a week or so, the shells of the eggs (pupae) broke and flies came forth, the same kind of fly appearing from the same type of pupa . Thereupon, he repeated the experiments on many occasions with various kind of dead animals, and in every case the result was the same with one or othe r kind of fly developing, sometimes all k inds. Moreover, he also observed that the meats became covered with true eggs fr om which the maggots hatched. This led him to the conclusion: Having considered these things, I began to believe that all worms found in meat were derived directly from the droppings of flies, and not from the putrefactions of meat. 169

This seemed especially likely as flies of the same kind as those that were bred had hovered over the meat before it grew maggotty. Nevertheless, compare d with other observers, Redi made a crucial step, remarking "Belief would be vain without the confirmation of experiment" 169. Thereupon, he put a snake, som e fish, some eels and a slice of veal from a m ilk-fed cow, each into separate, large, wide-mouthed flasks. Each flask was carefully sealed, then a duplicate serie s was set up except that the mouth of each vessel was left open to the atmosphere. He watched and found that no maggots developed in the closed flasks whereas flies entered and left the open containers at will and maggots eventuall y appeared. Redi repeated these experiments on many occasions. He not onl y showed that maggots were not bred spontaneously from meat, but traced th e development of eggs through larval and pupal sta ges to adulthood. Nevertheless, it must be conceded that Redi was led astray in his studies of the appearance of larvae in galls on plants. He began with the same hypothesis as he had proven with flies on meat, but was unable to demonstrate any way in which eggs could enter a plant. This led him back to an acceptance of spontaneous generation for these creatures: Hence I have changed my opinion and I think it probable that the generation of worms in trees does not....proceed from the eggs deposited by flies. 169

Redi believed that the principle which created the flowers and fruit in the first place was the same as that which produced the grubs: the efficient cause resided in the peculiar potency of that kind of soil or principle which creates the flowers and fruits of living plants, and is the same that produces the worms of these plants.169

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35

Moreover, Redi thought that worms found in the intestines and other parts o f humans probably arose in an analogous fashion by spontaneous generatio n through the agency of the same vital force: In this same manner it could perhaps be true, and I feel disposed to believe it, that in the intestines and other parts of man, are born the lumbricoids and flesh worms. 169

Thus, Redi showed clearly that some parasites arose from ova, but concede d that other parasites may arise by a process akin to spontaneous generation. Redi's experiments were soon followed by publication of the observations of the Dutchman, Jan Swammerdam. In 1669, he published his Algemeene verhandeling von bloedloose diertjens (General account of bloodless ani malculae) which dealt with the modes of transformation of insects and high lighted the different manner of development of the various types of insects. He also showed that the pupa was not an egg but a stage in development of the life cycle of a single individual. He demonstrated clearly, for example, that lic e developed from eggs, that insects found in various plant galls resulted from eggs laid by certain flies, and he noted that certain parasitic "worms" sometime s found in caterpillars or butterflies were the offspring of other insect s (Ichneumon flies) that were in the habit of laying their eggs beneath the skin of the caterpillars 189. The experiments and observations of these two pioneers were to prove turning points in the understanding of the origin of "lesser animals", as they were commonly known at that time. The Englishman, Edward Tyson, writing in 1683, was well aware of th e studies of Redi and others, which he described as indicating "univoca l generation", i.e. natural generation from the same type of organism: The consideration of Insects, and their manner of generation, as it is a subject of curious speculation; so of late hath been much illustrated by the laborious researches of many inquisitive persons: whose travels therein, tho' they have much advanced the doctrine of univocal generation; and bid very fair the exploding of that, too easily received, and common error, of their production from, putrefaction. 194

Tyson demonstrated the sexual apparatus o f roundworms (Ascaris lumbricoides which he called Lumbricus teres) by dissection and believed that once present in the gut, these worms reproduced sexually: yet once there, there is nothing more plain, than that the Lumbricus Teres propogated by univocal Generation; there being in this Sort so perfect a Distinction of Sexes, Male and Female.195

Tyson had greater trouble with tapeworms. He studied in detail their anatomy, discovering their head, but he could find no evidence of two sexes. Moreover, he could not conceive how these organs could have had their origins fro m outside of the body for they resembled nothing in the external world: yet one great difficulty still remains with me, how to account for several of those, that are bred in Animal bodies not such as we may suppose to be hatched from the eggs of the like kind, that are received with food or in other ways; but with whom we cannot meet with a parallel, or of the same Species, out of the body, in the whole world as is known besides.194

This problem was so insuperable for Tyson that he ended the title of his paper

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A History of Human Helminthology

with the words "and the whole urged, as a difficulty against the doctrine o f univocal generation" 194. Meanwhile, the invention of the microscope had opened up a new world of microorganisms. Furthermore, this technology was essential for the demon stration of ova and spermatozoa, the manner in which new life was produced, and the ways in which animal tissues were organized. These new vistas wer e ultimately to sound the death knell for the theory of spontaneous generation. It is difficult to assign proper credit for the invention of this instrument. The art of making convex and concave lenses had long been learnt, but the use of suc h lenses in microscopes first took place around the end of the sixteenth or th e beginning of the seventeenth century. It is not known with certainty wh o invented the compound microscope, but Harting 72 concluded that the accolade probably belongs to the Dutchman, Cornelius Drebbel of Almaar, or hi s countrymen, Hans and Zacharias Janssens of Middleburg. Little heed was paid at first to this innovation but it began to be used by a number of scientists including the Englishmen, Robert Hooke (1653-1703) and Nehemiah Grew (1641-1712), the Dutchman, Swammerdam, and the Italian, Marcello Malpighi (1628-1694). Most of these workers concentrated o n microscopical aspects of macroscopic plants and animals, however, and the real discoverer of the invisible world of microscopical living creatures was th e Dutch microscopist, Antony van Leeuwenhoek (1632-1723). Leeuwenhoe k made his own microscopes and improved upon their optics. In 1673, he published his first paper, in the Philosophical Transactions of the Royal Society , which dealt with mould, the morphology of the eye of the bee, and the microscopical appearances of lice. Over th e next fifty years, Leeuwenhoek sent letters to the Royal Society covering an eno rmous field of observations on microscopic biological matters101. Not only did he describe in abundance the group o f unicellular organisms now known as protozoa, but he was the first to visualize bacteria, a feat which was not repeated until improvements in microscope s made it possible for others to see them. Thomas Huxley suggested many years later that this demonstration of the abundance of microorganisms with thei r manifest provision for multiplication made it seem to many observers that the doctrine of spontaneous generation was not only untrue but also absurd 80. Leeuwenhoek himself was a preformationist and a firm opponent of the theory of spontaneous generation. Being aware of the general belief that Fasciola infection was acquired by animals feeding on contaminated pastures, h e examined green sods from a meadow on which some infected sheep had fed and looked for microscopical creatures resembling flukes, but failed to find any 100. Nevertheless, observations that many o f the innumerable small organisms found in water and moist soil resembled helminths led naturally to the conjecture by many helminthologists that, after their almost unavoidable introduction in th e human system, these creatures would grow into parasitic worms. The evolution of such ideas, both correctly and in error, will be traced in the followin g sections.

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As the century drew to a close, there were still many staunch believers in the theory of spontaneous generation. But the o pponents were becoming more vocal and were exemplified by Bidloo, who, no doubt girded by his discovery of eggs in Fasciola, in 1698 laid it: down as a certain truth, that these, as well as other small living creatures, are produced from their like, by the means of eggs, seed or spawn, according to the nature implanted in them at their first creation.16

and considered that these "seeds" were ingested in contaminated water.

THE FIRST HALF OF THE EIGHTEENTH CENTURY

The new century saw the publication in 1700 of a book on helminthology b y Nicholas Andry in which he attempted stoutly to refute the theory of spont aneous generation. Andry had been stimulated to write his book following a n incident with one of his patients. On 4 June 1698, Andry went to see a thirt y year old man with fever, haemoptysis, left-sided chest pain and dyspnoea who five days later became delirious and passed a tapeworm 4 ells 3 inches long (an English ell is 45" [113 cm] and a Flemish ell is 27" [68 cm]). Andry firs t defined worms then went on to a consideration of their origins: Worms breed in the bodies of men and other animals, by means of a seed that enters there, in which those worms are enclosed. For all animals....are bred of a seed which contains them....this Seed of Animals, contains in no little Bulk, the Animal that is to be formed in it, and that Microscopes discover them to us sometimes quite formed. 5

Andry went on to consider whence this "seed" first arose: the seeds of all Animals were created by the first Being, and put in the first individuals of the species.5

Next, he discussed the manner in which these "seeds" could enter human an d other animal bodies: there is nothing in Nature, into which the seeds of insects may not insinuate itself, and that a great Quantity of them may enter into the body of Man, as well as into those of other Animals, by means of the Air and Aliments....they likewise enter the Flesh very often by the outside....the skin is full of cavities. 5

Andry seems to have become a little confused, however, as to the course o f events once the seed entered a body, for he appears to have believed that th e internal milieu determined the type of worm that developed: a Man, whose body abounds with a certain sort of Humour, will produce Worms of a certain sort, whilst he who abounds with another Humour, will produce Worms of another; and he who has no Humour proper for the Eggs of Worms, will produce none, and so be free of them.5

By the latter remark, Andry foreshadowed the concept of immunity, whethe r natural or acquired, that was to become so important 200 years later. It must be admitted that Andry based his arguments upon logic and philosophy rather than upon experimentation, as is exemplified by his challenge to the proponents of

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spontaneous generation: Some Philosophers, pretend that the worms and several other Insects are bred of Corruption, only by a Fortuitous Combination of Matter without any seed. But if these Philosophers could explain to me two things, the one how casual disorder could range with so much order the Organical parts of Animals, and the other, from whence it comes that we see no new Species of Insect bred, since that must happen according to their System.5

In order to support his arguments, Andry included quotations from two of his correspondents. On 26 February 1699, Mr Niklaas Hartsoeker of Amsterdam had written to him: There's nothing has life, be it Animal or Plant, but which comes from Seed, and nothing is ever engendered by corruption....I am of the opinion that those Worms ingender by Male and Female in the Bowels, and that some of their coming to issue with the Excrements, and to fal l upon some Herb or other thing, are swallowed by another, in whose Intreals the Worms contain'd in those Eggs come forth and are fed.73

In like manner, Giorgio Baglivi in Rome wrote on 14 July of the same year: You ask me 1. If it proceeds from an Egg?....The beginning and original of all Animals and Vegetables is from an Egg....Since no Man says that Plants rise from Putrefaction, they ought not in reason to deduce the Original of Insects and other baser Animals from thence.... Worms Eggs lying hid in the Intestines are enliven'd and brought forth.... Therefore the Flat Worm derives its Original from an Egg of its own kind.11

Clericus (1721) accepted the views of Redi , Andry and those of like mind, but considered that "The most difficu lt Question remains yet to be discussed, to wit, From whence the first Seed of Worms is derived" 37. Not everyone was convinced by these arguments, however. Vallisnerius, for example, vigorously opposed the views of Andry and endeavoured to explain the presence of entozoa by supposing them to be transmitted from parent t o child via the placenta or through the breast milk 197. Vallisnerius was in fact a proponent of "emboitement" which was mentioned earlier. A logical extension of this theory was that Adam, the first man, harboured not only all mankind to be, but all of his worms as well. This created appalling theological problem s and Vallisnerius put the issues: It is not reasonable to suppose that God would have placed the first worm in his body, forasmuch as Man in this state of innocence was to be free of all kinds of diseases....But if on the other hand, after the lapsed state of Adam, we allow that worms were formed by God.... a greater difficulty will arise....for....it will follow that God made a new creation of worms, which is contrary to Holy Writ; since God hath taught us, that before Man was made, all other animals were created. 197

Vallisnerius attempted to solve this dilemma by assuming that before the Fall, parasitic worms ate contentedly from Adam's superfluities and even performed good works by gently licking any holes in the gut and healing them. But when Adam fell: all things were suddenly changed; so that these worms were made Ministers of Divine justice and raised an insurrection upon him.197

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39

Other ideas were also canvassed. The discovery of microscopic animal s everywhere, including in food a nd drinking water, led to the development of the theory of heterogony, i.e. that these creatures were introduced into the human body and under the influence of heat and nutriment matured into entozoa. Thus, men like Boerhaave 20 and Hoffmann78 erroneously traced many cestodes an d nematodes back to microscopic animals which in their free state were totall y different in appearance to the parasitic adult worms.

THE SECOND HALF OF THE EIGHTEENTH CENTURY The advocates of the theory of sponta neous generation received staunch support as the eighteenth century entered its second half from the writings of Georges Leclerc, Comte de Buffon (17017-1788) and John Turbeville Needha m (1713-1781). In 1749, Buffon's monumental Histoire Naturelle began to appear in France30. In this work, Buffon developed the idea that vitality was a n indestructible property of all living things. He regarded living matter as being composed of indestructible organic molecules which, in the process o f spontaneous generation, were rearranged to constitute vitality: excess molecules, unable to penetrate the interior mould of the animal, reunite with several particles of brute matter in the food and form organized bodies....This is the origin of tapeworms, ascarides, flukes and all other worms which are born in the liver, stomach and intestines.30

Similar views were expressed by Needham in Britain. Needham undertoo k some experiments which he interpreted as supporting these concepts. Fo r example, he took a portion of an almond germ and placed it in water in a phial closed with cork; subsequently, he claimed to see a swarm of minute, moving objects of "animalcules" which he believed came from the almond. Needha m repeated the experiment with hot mutton gravy which, despite being sealed , swarmed with life a few days later. Similar results were obtained in othe r experiments and Needham concluded that the organisms derived from a "vegetative force in every microscopic po int of matter and every visible filament of which the whole animal or vegetable texture consists" 146. The views of Buffon and Needham were attacked by the Italian abbott , Lazzarro Spallanzani (1729-1799) who undertook numerous, well-conceived experiments which included heating infusions as well as hermetically-sealin g them. He concluded that animalcules may be carried into the infusions by the air and that this was the explanation of their supposed spontaneous generation 184. Moreover, Spallanzani found that there were two distinct classes of thes e microscopical creatures, or "infusoria". One, which he called ordini superior i (superior order), was easily destroyed by boiling for half a minute, whereas the other, which was exceedingly minute microscopically and which he calle d ultime ordini, sometimes survived boiling for half an hour; these wer e presumably bacteria. Nevertheless, Spallanzani was criticized by the proponents

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of spontaneous generation on the gr ound that he had "spoiled" the air by heating it. Some of the various erroneous ideas were expanded and magnified by many students of helminthology in the latter years of the century. Thus, the grea t classifier, Linnaeus, took the theory of heterogony and applied it to large r free-living creatures. He found a free-living tapeworm, Schistocephalus solidus , and regarded it as an immature tapeworm which would develop into the adult broad tapeworm, Diphyllobothrium latum , when swallowed. Similarly, h e believed that he had discovered the free-living stages of Fasciola hepatica and Enterobius vermicularis; he mistook a planarian for the former and a free-living Rhabditis-like worm for the latter 117. The discovery of the existence of eggs in many helminths was explained i n different ways. Some believed that eggs hatched out in the external world gave birth to free-living creatures and that these in turn were transformed into adult worms after their introduction into the intestines. Such concepts fitted nicel y with the theory of heterogony as developed by Linnaeus. Others would hav e none of this and considered them mere by-products. Others again seized hold of Vallisnieri's idea that entozoa were transmitted by the transplacental o r transmammary routes or by kissin g. The major evidence for this hypothesis was the assertion by a number of observers that they had found entozoa, not only in the young of animals, but even in the fetus within the body of the mother. Other investigators, however, adduced the se same observations in favour of the theory of spontaneous generation. Such was the interest in the origins of parasitic worms that the Royal Society of Copenhagen in 1780 set a prize essay on this subject. The first prize was won by Marcus Bloch, a medical practitioner from Berlin, while the second wa s taken by the Reverend Johann Goeze in Dudlinburg, Germany. Both of thes e men argued for the spontaneous origin of parasitic worms. Among the twelve "facts" which Bloch used to support this position were: - worms are sometimes located in very young animals, recently born animals, and even in abortions - many worms which are never found in the gut occur in the interior parts of the animal without any passage to the exterior - worms live in locations where other organisms are digested - worms die rapidly on removal from the host body - most animals have their own peculiar parasitic worms 19

Bloch believed that worms destined to live in a particular location within a particular animal could not have arrived there by chance and that therefore they must have been generated spontaneously. He acknowledged that many worms produced a vast number of eggs, as did Goeze who considered that egg s excreted in the faeces were lost for ever as far as the parasitic intestinal worm was concerned though they may serve as food for other animals 65. There were opponents of such views, however. Pallas wrote that: It cannot be doubted that the eggs of Entozoa are scattered abroad and undergo various changes without loss of vitality, and that immediately they reach the body of a suitable

Origin and Migration of Worms

41

animal, through the medium of its food and drink, they grow into worms. 158

Pallas even attempted to prove hi s views by experiment. In 1781, he introduced the small red eggs of the dog tapeworm, now known as Dipylidium caninum, through a small wound into the abdominal cavity of a pup. One month later, he claimed to be able to find there small tapeworms and adduced this observation as in favour of his views 159. Whereas, in general, his hypothesis that worm s arose from eggs was correct, his experiment was totally in error and the worms he found, in retrospect, had nothing whatever to do with the ova h e administered. The concept of heterogony, however, led to an extremely important observation in 1790 by the Dane, Peter Christian Abildgaard. Abildgaard noticed that a cestode worm which lived in the intestine of the little fish known as a stickleback had no reproductive organs but bore certain resemblances to tapeworms that he had seen in mergan sers and other fish-eating birds. He wondered whether the worms in the fish cou ld be an immature form of the bird parasite so he decided to test this hypothesis: I collected a great number of stickleback fishes and for three days I fed those to two ducks. After another three days I killed the ducks and opened their intestines. In one of the duck's intestines I found 63 pieces of the tapeworm from the fish; they were all living and more active and faster in their movements than those taken from the belly of the fishes. They had the same length and shape as in the before-mentioned seabirds. In the other duck, I found only one tapeworm which was living. 1

This epochal observation was the first successful experiment designed t o elucidate the life cycle and transmission of an internal parasite. Voices like his, however, were largely crying in the wilderness. As thousands of animals were examined for the presence of parasites and as the number o f known entozoa became larger and larger, helminthology became separated from zoology and was treated as a distinct discipline. It became mere descriptiv e enumeration hardly concerned at all with the life-histories and development of the animals that were so carefully registered. Helminthologists were content to point out the inadequacy of earlier attempts to explain the presence an d acquisition of entozoa and returned to the convenient theory of spontaneou s generation. This trend seemed to be supported by the discovery that many cysts were verminous in nature (described in chapter 12) but were manifestly devoid of reproductive organs as were the microscopic organisms now known a s cercariae that had been discovered by OF Müller in 1773 and which h e classified as belonging to the "Infusoria" 136.

THE FIRST QUARTER OF THE NINETEENTH CENTURY Some of the foremost helminthologists of the early nineteenth century including Rudolphi and Bremser continued to proclaim the doctrine of spontaneou s generation. Rudophi, for example, discovered the tapeworm now recognized

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A History of Human Helminthology

as Echinococcus granulosus and concluded that it arose from the intestina l epithelium172. Bremser considered it very improbable that eggs could b e transmitted through the medium of food, water or air in the case of intestina l worms and believed that this was even more so in the case of hydatid cyst s which appeared to have no access to the external environment 25. In support of this thesis, he cited the experiment of Schreiber 173 who fed a polecat for six weeks with milk containing eggs of various species of intestinal worms, ye t when it was killed, not a single worm was found. Furthermore, the acceptance by these authors of the claims by Kerckringiu s85, Brendel26 and Doloeus 47, Reim and others that intestinal worms had been found in the bowels of newbor n children and even in the fetus seemed to settle the point. Thus, Bremser wrote in 1819: The original formation of these worms, in my opinion, takes place in the following way. A part of the intestinal mucus, the living unformed substance, coagulates forming a more solid mass which covers itself by an epidermis and then lives its own life. Subsequently the head is formed and ultimately the generative organs also appear.25

Nevertheless, critical observations continued to be made which would lead to a turning of the tide. CL Nitzsch in Germany took up the study of th e organisms discovered by Müller and which Müller had placed in the genu s Cercaria. Nitzsch noticed that many of these cercariae transformed into a "pupa" or else "encysted" on foreign bodies and he also recognized a resem blance between the anterior part of the body of these organisms with flukes. He was not able to put these pie ces of information together correctly, however. He assumed that the pupal stage merely signified the termination of life 148 and concluded that a cercaria was a combination of a fluke with a vibrio, which he believed provided the characteristic tail of the cercaria 149. At the beginning of the winter of 1817-1818, a momentous discovery wa s made by the German, Ludwig Bojanus. While dissecting some snails obtained from a fresh-water pond, he noticed that s ome cercariae crept out of motile sacs in the viscera of the snails and concluded that they were probably generate d within them. He called these sacs "royal yellow worms": When the Lymnaea [snails] were taken from the dish, a very large number of royal, yellow, living, but in movement very indolent, cylindrical worms (Distomata?) were found in many of them....In the yellow worm one saw, under the microscope, active movements which came from the enclosed winding animals....Some of the animals succeeded, finally, at various places, in breaking through. All that slipped out by themselves had the appearance of....cercariae.21

It caused much astonishment that cercariae were not derived from parent s resembling themselves, but came from these peculiar, royal yellow worm s (subsequently called Redia by de Filippi 57). Oken, in whose journal Bojanu s published news of his discovery, re marked that "observations of this kind make one dizzy"151. With great perspicacity, he went on to add "one might lay a wager that these cercariae are the embryos o f distomes"152. There, however, the matter was to lay for some years.

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In the year after Bojanus published his observations, another importan t phenomenon was described, although its relevance to the life cycles of certain parasitic worms was not immediately recognized. The German, A von Chamisso, showed that in the Salpae, a form of marine animal, free individuals and individuals bound together in chains alternated with one another in eac h successive generation. To this phenomenon, Chamisso gave the name "Alternation of Generations" 34. This theme was to be taken up again and applied t o parasitic helminths nearly 25 years later by Steenstrup, as will be described in the next section.

THE SECOND QUARTER OF THE NINETEENTH CENTURY

Criticism of the theory of spontaneous generation began to gather apace. In his review of worms in 1829, the English surgeon, William Rhind, wrot e disparagingly: If we admit that a complex worm could be formed by spontaneous action of combination of animal particles, there would be no end to the extension of the theory. A field of meadow gas, by the spontaneous arrangement of its particles might produce an ox, or the fermenting dunghill, charged with animal particles in abundance, might be the matrix from whence springs the hog that feeds on it. 170

Likewise, one wit, in commentating cynically on the improbable spontaneous generation of dioecious worms, wrote: two clots must consult together in order to determine into what they shall become transformed. Without this millions of males might be formed without a corresponding female, and millions of females be condemned to live and die in single blessedness. 48

Pari passu with comments like this, important observations of trematode s continued to be made which would eventually allow all the pieces in the puzzle to fall into place. In 1827, CE von Baer confirmed Bojanus's observations and showed that cercariae developed from "germ granules" within the royal yellow worms or "germinating tubes" (rediae) 10. Several years later (1831), Mehli s discovered that the eggs of certain flukes contained a larva which in shape and ciliation resembled some of the known "Infusoria" for he saw an infusorian-like embryo slip out of the eggs of worms then known as Monostomum flavum and Distomum hians 129. This observation was confirmed in the following year by von Nordmann in Helsinki, Finland, who speculated that these embryos: always sojourn during their first life period in water, and subsequently enter the body of some animal where they lose their eye-specks and become sexually mature. 150

Similar observations were report ed in 1837 by Creplin 42 who, incidentally, had confirmed in 1829 Abildgaard's reports on larval tapeworms in fish and their maturation after ingestion by birds 41. The next important link in the chain of evidence concerning these trematodes was furnished in 1835 by the German, Carl von Siebold, in present-day Poland.

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A History of Human Helminthology

Von Siebold examined large numbers of the fluke, Monostomum mutabile , which lived in the orbital cavities of geese. Like Mehlis, he noted the hatching of ciliated larvae (now called miracidia) from the eggs and watched the m swimming around in water. After a wh ile, they died and disintegrated, each one releasing from its interior a motile, cylindrical body with two short latera l processes and furnished with a pharynx and simple gut. Von Siebold realized that these organisms were closely related to the rediae (or cercaria-sacs) that he had seen before in snails. Although he was not able to actually witness the process, he theorized that adult trematodes may produce eggs from whic h larvae hatch, swim around to find an appropriate snail host, penetrate th e tissues of the mollusc, then die releasing rediae containing cercaria 174. Shortly afterwards, von Siebold made another important observation when he showed that some cercariae such as Cercaria echinata encysted in snails 175. It remained, however, for Steenstrup in 1842 to put all these disparat e observations together, as will be detailed below. Progress in the understanding of the life cycles of cestodes, and especiall y nematodes, lagged somewhat behind these discoveries concerning trematodes. In the same year (1835) that von Siebold correlated miracidia with rediae, he made an important discovery about tapeworm eggs when he found that the y contained an embryo furnished with six hooklets within them 174, but he did not follow up the implications of this finding. Speculation about the life cycles of tapeworms and other helminths was undertaken by Eschricht. After recalling Abildgaard's experiments with fish worms and bird tapeworms and remarking on the great fertility of intestinal worms, he wrote in 1841: Their limitation to distinct species is too well ascertained, their anatomy too complicated, and their fertility too striking, not to force the conviction upon us, that intestinal worms are the offspring of other similar worms. 54

He then went on to add: If this view be correct, the entozoon will spread by a kind of emigration....The life history of Entozoa must be considered as analogous on the whole to that of the parasitic larvae of ichneumon or bot flies but that each instance demands a special explanation on account of the complexities possibly introduced - the various asexual parasites so frequently met with e.g. Trichina spiralis must be regarded as immature forms retaining their primitive larval situations.54

Many of these ideas were formalized in the following year (1842) when the Dane, Johannes Japetus Steenstrup, publ ished his seminal work entitled On the alternation of generations; or, the propogation and development of animals through alternate generations: a peculiar form of fostering the young i n lower classes of animals 186. Steenstrup brought together numerous, divers e observations and proposed a unifying hypothesis to explain the various phenomenona. Steenstrup considered first coelenterates (medusae and clavifor m polyps), then pelagic tunicates (Salpae), and finally trematodes. In all of them he found a common phenomenon whic h he summarized in the following terms: An animal bears young which are, and remain, dissimilar to their parent, but bring forth a new generation, whose members either themselves, or in their descendants,

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return to the original form of the parent animal. 186

Thus, Steenstrup believed that just as the polyp originating from the ovum of a medusa represented an alternate generation, so did the redia and cercariae derived from the miracidium of a fluke. He observed that in some of th e Trematoda, the latter generations remained within the earlier forms until they attained full development, whereas others forsook them sooner to becom e free-swimming then underwent a complete metamorphosis. Steenstru p conjectured that cercariae might penetrate into other animals, lose their tails and become adult flukes. He knew that Cercaria echinata encysted in snails so he extracted them at various inter vals after encystation and observed typical fluke-like forms. He was mistaken, however, in supposing that the worm s matured in the body of the snail host. This idea was contradicted by vo n Siebold who maintained that further developm ent could not take place until the encysted trematodes were transmitted to some other host, for example, when they were devoured together with the snails by an animal 176,177. Von Siebold came to realize, however, that many encysted cercariae were located i n organisms which would never be consumed by another animal in which a n adult fluke would develop. This led him to the concept of "stray" worms , doomed to perish, which was to bedevil his views on the relationship between cystic worms and tapeworms. Likewise, Dujardin, who accepted spontaneous generation at first, considered that cercariae would never become adult worms once they had been shut in an "excreted prison" 49. Steenstrup failed to make the c orrect deductions with regard to cestodes. He conjectured that cystic worms were early stages in the development o f helminths that were unknown to him. He argued that they should no longer be classified as a separate group but he did not connect cystic worms wit h tapeworms. This is rather surprising as not only had Pallas and Goeze in the previous century recognized the relationship, but a number of more contemporary authors including Nitzsch, FS Leuckart and F Müller had urged abandonment of this unnatural cleavage of cystic worms from tapeworms. Nevertheless, Steenstrup's promulgation of the doctrine of "Alternation of Generations" put others on the right tr ack. Dujardin in France in 1845 asserted that cystic worms were formed by the germs of tapeworms which, instead of going into the intestines of their natural hosts, somehow arrived in the tissues, and under the influence of an unusual dwelling-place, developed abnormally to become "monstrous" cystic worms 49. At about the same time, von Siebold began to express similar convictions. Initially, von Siebold held the correc t view that cystic worms were simply undeveloped, larval tapeworms 177. Moreover, he thought that the adult and larval forms of the worms must b e found in different animal hosts since the two forms rarely occurred together. He then modified this theory and began to move down the wrong path, contending that cystic worms were strayed larval tapeworms which becam e dropsically degenerated when they reached aberrant sites 181.

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Little advance in understanding of nematodes was achieved during this period although some attention was paid to the mode o f transmission of Guinea worm. With the realization at this time that the adult worms released large numbers of embryos, there was conside rable speculation that transmission occurred via water. In 1838, Forbes tried to transmit infection by administering orally t o two pups larvae that had been obtained from a human patient; he found dead worms in the gut thus giving credence to some earlier suggestions based upon epidemiological evidence that infection was acq uired by worms penetrating the skin59.

THE THIRD QUARTER OF THE NINETEENTH CENTURY The second half of the nineteenth century opened with a flurry of speculation and activity concerning tapeworms and cystic wo rms. Following the statements of Dujardin and von Siebold, the Belgian, PJ van Beneden, theorized that the head of a tapeworm is produced from the eggs of a tapeworm and conjectured that if the egg reached the gut of a suitable animal host, then the jointed adult tapeworm would mature. On the other hand, he postulated that if the egg found its way into the gut of an unsuitable host, then the larva would develop but the hind part would become inflated and the head would sink into it, thus forming a cysticercus13. Van Beneden was correct in deducing that bladderworms were larval tapeworms but was wrong in his belief that adult worms would develop directly from eggs when ingested by an appropriate host. In any case, h e provided no hard evidence to substantiate his views. It was at this point that a major wind of change blew upon the scene . Friedrich Küchenmeister in Germany became interested in the problem o f cystic worms and tapeworms and began to experiment in order to solve th e problem. Although there had been previous essays into experimentation i n helminthology, some of which had been successful, by investigators such as Pallas, Abildgaard Creplin and Herbst, none had been as dramatic as Küchenmeister's were to prove, nor did they achieve such widespread recognition . Küchenmeister began with two of the most easily accessible bladderworms, Cysticercus pisiformis, of the rabbit and C. fasciolaris of the mouse. In 1851, Küchenmeister fed a large number of C. pisiformis to foxes which are natural predators of rabbits, then recovered many young tapeworms which he initially called Taenia crasscipes (= crassiceps = Taenia pisiformis)92,93. He wrote in Gunsburg's Zeitschrift für klinische Medicin : Preliminary communication: I hereby give notice, in order to achieve priority for my scientific observations and the further development of this subject, that between 18 March and 19 April 1851, I recovered 35 individual Taenia crasscipes from foxes that had been given approximately 40 Cysticercus pisiformis of rabbits 22, 15 and 8 days and 30 hours previously.92

Küchenmeister then gave C. fasciolaris to a cat and again succeeded in rearing

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tapeworms that were rapidly approaching maturity 94. Furthermore, he showed that when cysticerci were fed to an inappropriate host, the cysticerci died and no development took place. He concluded that cystic worms were not strayed, dropsical tapeworms as portrayed by von Siebold, but were tapeworm larvae that were an essential stage in the development and maturation of taenia: the larva (Cysticercus) is not a wandering strayed dropsical tapeworm nurse, in the sense of Steenstrup's Alternation of Generations, but a tapeworm larva provided with a temporary organ, probably functioning as a reservoir of nourishment. 95

Küchenmeister's first reports were received with some scepticism, partl y because he changed his identification of the tapeworms that he reared in foxes several times. Shortly afterwards (1853), however, he successfully reare d tapeworms in dogs from Cysticercus tenuicollis and from Coenurus cerebralis of sheep96. Von Siebold lost little time in repeating Küchenmeister's experiments. I n 1852 he confirmed the metamorphoses of C. pisiformis and C. fasciolaris then reported the same phenomenon with Coenurus 178,179. For a number of years von Siebold clung to his theory that cystic worms were degenerate, straye d worms which would develop properly when transplanted to the correct site . Moreover, he also believed that, with the exception of echinococci, all th e cystic worms were derived from on e species of tapeworm, Taenia serrata, the nature of the cysticercus depending upon the host in which it developed 181. These observations also stimulated von Siebold to begin feeding exper iments with hydatid cysts in 1852. He obtained cysts from sheep, saturate d milk with echinococcal scolices, then fed it to a number of dogs. Dogs were killed after varying periods and von Siebold found innumerable small adul t tapeworms, which were producing ova, in the intestines 180. Von Siebold's experiments were repeated and his results confirmed by Küchenmeiste r (1853), Wagner (1854) and others who used hydatid cysts obtained fro m sheep, pigs and cattle. It was not until 1863, however, that Naunyn succeeded in rearing adult echinococci in the intestines of a dog fed with hydatid cys t material obtained from a human 145. To prove beyond all doubt that cystic worms were necessary steps in th e development of tapeworms, however, it was also necessary to show thei r development from taeniid eggs. Such an experiment was first undertaken by Küchenmeister with the parasite he knew as Coenurus cerebralis (= Taenia multiceps). First he obtained coenuri from sheep then he administered them to a dog in order to obtain mature proglottids of the tapeworm. These in tur n were fed to a healthy sheep on 25 July 1853. Sixteen days later, the shee p became vertiginous and when it was kill ed three days later, small coenuri were found on the surface of the brain 96. In collaboration with Haubner, Küchen meister obtained similar results with Cysticercus pisiformis , C. tenuicollis and C. cellulosae 99. The first person to have demonstrated the generation of C. cellulosae, in fact, was van Beneden. In 1853, he fed large numbers of Taenia solium eggs to a pig then slaughtered it four and a half months later at which

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A History of Human Helminthology

time he found a large number of cysticerci 14. At around the same period , Leuckart was able to produce C. fasciolaris in the livers of mice after feeding these animals with eggs from T. crassicollis from cats. It was not until 1867, however, that Leuckart produced hydatid cysts in suckling pigs after feeding them with ova of Taenia echinococcus (= Echinococcus granulosus )112. Another observation which helped finally to spell the lie to von Siebold' s concepts of "strayed tapeworms" flowed from t he studies in 1852 of the Prague zoologist, von Stein. Von Stein examined the development of a small blad der-worm in the larva of the meal-worm, Tenebrio molitor, and demonstrated that, as Goeze had already proven in the case of C. fasciolaris of mice (but which had been ignored), the caudal vesicle was formed first and then th e scolex developed within it, whereas von Siebold believed that the scolex was formed first and that the tail then underwent hydropic degeneration 187. This, together with an increasing m ass of experimental observations made it abundantly clear that development of these cestodes is divided between two kinds of animals. In one, the definitive host, the adult tapeworm is found, while in the other, the intermediate host, some form or other of an intermediary stag e occurs. Although, as indicated above, Küchenmeister was able to produce C. cellulosae by feeding Taenia solium eggs to pigs, success did not attend his efforts to generate the adult tapeworm w hen he fed cysticerci to dogs. Others, such as von Siebold and May, claimed to be able to do so, but Küchenmeister (quite correctly) did not believe them. He ther efore determined to examine the effects of administering C. cellulosae to humans under the sentence of death. In 1854, in collaboration with two medical colleag ues, he induced a convicted murderer (unknowingly) to ingest over 70 cysticerci during the several days prior t o execution. Forty eight hours after de ath, he found a number of small, immature tapeworms in the intestine of the condemned man 97. In the same year that Küchenmeister reported these observations (1855), Aloys Humbert produced a patent infection in himself; three months after consuming 13 C. cellulosae, he began to pass T. solium segments79. A similar experiment with like result was undertaken by Leuckart in the following year 108. In late 1859 and early 1860, Küchenmeister had an opportunity to repeat his original experimen t except that on this occasion he was able to infect the prisoner twice severa l months before execution. On this occasion, he recovered eleven tapeworms, the largest of them being five feet in length 98. It took a little time to define the life cycle of the related human parasit e Taenia saginata. In late 1861 and early 1862, Leuckart undertook a number of experiments in which he fed T. saginata segments to calves and eventually recovered the cysticercus known as C. bovis 111. Leuckart's findings were soon confirmed by Mosler and many others. No-one has ever gone to Küchen meister's lengths and fed C. bovis to criminals in order to recover adult T. saginata from the intestines at autopsy. In 1870, John Oliver in India in some

Origin and Migration of Worms

49

poorly-controlled experiments claimed to produce patent infections after feeding C. bovis to three human subjects 153, then Perroncito in Italy in 187 7 administered cysticerci to a subject who began to pass segments eight weeks later and from whom an adult worm over four metres long was recovered after treatment with anthelmintics 163. Despite the mass of accumulated evidence, there were still some recal citrants. Pouchet and Verrier in 1862 attacked the whole concept of the cystic migration of tapeworms, claiming that all these experiments were "to o successful". Despite all argument to the contrary, they remained obdurate , writing: we cannot believe that a microscopic embryo of a taenia enclosed in the intestines of a sheep can make for itself a passage up into the brain of the ruminant, and then undergo transformation into a vesicle, which engenders numerous scolices. 166

Nevertheless, this was the last gasp of the sceptics and the views o f Küchenmeister and others became generally accepted. In reviewing all of these events, and in particular Küchenmeister's con tribution, Leuckart wrote a few years later: It was only with introduction of Helminthological experiment that a new path was opened to the field of knowledge....It was not merely the proof that bladderworms which had for so long formed an impregnable fortress for the theory of spontaneous generation, were really the immature stages that excited so wide an interest, but it was also the circumstance that Küchenmeister....did not discover it merely by chance, but by direct experiment, by the method of feeding, which is so easy to control and repeat.116

It must be remarked, however, that the feeding experiments of Küchenmeister and others were not designed primarily to refute the doctrine of spontaneous generation55. This was not an issue in the minds of these investigators. Rather, they were interested in defining the relationship between cystic worms an d tapeworms. Nevertheless, these studies inevitably had a critical effect on the tenability of the hypothesis of spontaneous generation. The successes with these tapeworms did not similarly attend at this tim e attempts to elucidate the life cycle of the other tapeworm of major huma n importance, Diphyllobothrium latum . Indeed, such experiments as wer e undertaken were positively misleading. A number of workers includin g Schubart, Kölliker, Knoch, Leuckart and Bertolus independently observed the hatching of larvae from D. latum eggs but their subsequent fate remained a mystery. Knoch claimed in 1862 that there was direct transmission from one vertebrate host to another when he asserted that he had found diphyllobothria in the intestines of dogs after administration of ova whereas he had bee n unable to infect potential intermediate hosts 87. Trematodes did not evoke interest and activity comparable to that seen with the cestodes in the third quarter of the nineteenth century although severa l important contributions were made. La Valette de St. George provide d important information in 1855. He showed that when tailed, non-encyste d cercariae were administered orally to experimental animals they failed t o

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A History of Human Helminthology

develop, yet when certain encysted cerc ariae were ingested, the larvae escaped rapidly from the cyst walls and matured in the gut. Thus, Cercaria echinifera was converted very rapidly in the intestine of warm-blooded animals int o Distoma echinfera while C. flavum became transformed into Monostomum flavum in finches and sparrows 196. Likewise, G Wagener in 1857 proved that the original hypothesis of von Sieb old was correct when he witnessed in snails the metamorphosis of the miracidium of Distoma cygnoides of the frog into a redia204. Investigations of the life cycles of nematodes during this period wer e sporadic and did not follow a common theme. The most significant advances were made with Trichinella spiralis. The larvae of this parasite had bee n discovered in 1835 and although von Siebold had suggested that they wer e intermediate stages awaiting tran sfer to another host, it was uncertain how this was achieved. In 1851, however, Herbst reported a major discovery. A fe w years earlier, he had tried without success to transmit infection to a cat b y inserting cysts subcutaneously. In November 1850, he fed some trichinou s flesh obtained from a dead badger to three dogs then identified trichinellae in their muscles at variable intervals thereafter 75. This report was treated wit h much reservation, however, and the problem was not solved for anothe r decade. After a false start in which Leuckart concluded that Trichuris trichiura adults developed in pigs after they were fed trichinous flesh 109, Virchow in 1859 discovered the adult T. spiralis in the intestines of a dog three and a half days after it was fed with trichinous meat 200-202. This finding was confirmed by Leuckart110, then shortly thereafter, Zenker identified the adult worms in th e small bowel of a human 212. All three of these investigators demonstrated the migration of newborn larvae, thus making the complete life cycle clear (se e chapter 22). Some desultory experiments were undertaken with Ascaris lumbricoides during this period. Davaine faile d to infect a cow with A. lumbricoides but did observe that larvae hatched from the eggs and were passed in the faeces when ova were fed to rats45. Davaine thought it unlikely that an intermediate hos t was required for transmission, but this view was challenged by others, particularly in view of a number of negative experiments: Mosler in 1860 failed to infect himself by swallowing eggs 134, while Leuckart in 1867 was unable t o infect a variety of animals with embryonated A. lumbricoides eggs or a horse with Ascaris megacephala (= Parascaris equorum), a dog with Ascaris marginata (= Toxocara canis), or a cat with Ascaris mystax (= Toxocara cati) ova112. Nevertheless, Unterberger in 1868 showed that Ascaris maculosa (= Ascaridia columbae) of the pigeon developed directly while Henry in 1873 demonstrated direct transmission of T. cati to cats. Success was achieved, however, with such challenge infections with on e important nematode parasitic in humans, Enterobius vermicularis. In 1865, Leuckart and three of his students swallowed a few dozen eggs of this worm that had been kept in a humidified incubator. Over the next several weeks, they

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all recovered adult parasites from their faeces 112. An important landmark also occurred in 1865 when Leuckart reported that the embryos that had hatched from ova of the nematode, Cucullanus elegans, a parasite of perch, developed in minute water crustaceans. In 1869 , Fedchenko made use of Leuckart's observations and himself made a majo r discovery concerning the transmission of Dracunculus medinensis . In July of that year, a doctor brought him a Guinea worm in a small bottle. In th e surrounding water, Fedchenko noticed some small crustaceans, Cyclops, in which he saw larvae similar to those of the Guinea worm. He therefore undertook an experiment in which he added fresh embryos to parasite-free Cyclops and noted that they were ingested by the crustaceans. Further, he observed the moulting and development of these larvae within the crustaceans over the next several weeks. He was unable to complete the life cycle but speculated tha t infected Cyclops may be ingested by humans with release of the larvae in the gut and their subsequent development in the tissues 56. The effects of all these experiments on the doctrine of spontaneous gen eration of worms must also be viewed in the light of two other factors which had become apparent by this time. The first was the development of histo pathology which climaxed in the cellular pathology of Virchow. Vircho w expounded the dictum "omnis cellula e cellula" (all cells out of cells). Th e corollary was that an organized being could not be formed out of formles s fluid. Thus, he wrote in 1859: Just as little as we can now admit that a Taenia can arise out of saburral [= foul] mucus, or that of the residue of the decomposition of animal and vegetable matter an infusorial animal....can be formed, equally little are we disposed to concede....that a new cell builds itself up out of any noncellular substance. Where the cell arises, there a cell must have previously existed....in pathology we can now go so far as to establish, as a general principle, that no development of any kind begins de novo and consequently as to reject the theory of spontaneous generation. 199

The other factor was the grad ual acceptance of the value of statistical methods in medicine and biology. Statistics had been popularized by Laplace in hi s Philosophical Essay on Probability then was put to use by Pierre-Charle s Louis in his 1828 Researches on the Typhoid Affection or Fever . Not only was this eventually to aid in the interpretati on of the results of experimentation, but the chance element in transmission, which had previously seemed to be a point in favour of spontaneous generation, now appeared to be an example of a general biological law. Thus, the great fecundity of worms was now seen as a response to the low probability of continuity and survival of the species. The coup-de-grâce was finally delivered to the theory of spontaneou s generation during this period. The theory had gradually become intermingled with the problems of fermentation and putrefaction which were generally regarded as the result of some spontaneous chemical change in fermentible or putrescible matter. For many years, the influence of air on fermentation an d putrefaction had been the subject of much discussion. A number of important experiments were made by Schulze, S chwann, Helmholtz, Schroeder and Ber-

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nard, but the critical experiments were those of Louis Pasteur which wer e published in 1860 and 1861. In 1858, however, FA Pouchet had begun to present a series of papers to the Academy of Sciences in Paris in which he claimed to have proved th e existence of spontaneous gene ration, which he called heterogenesis, by experiments using flasks, air, hay, water and heat. In 1859, he published his book, Hétérogonie, in the preface of which he explained how he had come to study the phenomenon: when by meditation it was evident to me that spontaneous generation was one of the means employed by nature for the reproduction of living things I applied myself to discover the methods by which this takes place.165

Pouchet believed that spontaneous generation required the presence of a vital force coming from pre-existin g living matter; he did not believe that life could be generated from non-living matter. Meanwhile, Pasteur had become interested in the problems of fermentation. In 1857 he isolated a ferment (since shown to be bacterial) that soured milk, then he showed that yeasts or moulds on grapes were necessary for th e fermentation of sugar into alcohol in the making of wine. These observations convinced him that fermentation and putrefaction were vital processes; thi s view compared starkly with that of Baron von Liebig, the premier authority on the matter, who regarded fermentation as being "of the nature of death". Like Spallanzani, Pasteur believed that organisms associated with fermentatio n came from the air. The major criticism of Spallanzani's work had been that in boiling his sealed flasks, he had also altered in some way the contained air . Pasteur therefore set about proving the crux of his hypothesis, that is that air carried germs. First, he showed that germs or bodies resembling them existed in the air by filtering air through gun-cotton then examining the sedimen t microscopically; these were similar to the organisms that had already bee n observed in fermenting substances. The next problem was to demonstrate that these germs were alive. This he did by showing that sterile infusion s containing air which had been heated became infected if dust from the air was introduced into it. He then took a series of flasks containing an infusion o f fermentable substances but in which the neck of each flask was very narrow and long, more or less horizontal in orientation, and drawn out into an "s " shape. The flasks and their contents were then heated to boiling point for a long period. Even though they were then left for months, the contents did not ferment. When the neck was seve red, however, fermentation became apparent within a few hours and organisms were demonstrated in it under the micro scope. These experiments were brought together in Pasteur's Mémoire sur les corpuscles organisés qui existent dans l'atmosphère. Examen de la doctrine des générations spontanées which was published in 1861 162. The success of these experiments was the final turning point and marked the downfall of the doctrine of spontaneous generation, although a vociferous rear-guard actio n

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53

was fought for a number of years by a few workers including Pouchet, Häckel, and the English physician, Charlton Bastian, who a few years earlier had described in detail the anatomy of the Guinea worm. The word "biogenesis" was coined by TH Huxley80 in 1870 to express the hypothesis that living matte r always arises by the agency of pre-existing living matter, while the ter m "abiogenesis" was used for the opposite view. Perhaps the most extreme supporter of abiogenesis during this period was Bastian who, in a book of greater that one thousand pages published in 1872, promulgated the doctrine o f "archebiosis", i.e. that animals can be gen erated spontaneously from non-living matter12. Bastian continued the fight until his death in 1915. He is a classi c example of the principle enunciated by Max Planck: A new scientific truth does not become accepted by way of convincing and enlightening the opposition. Rather, the opposition dies out and the rising generation becomes well-acquainted with the new truth from the start. 164

THE FINAL QUARTER OF THE NINETEENTH CENTURY It took some time for the dust to clear and for the controversy over spont aneous generation to be seen in perspective. In reviewing the whole question in 1881, the learned The New Sydenham's Society's Lexicon of Medicine and the Allied Sciences summarized the problem thus: This subject has attracted much attention of late years. Pouchet in France, Häckel in Germany and Bastian in this country have been its most prominent supporters....The most ingenious apparatus and modifications of experiments have been suggested by both sides....Unfortunately, the evidence that one side regards as irrefutable is either entirely ignored or met with a direct denial by the other. The results of one's experiments are the negative ones of his opponent....On the whole, it may be said that no conclusive proof has been obtained of the occurrence of abiogenesis. 167

In the event, the proponents of spontaneous generation gradually disappeared from view and the doctrine of spontaneous generation became abandoned by biologists. Certainly, no experimental helminthologists still supported th e concept. All their time and energy was devoted to elucidate the complex and mysterious life cycles of many parasitic worms. The first major success came with Fasciola hepatica when Thomas in England190,191 and Leuckart in Germany113-115 independently worked out the life cycle of this parasite between 1879 and 1882. In a series of epidemiological studies and laboratory experiments, both authors discovered that miracidi a hatched from Fasciola eggs invaded Lymnaea snails and there metamorphosed into brood sacs or sporocysts in which rediae subsequentl y developed. The latter in turn developed cercariae within them. Bot h investigators were uncertain as to the subsequent course of events, postulating that either the snails containing cercariae were ingested or that cercaria e escaped from the molluscs, encysted on grass, then were ingested. The matter was not settled until 1892 when Lutz showed that Fasciola cercariae were

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liberated from damaged or dead snails then en cysted on plant or other material. He then demonstrated that when these cysts were fed to guinea pigs, the life cycle was completed 123. These findings with Fasciola led to an intensive search for a snail intermediate host for Schistosoma haematobium , but as is related in chapter 8, nothing was found and controversy continued until well into the next century as to whether an intermediate host was necessary. The remaining cestode of major human importance of which the life cycle was obscure was Diphyllobothrium latum . A partial solution to this problem was provided during this period by Max Braun in the eastern Baltic region. He found immature worms, the head of which resembled that of the broa d tapeworm, in a variety of fresh-water fish (pike, perch, ruff and burbot). H e then fed in 1881 these parasites to dogs and eventually recovered adult D. latum 22, then repeated the experimental process in humans 22,23 . The second intermediate host was now clear, but how the fish became infected remained unsolved for another 35 years. During this period, observations were made upon the life cycles of certain cestodes of lesser significance for humans. Grassi found in 1887 tha t Hymenolepis nana could be transmitted directly from one definitive host to the next68. In 1889, Grassi and Rovelli showed that Dipylidium caninum developed in fleas70. Three years later, they showed that Hymenolepis diminuta developed in a variety of arthropod intermediate hosts 71. Pieces were put into place partially or completely during this period for a number of nematodes. In 187 6, Leuckart reported that when he had fed ova of Trichuris affinis to a lamb and T. crenatus eggs to pigs, he was able to recover subsequently adult worms 112 then Railliet in 1884 reported a simila r phenomenon with dogs and T. depressiusuculus. This was applied to the human parasite, T. trichiura, in 1886 when Calandruccio successfully infected himself after swallowing eggs, the results being reported by Grassi 67. In the same year, Calandruccio likewise i nfected a boy with Ascaris lumbricoides by administering embryonated ova to him. This experiment was also reported by Grassi67, who had claimed a similar result in a few years earlier 66, although that claim must be viewed with considerable circumspection in view of th e unusually short incubation period that he reported. Similar attempts were made to transmit hookwor m infection. In 1878, Grassi and his colleagues failed to infect humans b y ingestion of either hookworm ova or larvae (presumably first-stage), nor could they infect a dog by administering eggs orally69. In 1886, however, Leichtenstern undertook feeding experiments and reported that he was able to infect humans by administering third-stag e hookworm larvae orally 102, a feat which Wilms repeated in 1897 with th e similar parasite, Strongyloides stercoralis 206. A far more important even t occurred when the German, Looss, working in Egypt reported in 1898 tha t infective larvae were able to penetrate the intact skin, migrate to the gut and mature119. This was greeted with considerable scepticism, but several year s later he was able to prove his point as will be described in the next section.

Origin and Migration of Worms

55

Meanwhile, a discovery of great significance was made in 1877 by th e Englishman, Patrick Manson, working in China. The scene was set for hi s epochal discovery by the finding in 1872 by Lewis that the embryonic forms of the filarial parasite, Wuchereria bancrofti, circulated in the periphera l blood. Manson puzzled about the fate of these larvae and tried to ascertai n their destiny. He deduced that the most likely means of exit was via a blood-sucking insect, and with a stroke of luck selected mosquitoes as th e most likely candidate. He thereupon procured some mosquitoes and fed them upon his gardener who happened to have a microfilaraemia. He then examined the mosquitoes at daily intervals and found that the parasites metamorphosed in the insects' abdomen 128. Manson was incredibly lucky in that he knew little about mosquitoes and happened by chance to use a species that wa s susceptible to infection. He was incorrect, however, in his surmise tha t mosquitoes flew off to stagnant water to deposit their eggs and there died , releasing larvae which reached the human host via drinking water. Manson's observations on the uptake and development of microfilariae in mosquitoe s were soon confirmed by Lewis and S ilva Araujo, but it was not until 1900 that the final link in the chain was put in place. Thomas Bancroft in Australi a infected mosquitoes, that had been reared in the laboratory and were free o f parasites, by allowing them to feed on an infected person then sent the specimens to Manson in London. Manson passed them on to George Low wh o prepared histological sections of the mouthparts and demonstrated th e infective larvae in the proboscis 122. Almost immediately afterwards, Jame s independently made similar observations 81.

THE FIRST QUARTER OF THE TWENTIETH CENTURY At the turn of the nineteenth century, great interest centred on Looss's claim of 1898 that hookworm larvae could p enetrate the intact skin. As indicated in the preceding section, this report was greeted with considerable scepticism. I n order to prove his point, he applied filariform larvae to the skin of a thirteen year old boy one hour before he was due to have his leg amputated. Immediately following removal of the leg, the exposed skin was excised and histo logical sections disclosed larvae in the dermis. Looss reported his findings in 1901 120 , but disbelief was still rampant. He therefore persuaded an hospita l attendant to allow himself to be infected ex perimentally. After ascertaining that the person was not infected already, a drop of culture fluid containing infective larvae was placed on his forearm; hookworm ova were found in his faeces 71 days later, thus proving that the life cycle of this parasite could be completed in this manner 121. These observations with hookworm were then applied to the similar parasite, Strongyloides stercoralis. Van Durme showed with histological studies i n 1901-2 that Strongyloides infective larvae were able to invade the skin o f

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guinea pigs50. Over ten years later, Fülleborn took the final step in experiments with dogs and showed that larvae applied to the skin migrated through the lungs and then were able to develop into adult worms in the intestines 62. In 1905, Robert Leiper went to the Gold Coast (Ghana) to further in vestigate the life cycle of Dracunculus medinensis . First, he repeated Fedchenko's experiments and examined the manner in which Cyclops were infected. He then fed a monkey on bananas contaminated with copepods that had been infected with guinea worm embryos five weeks earlier. Six months later, he found five immature Dracunculus in the tissues at post-morte m examination103. In 1913, Turkhud in India gave a small number of infecte d Cyclops in water to five "volunteers". Just over one year later, one of thes e persons developed a clinical infection, although whether this was as a result of the experimental exposure or was acquired naturally cannot be determined with certainty193. By analogy with Wuchereria bancrofti, it seemed very likely that Loa loa was also transmitted by some form of biting insect. In 1912, Leiper journeyed to West Africa and fed many type s of arthropods on infected persons. He found that development of microfilariae occurred in flies of the genus Chrysops 104 but he did not publish details of the developmental changes. His results wer e confirmed several years later by Kleine and then by Connal and his wife, th e latter pair of investigators providing considerable detail 39,40. Another question that burned in the minds of many helminthologists at this time concerned the manner of transmission of schistosomiasis. As is discussed in chapter 8, investigators fell into one of two camps - those that favoure d direct transmission and those that believed that there must be an intermediate host. The answer came not from a study of Egyptian schistosomiasis, but from investigation of Schistosoma japonicum infection that had just been discovered in Japan. In 1909, Fujinama and Nakamura showed by a series of experiments using cows that infection was acquired via the skin rather than by the ora l route 60,61. The events leading up to such infection were described by Miyair i and Suzuki in 1913. They reported that they had collected snails of uncertain identity (subsequently shown to belong to the genus Oncomelania) from a roadside ditch, found that they were free of trematode infections, then exposed them to S. japonicum miracidia hatched from eggs. They observed that th e miracidia invaded the snails, developed into sporocysts then ultimatel y produced and released cercariae. They then exposed the skins of mice t o cercariae released from naturally-infected snails and a few weeks late r recovered adult schistosomes from the portal veins of the infected mice 132,133. These results were then soon confirmed by Leiper and Atkinson 107 and by Yokogawa210. In the light of these observations, Leiper then turned his attention t o schistosomiasis in Egypt. After a rapid series of experiments, he was able t o report in 1915 that he had infected Bulinus snails with miracidia derived from terminal-spined eggs (S. haematobium), observed their development through

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sporocysts to cercariae in the snails, then infected mice percutaneously an d recovered adult worms 105. In the following year, he showed that miracidi a derived from lateral-spined ova (S. mansoni) underwent development in snails of the genus Biomphalaria 106. Almost contemporaneously with these e vents, the life cycles of the liver fluke, Clonorchis, and the lung fluke, Paragonimus, were elucidated. In 1911, th e Japanese zoologist, Kobayashi, while working i n Korea, found that an immature, encysted fluke occurred commonly in certain freshwater fish in an area where clonorchiasis was endemic. He then fed flesh of fish containing these cysts t o cats and recovered adult Clonorchis from the biliary system 88,89. The mode in which fish became infected, however, remained a mystery although Kobayashi suspected that snails may be involved. That this was so was proven by th e Japanese pathologist, Muto, in 1918. He found a species of snail ( Bithynia, now called Parafossarulus) naturally infected with several forms of cercariae. H e used these molluscs to infect fish then fed these fish to dogs and eventuall y found Clonorchis adults in the biliary tract 138,139. Kobayashi's discovery stimulated his compatriot, Nakagawa, working in an area of Taiwan where paragonimiasis was endemic , to search the local molluscs, fishes, amphibia and insects for the intermediate stages of Paragonimus. In 1914 he found two sorts of en cysted trematodes in crabs of the genus Potamon. He fed tissues from infected crabs to dogs and eventually recovered adul t Paragonimus from their lungs 140,141. It was not until 1917, however, tha t Yokogawa proved which form of encysted larva was the precursor of the adult Paragonimus 211. Again the problem remained as to the manner in which crabs, clearly a second intermediate host, became infected. Attempts to solve thi s problem were confused initially by the uncertainty as to which form of encysted larva in the crab was really Paragonimus. Independently, and at around th e 131 same time between 1917 and 1919, Ando 4, Kobayashi90 , Miyairi , 142 Nakagawa and Yokogawa all concluded that snails of the genus Melania (= Semisulcospira) were probably the first intermediate host. Following his success with Clonorchis, Nakagawa turned his attention to the intestinal fluke, Fasciolopsis buski. In 1920, he found that miracidia hatche d from Fasciolopsis eggs invaded, then developed into sporocysts, rediae an d cercariae in snails now known as Segmentina haemisphaerula 143. Furthermore, he noted that the cercariae escaped from the snails and encysted on grass. H e then infected a dog and pigs with these encysted worms and succeeded i n recovering adult Fasciolopsis from the intestinal tract; these details wer e published in 1922 144. Similar success was achieved with Metagonimus yokogawai . In 1911 Yokogawa showed that trout were the second intermediate host of this infection 209. Six years later, Muto found that snails of the g enus Semisulcospira were the first intermediate host of this parasite 137. In 1915, Onji and Nishio showed tha t certain fish were the second intermediate host of the fluke, Heterophyes heterophyes 154 but the first intermediate host remained obscure for a number

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of years. In 1917, Ciurea found that certain species of fish were the secon d intermediate host of Opisthorchis felineus 36, but again, the nature of the firs t intermediate host remained unknown. During this period, the missing link in the chain of transmission of the broad tapeworm, Diphyllobothrium latum , was finally put into place. Janicki an d Rosen in Switzerland attempted to infect fish directly with larvae hatched from D. latum eggs. When this failed, Janicki examined the stomach contents o f species of fish that were known to transmit the infection. He found by a process of exclusion that all fish containing younger stages of the tapeworm ha d copepods in their gut 82. Likewise, Rosen examined a number of potentia l primary intermediate hosts without success until he turned his attention t o copepods. In the body cavity of certain Cyclops, he found oncospheres typical of D. latum 171. Both investigators came to this conclusion independently in June 1917. In order to complete the life cycle experimentally, Rosen infecte d copepods by exposing them to tapeworm eggs then six weeks later placed trout in the aquarium. When the fish were killed s ubsequently, he found plerocercoids in the musculature 171. In 1911, Nicholl and Minchin found t hat Hymenolepis nana, in addition to its direct cycle of transmission, could also be acquired by ingestion of infecte d fleas147.

THE REMAINDER OF THE TWENTIETH CENTURY The only helminth infection of major human importance in which the life cycle was still uncertain at the beginning of the seco nd quarter of the twentieth century was Onchocerca volvulus. A number of investigators had studied a number of potential intermediate hosts without success, and in 1917 Robles in Guatemala had suggested on epidemiological grounds that blackflies of the genus Simulium may be involved but he offered no definitive evidence. That these flies wer e indeed the vector was proven by Blacklock in Sierra Leone. He reported i n 1926 that Onchocerca microfilaria were present in the gut of these insects and he traced their development into infective larvae which migrated into th e proboscis 17,18. Like most of the other filarial nematodes, this worm has neve r been transmitted experimentally to humans. The remainder of the century saw several small points in the life cycles of the important human parasites tidied up and observations made upon the lif e histories of a number of worms of lesser signifi cance. With respect to nematodes of lesser importance for humans, Dyce Sharp showed in 1927 that Mansonella perstans developed in Culicoides 51,52. Buckley reported in 1933 that insects of the same genus were the vectors of Mansonella ozzardi 28,29. Likewise, Culicoides were found by Chardome and Peel in 1949 to be the intermediat e hosts of Mansonella streptocerca 35. In 1960, Edeson and his colleague s reported that they had induced a patent infection in a human with Brugia

Origin and Migration of Worms

59

pahangi although they had failed to achieve this result with B. malayi 53. The latter infection was transmitted success fully to monkeys by Orihel and Pachecho in 1968157. Likewise, Cross and his colleagues reported in 1979 that they had transmitted successfully Wuchereria bancrofti to monkeys44. Four years earlier, Orihel and Moore had transmitted Loa loa to two species of subhuma n primates156. The details of the first and second intermediate hosts of Gnathostoma spinigerum were described by Prommas and Daengsvang in in 1936 168. Mackerras and Sandars described the molluscan inte rmediate host of Angiostrongylus cantonensis in 1955124 while Morera and Ash in 1971 described the slug vector of Angiostrongylus costaricensis. Infection with Capillaria philippinensis was shown to be by ingestion of infected fish by Cross and his colleagues in 1972 43. With respect to trematodes of lesser human significance, Asada in 192 8 discovered the snail first intermediate host of Heterophyes heterophyes 7. Cameron in 1931 showed that certain snails were the intermediate host o f Dicrocoelium dendriticum 32, while Krull and Mapes later found that meta cercariae developed in ants 91. In 1933, Tubangui and Pasco identified the snail intermediate hosts of Echinostoma ilocanum 192. In 1934, Vogel showed tha t snails of the genus Bithynia were the first intermediate host of Opisthorchis felineus 203. The first and second intermediate hosts of O. viverrini were described by Wykoff and his colleagues in 1966 208. Concerning cestodes of less importance for huma ns, Stunkard showed in 1940 that mites were the vector of Bertiella studeri 188.

OVERVIEW

In retrospect, it is clear that almost no progress in an understanding of the nature of the origin and transmission of worms was achieved for most of recorde d history. Spontaneous generation of helminths seemed a perfectly respectabl e explanation and only began to be seriously questioned in the late seventeent h century. Even then, it took nearly 200 years for the issue to be settled finally with general acceptance that worms, like other living creatures, were produced from gametes. This coincided with elucidation of the means by which parasiti c helminths were transferred from one host to another. A landmark in theoretical understanding was the publication of the theory of "Alternation of Generations" by Steenstrup in 1842, but perhaps even more important was the popularization by Küchenmeister beginning in 1851 of the use of experimental method i n solving these problems. A veritable explosion of information and discovery then followed, so that within three quarters of a century, the life cycles of all the major human helminth infections were understood. Today's helminthologists ar e attempting to apply all of these achievements to the control of these ubiquitous

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parasites and prevention of infections in human populations.

REFERENCES 1. ABILDGAARD PC. Almindelige Betragtninger over Indvoldeorme, Bemaerkingner ve d Hundstelens Baendelorm, og Beskrivelse med Figurer of nogle nue Baendeloreme. Skrivter af Naturhistorie-Gelskabet, Kjøbenhavn 1: 26-64, 1790. German translation in Schriften der Naturforschen der Gesellschaft, Köpenhagen 1: 24-59, 1793. Partly translated in 84 2. ALDROVANDI U. De animalibus insectis libri septem denuo impressum, Ferronius , Bononiae, pp 767, 1638. Cited in 77 3. AL-QAZWINI. Cited in 77 4. ANDO A. (The first intermediate host of Paragonimus westermani .) Tokyo Iji Shinshi Nos. 2175-2178, pp 21, 1920. In Japanese. Abstracted in Tropical Diseases Bulletin 17: 51, 1921 5. ANDRY N. De la génération des vers dans le corps de l'homme. Avec trois lettres sur les sujets des vers, les deuxs premières.... par M Nicolas Hartsoeker et l'autre....par M Georges Baglivi, Laurent d'Houry. Paris, pp 468, 1700. An account of the the breeding of worms in humans bodies, etc., translated by H Rhodes and A Bell, London, pp 266, 1701 6. ARISTOTLE. Generation of animals, translated by AL Peck, Loeb Classical Library , Heinemann, London, 1953 7. ASADA J. (Determination of the first intermediate host of Heterophyes heterophye s occurring parasitic in human body in Japan and an experimental investigation of it s development.) Tokyo Iji Shinshi No. 2564, pp 6-12, 1928. In Japanese. Abstracted in Japan Medical World 8: 134, 1928 8. AVICENNA. Libri in re medica omnes, qui hactenus ad nos perverene etc., V Valgrisius, Venetiis, pp 966, 1564. Original Arabic version, "Al Canon fi Al Tib", c. 1000 AD. Partly translated in 86 9. von BAELLSTADT A (ALBERTUS MAGNUS). De animalibus, written about 1260. In, Beiträge zur Geschichte der Philosophie der Mittelalters, volumes 15 and 16, 1916 and 1920 10. von BAER KE. Beiträge zur Kenntnis der niedern Thiere. Nova Acta Academiae Ceasareae Leopoldino-Carolinae Naturae Curiosorum, Vratislaviae etc 13: 523-762, 881-882, 1827 11. BAGLIVI G. Cited in 5 12. BASTIAN HC. The beginnings of life: being some account of the nature, modes of origin and transformation of lower animals, MacMillan and Co., London, two volumes, pp 1115, 1872 13. van BENEDEN PJ. Les ver cestoïdes ou acolytes, considérés sous le rapport de leu r classification, de leur anatomie et de leur développement. Extracted from Mémoires d e l'Académie Royale de Belgique de Bruxe lles, volume 25, pp 190, 1850. Abstracted in British and Foreign Medico-Chirurgical Review 10: 322-335, 1852 14. van BENEDEN PJ. Note sur des expériences relatives au développement des cysticerques. Annales des Sciences Naturelles 1: 104, 1854 15. BERTOLUS G. Dissertation sur les métamorphoses des Cestoieds, Thèse de Montpellier, 1856 16. BIDLOO G. Brief van G Bidloo, aan Antony van Leeuwenhoek, wegens de dieren, welke men zomtyds in de lever der schaapen en andere beesten vind, H van Kroonevelt, Delft, pp 34, 1698. Cited in 101 17. Blacklock DB. The development of Onchocerca volvulus in Simulium damnsosum . Annals of Tropical Medicine and Parsitology 20: 1-48, 1926 18. BLACKLOCK DB. The further development of Onchocerca volvulus in Simulium damnosum Theob. Annals of Tropical Medicine and Parasitology 20: 203-218, 1926 19. BLOCH ME. Abhandlung von der Erzeugung der Eingeweidewürmer und den Mittel n wider dieselben. Eine von der königlich dänischen Societät der Wissenschaften z u Copenhagen gekrönte Preisschrift, Sigismund Friedrich Hesse, Berlin, pp 54, 1782. Partly translated in 55

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20. BOERHAAVE H. Aphorismi de cognoscendis et curandis morbis in usum doctrina e domesticae digesti. Editio Leydensis quarta auctior, S Leuchtmans et T Haak, Lugdun i Batavorum, pp 350, 1728 21. BOJANUS LH. Kurze Nachricht über die Zerkari en und ihren Fundort. Isis (Okens's), Oder Encyclopädische Zeitung, Jena, pp 729-730, 1818. Partly translated in 84 22. BRAUN M. Zur Frage des Zwischenwirthes von Bothriocephalus latus Brems. Zoologischer Anzeiger 4: 593-597, 1881; 5: 39-43, 1882; 5: 194-196, 1882; 6: 97-99 , 1883. Partly translated in 84 23. BRAUN M. Bothriocephalus latus und seine Herkunft. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 92: 364-366, 1883 24. BRAUN M. The animal parasites of man. A handbook for students and medical men , translated by P Falcke, revised by LW Sambon and FV Theobald, John Bale, Sons an d Danielsson, London pp 453, 1906 25. BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst eine m Anhange über Pseudo-Helminthen, Carl Schaumburg und Comp., Wien, pp 248, 1819 . Partly translated in 77 26 BRENDEL. Cited in 46 27. BROWNE T. Pseudoxia, 1645. Cited in 38 28. BUCKLEY JJ. Some observations on two West Indian parasites of man. Proceedings of the Royal Society of Medicine 27: 134-135, 1933 29. BUCKLEY JJ. On the development in Culicoides furens Poey of Filaria (Mansonella) ozzardi Manson, 1897. Journal of Helminthology 12: 99-118, 1934 30. BUFFON, Comte de (LE CLERC GL). Histoire naturelle, Sonnini-Dupont, Paris, 4 4 volumes, 1749-1804. Partly translated in 55 31. BULLOCH W. The history of bacteriology, Oxford University Press, London, pp 442 , 1938 32. CAMERON TW. Experimental infection of sheep with Dicrocoelium dendriticum . Journal of Helminthology 9: 41-44, 1931 33. CARDANUS. Cited in 77 34. CHAMISSO A. De animalibus qulbusdam e classe vermium Linneana, i n circumnavigatione terrae annis 1815, 16, 17, 18 peracta observatis. Fasc. 1: De Salpa, F Dümmlerum, Berolini, pp 24, 1819 35. CHARDOME M, PEEL E. La répartition des filaires dans la région de Coquilhatville et la transmission de Dipetalonema streptocerca par Culicoides grahami . Annales de la Société Belge de Médecine Tropicale 29: 99-119, 1949 36. CIUREA J. Die Auffindung der Larven von Opisthorchis felineus , Pseudoamphistomum danubiense und Metorchis albidus und die morphologische Entwicklung dieser Larven zu den geschlechstreifen Würmen. Zeitschrift für Infektionskrankheiten, parasitäre Krankheiten und Hygiene der Haustiere 18: 301-333, 345-356, 1917 37. CLERICUS D (LE CLERC D). Historia naturalis et medica latorum lumbricorum intr a hominem et alia animalia, nascentium etc., Fratres de Tournes, Genevae, pp 449, 1715. A natural and medicinal history of worms bred in the bodies of men and other animals etc., translated by J Browne, printed for J Wilcox at the Green-Dragon, Little Britain, pp 436, 1721 38. COLE R. Francesco Redi (1626-1697), physician, naturalist, poet. Annals of Medica l History 8: 347-359, 1926 39. CONNAL A, CONNAL SL. A preliminary note on the development of Loa loa (Guyot) in Chrysops silacea (Austen). Transactions of the Royal Society of Tropical Medicine and Hygiene 15: 131-134, 1921 40. CONNAL A, CONNAL SL. The development of Loa loa (Guyot) in Chrysops silacea (Austen) and in Chrysops dimidiata (Van der Wulp). Transactions of the Royal Society of Tropical Medicine and Hygiene 16: 64-89, 1922 41. CREPLIN FHC. Novae observationes de entozois, Berolini, pp 134, 1829

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42. CREPLIN FHC. "Distoma". In, Allge meine Encyclopädie der Wissenschaften und Kunste, JS Ersch und JP Grüber (Editors), Leipzig, Sect. 1. Part 29: 309-329, 1837. Partl y translated in 84 43. CROSS JH, BANZON T, CLARKE MD, BASACA-SERVILLA V, WATTEN RH , DIZON JJ. Studies on the experimental transmission of Capillaria philippinensis in monkeys. Transactions of the Royal Society of Tropical Medicine and Hygiene 66 : 819-827, 1972 44. CROSS JH, PARTONO F, HSU MK, ASH L R, OEMIJATI S. Experimental transmission of Wuchereria bancrofti to monkeys. American Journal of Tropical Medicine and Hygiene 28: 56-66, 1979 45. DAVAINE CJ. Nouvelles re cherches sur le développement de la propogation de l'ascaride lombricoide et du trichocéphale d e l'homme. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences, third series, 4: 261-265, 1862. Translated in 84 46. DAVAINE CJ. Traité des entozoaires et des maladies vermineuses de l'homme et de s animaux domestiques, second edition, J B Baillière et fils, Paris, pp 1003, 1877 47. DOLOEUS J. De infantum et puerorum morbis. In, Encyclop. medicinae, Francofurti, 4: 10, 1684-1691. Cited in 46 48. DRUMMOND JL. Thoughts on equivocal generation of entozoa., Annals of Natura l History 6: 101-108, 1841 49. DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairi e Encyclopédique de Roret, Paris, pp 654, 1845 50. van DURME P. Quelques notes sur les embryons de "Strongyloides intestinalis" et leu r pénétration par la peau. Thompson Yates Laboratories Report 4: 471-474, 1901-1902 51. DYCE SHARP NA. Development of microfilaria perstans in Culicoides grahami : a preliminary note. Transactions of the Royal Society of Tropical Medicine and Hygiene 21: 70, 1927 52. DYCE SHARP NA. Filaria perstans: its development in Culicoides austeni . Transactions of the Royal Society of Tropical Medicine and Hygiene 21: 371-396, 1928 53. EDESON JF, WILSON T, WHARTON RH, LAING AB. Experimental transmission of Brugia malayi and B. pahangi to man. Transactions of the Royal Society of Tropica l Medicine and Hygiene 54: 229-234. 1960 54. ESCHRICHT DF. Inquiries, experimental and philosophical, concerning the origin o f intestinal worms. Edinburgh New Philosophical Journal 31: 314-356, 1841 55. FARLEY J. The spontaneous generation controversy (1700-1860): the origin of parasitic worms. Journal of the History of Biology 5: 95-125, 1972 56. FEDCHENKO (FEDTSCHENCKO) AP. (Concerning the structure and reproduction of the Guinea worm [Filaria medinensis L.]. Izvestiia Imperatorskago Obshchestva Liubitelei Estestvoznaniia Antropologii i Ethnografii - Moskva, 8: columns 71-81, 1870. In Russian. Translated in 84 57. de FILIPPI. Descrizione di nuovi entozoi trovati in alcuni molluschi d'aqua dolce . Bibliotheca Italiana, an 22, 87: 333-340, 1837 58. FILLIOZAT J. La doctrine classique de la médecine Indienne, Imprimerie Nationale, Paris, 1949 59. FORBES D. Extracts from the half yearly reports of the diseases prevailing at Dharwar in the 1st grenadier regiment, for the year 1836. N.I. for the year 1836. Transactions of the Medical and Physical Society of Bombay 1: 215-225, 1838 60. FUJINAMI A, NAKAMURA H. (The mode of transmission of Katayama disease in the Hiroshima prefecture, Japanese schistosomiasis, the development of its causative worm , and the disease in animals caused by it.) Hiroshima Iji Geppo 132: 324-341, 1909. I n Japanese. Abstracted in 205 61. FUJINAMI A, NAKAMURA H. (Route of infection, development of the worm in the host and animals in Katayama disease in Hiroshima Prefecture [Japanese blood sucking worm disease - schistosomiasis japonica].) Kyoto Igaku Zasshi 6: 224-252, 1909. In Japanese. Translated in 84

Origin and Migration of Worms

63

62. FÜLLEBORN F. Untersuchungen über den Infektionsweg bei Strongyloides und Ankylostomum und die Biologie dieser Parasiten. Archiv für Schiffs- und Tropen-Hygiene 18: 26-80, 1914 63. GABUCINUS H. De lumbri cis alvum occupantibus, ac de ratione curande eos, qui ab illis infestantur, Commentarius, H Scotus, Venetiis, pp 56, 1547 64. GALENUS CC. Works of, In, Medicorum Graecorum opera quae exstant, edited by KG Kühn (Greek text with Latin translation), Leipzig, 20 volumes, 1821-1833 65. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, PA Pope, Blankenburg, pp 471, 1782 66. GRASSI GB. Note intorno ad alcuni parassiti dell'uomo. III. Intorno all' Ascaris lumbricoides. Gazzetta degli Ospitali, Milano 2: 432, 1881 67. GRASSI GB. Trichocephalus und Ascarisentwicklung. Preliminärnote. Centralblatt fü r Bakteriologie und Parasitenkunde, Abteilung originale 1: 131-132, 1887 68. GRASSI GB. Entwicklungsc yclus der Taenia nana. Dritte Praliminärnote. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 2: 305-312, 1887 69. GRASSI GB, PARONA C, PARONA E. Intorno all' Anchilostoma duodenale (Dubini). Gazzetta Medica Italiana Lombardia 38: 193-196, 1878. Translated in 84 70. GRASSI GB, ROVELLI G. Embryolische Forschungen an Cestoden. Centralblatt fü r Bakteriologie und Parasitenkunde, Abteilung originale 5: 370-377, 401-410, 1889 71. GRASSI GB, ROVELLI G. Ricerche embriologiche sui cestodi. Atti dell'Accademi a Gioenia di Scienze Naturali, Catania, volume 4, memoir 2, 1892 72. HARTING P. Het mikroskoop, four volumes, 1848-1854; Das Mikroscop: Theorie , Gebrauch, Geschichte und gegenwärtiger Zustand desselben, translated by FW Theile, F Vieweg und Sohn, Braunschweig, three volumes, 1866 73. HARTSOEKER N. Cited in 5 74. HARVEY W. Exercitationes de generatione animalium, 1651. The works of Willia m Harvey, translated by R Willis, The Sydenham Society, London, 1847 75. HERBST M. Beobachtungen über Trichina spiralis. Nachrichten von der Georg-August Universität, Göttingen. Königliche Gesellschaft der Wissenschaften, pp 260-264, 1851 . Abstracted in Quarterly Journal of Microscopical Science 1: 209-211, 1853. Translated in 84 76. HIPPOCRATES. Works of, translated by WH Jones and ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953 77. HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 78. HOFFMANN FH. Opera omnia physico-medica et supplementa etc, Genevae, pp 508 , 1740-1753 79 HUMBERT A. Cited in 15 80. HUXLEY TH. Biogenesis and abiogenesis (1870). In, Collected essays, MacMillan and Co., London, nine volumes, 1894-1908 81. JAMES SP. On the metamorphosis of the Filaria sanguinis hominis in mosquitos. Especially with reference to its metamorphosis in Anopheles rossi and other mosquitos of the Anopheles genus. British Medical Journal ii: 533-536, 1900 82. JANICKI C. Observations sur quelques espèces de poissons afin d'arriver à connaître plus à fond le contenu de leur estomac et pour trouver des stades encore inconnus d e plerocercoïde. Bulletin de la Société Neuchâteloise des Sciences Naturelles 42: 22-29 , 1917. Partly translated in 84 83. JOLLY J. Indian medicine, translated from the German and supplemented with notes by CG Kashikar, Poona, 1951 84. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, pp 677, 1978 85. KERCKRINGIUS T. Spicilogium anatomicus etc, A Frisii, Amstelodami, pp 280, 1670. Cited in 46 86. KHALIL M. An early contribution to medical helminthology translated from the writings

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of Ibn Sina (Avicenna) with a short biography. Journal of Tropical Medicine and Hygiene 25: 65-67, 1922 87. KNOCH J. Vorläufige Mittheilung über den Bothriocephalus latus die Entwicklung desselben, die Wanderung und endliche Uebertragung seines Embryo's in den Menschen. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 24: 453-461, 1862 88. KOBAYASHI H. (A preliminary report on the source of the human liver distome , Clonorchis endemicum (Bälz)(= Distoma spathulatum Leuckart.) Annotatione s Zoologicae Japonenses 271-277, 1911. In Japanese, with English summary 89. KOBAYASHI H. A preliminary report on the source of the human liver distome , Clonorchis endemicum (Bälz) (Distomum spathulatum , Leuckart). Far Easter n Association of Tropical Medicine: Transactions of the Second Biennial Congress, Hong Kong, pp 108-112, 1912 90. KOBAYASHI H. Studies on the lung fluke in Korea. I. On the life-history an d morphology of the lung fluke. Mittheilungen aus der medizinischen Fachschule zu Keijo 2: 97-115, 1918 91. KRULL WH, MAPES CR. Studies on the biology of Dicrocoelium dendriticu m (Rudolphi 1819) Looss, 1899 (Trematoda: Dicrocoeliidae) including its relation to th e intermediate host, Cionella lubrica (Muller). IX. Notes on the cyst, metacercaria, an d infection in the ant, Formica fusca. Cornell Veterinarian 43: 389-409, 1953 92. KÜCHENMEISTER F. Vorläufige Mittheilung. Über Cysticercus pisiformis der Kaninchen. Zeitschrift für klinische Medicin (G unsburg) 2: 240, 1851. Translated by L Herzberg 93. KÜCHENMEISTER F. Einiges über den Übergang der Finnen in Taenien und über das Digitalin. Zeitschrift für klinische Medicin (Gunsburg) 2: 295-299, 1851 94. KÜCHENMEISTER F. Ueber die Umwa ndlung der Finnen (Cysticerci) in Bandwuermer (Taenien). Prager Vierteljahrsschrift für die Praktische Heilkunde 33: 106-158, 1852 95. KÜCHENMEISTER F. Über Cestoden im Allgemeinen und die des Mensche n insbesondere etc., Zittau, 1853. Partly translated in 55 96. KÜCHENMEISTER F. Experimente über die Entstehung der Cestoden Zweiter Stuf e zunächst des Coenurus cerebralis . Under Mitwirkung des Herrn Professor Haubner auf Befehl und Kosten des hohen königliche sächsischen Staatsminsterii des Innern. Zeitschrift für klinische Medicin (Gunsburg) 4: 448-451, 1853 97. KÜCHENMEISTER F. Offenes Sendschreiben an die k.k. Gesellschaft der Zertze z u Wien. Experimenteller Nachweiss, da ssCysticercus cellulosae innerhalb des menschlichen Darmkanales sich in Taenia solium umwandelt. Wiener medicinische Wochenschrift 5: 1-4, 1855. Translated in 84 98. KÜCHENMEISTER F. Erneuter Versuch der Umwandlung des Cysticercus cellulosae in Taenia solium hominis . Deutsche Klinik 12: 187-189, 1860. Abstracted in Medica l Times and Gazette ii: 414, 1860 99. KÜCHENMEISTER F, HAUBNER GC. Weitere Mittheilungen über die Entwicklung der Band- und Blasenwürmer Nach den Versuchen von Dr. Küchenmeister und Dr . Haubner. Magazin für die Gessamte Thierheilkunde 20: 366-368, 1854; 21: 100-118 , 1855 100. van LEEUWENHOEK A. Part of a letter from Mr. Anthony van Leeuwenhoe k concerning worms observ'd in sheeps' livers and pasture grounds. Philosophica l Transactions of the Royal Society 24: 1522-1527, 1704 101. van LEEUWENHOEK A. The selec t works of Anthony van Leeuwenhoek containing his microscopical discoveries in many of the works of nature, translated by S Hoole from the Dutch and Latin editions, Henry Fry, London, 1798 102. LEICHTENSTERN O. Futterungsversuche mit An kylostomalarven. Ein neue Rhabditisart in den Fäces von Ziegerlarbeitern: Berichtigung. Centralblatt für klinische Medicin 7 : 673-675, 1886 103. LEIPER RT. The etiology and prophylaxis of dracontiasis. British Medical Journal i : 129-132, 1907

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104. LEIPER RT. Filaria loa. Cited in British Medical Journal i: 39-40, 1913 105. LEIPER RT. Report on the result s of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 25: 1-55, 147-192, 253-267, 1915 106. LEIPER RT. On the relation between the terminal-spined and lateral-spined eggs o f Bilharzia. British Medical Journal i: 411, 1916 107. LEIPER RT, ATKINSON EL. Observations on the spread of Asiatic schistosomiasis . British Medical Journal i: 201-203, 1915 108. LEUCKART R. Die Blasenbandwürmer und ihre Entwicklung. Zugleich ein Beitrag zur Kenntnis der Cysticercusleber, J Ricker, Giessen, pp 162, 1856 109. LEUCKART R. Expériences sur la trichina spiralis (le ver devient un trichocéphale dans l'intestin du porc). Comptes Rendus Hebdomadaires des Séances de l'Académie de s Sciences 49: 453-457, 1859 110. LEUCKART R. Der geschlechstreife Zustand der Trichina spiralis. Eine vorläufige Mittheilung. Zeitschrift für rationale Medicin 8: 259-262, 334-335, 1860. Translated in Quarterly Journal of Microscopical Science 8: 168-171, 1860 111. LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 1, pp 776, 1863 112. LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876 113. LEUCKART R. Zur Entwickelungsgeschichte des Leberegels. Zoologischer Anzeiger 4: 461-464, 1881. Translated in 84 114. LEUCKART R. Zur Entwickelungsgeschichte des Leberegels ( Distomum hepaticum ). Archiv für Naturgeschichte 1: 80-119, 1882 115. LEUCKART R. Zur Entwickelungsgeschichte des Leberegels. Zweite Mittheilung . Zoologischer Anzeiger 5: 524-528, 1882 116. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührende n Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sch e Verlagshandlung, Leipzig, volume 1, pp 1009, 1879-1886. The parasites of man and the diseases which proceed from them, translated by WE Hoyle, Young J Pentland , Edinburgh, pp 771, 1886 117. LINNAEUS C. Cited in 24 118. von LIPPMANN E O. Urzeugung und Lebenskraft. Zur Geschichte dieser Probleme von den ältesten Zeiten an bis zu den Anfängen des 20. Jahrhunderts, Julius Springer, Berlin, pp 135, 1933 119. LOOSS A. Zur Lebensgeschichte des Ankylostoma duodenale . Centralblatt für Bakteriologie und Parasitenkunde, Abteilu ng originale 24: 441-449, 483-488, 1898. Partly translated in 84 120. LOOSS A. Ueber das Eindrigen der Ankylostomalarven in die menschliche Haut. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 29: 733-739, 1901 121. LOOSS A. The anatomy and life histo ry of Agchylostoma duodenale Dub. A monograph. Part II. The development in the free state. Translated from the German by M Bernhard. Records of the School of Medicine, Egyptian Ministry of Education, 4: 163-613, 1911. Pp 252-277 reprinted in the Journal of Tropical Medicine and Hygiene 15: 155-157 , 171-174, 182-185, 199-201, 235-238, 1912. Abstracted in Journal of the Royal Arm y Medical Corps 19: 42-55, 1912 122. LOW GC. A recent observation on Filaria nocturna in Culex: probable mode of infection in man. British Medical Journal i: 1456-1457, 1900 123. LUTZ A. Zur Lebensgeschichte des Distoma hepaticum . Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 11: 783-796, 1892. Partly translated in 84 124. MACKERRAS MJ, SANDARS DF. The life-history of the rat lung-worm , Angiostrongylus cantonensis (Chen) (Nematoda: Metastrongylidae). Australian Journal of Zoology 7: 1-21, 1955

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125. de MALEBRANCHE N. De la recherche de la verité, 1673. Malebranche's Search after Truth, translated by T Taylor, London, two volumes, 1694 126. MALPIGHI M. De formatione pulli in o vo, 1673. In, Opera omnia, R Scott, Londini, two volumes, 1686 127. MALPIGHI M. De ovo incubato, 16 75. In, Opera omnia, R Scott, Londini, two volumes, 1686 128. MANSON P. Further observations of Filaria sanguinis hominis . China Imperial Maritime Customs, Medical Reports for the half year ended 30th September, 1877, 14th issue, pp 1-26, 1878. Reprinted without illustrations as "On the development of Filaria sanguinis hominis and on the mosquito considered as a nurse." Journal of the Linnean Societ y (Zoology) 14: 304-311, 1878 129. MEHLIS E. Novae observationes de entozois. Auctore Dr. Fr. Chr. H. Creplin. Isi s (Oken's), Oder Encylopädische Zeitung, Jena, pp 68-99, 166-199, 1831 130. MERCURIALIS H. De internis puerorum morbis, Lugduni, 1623 131. MIYAIRI K. (A contribution to the knowledge and development of the lung fluke.) Sai Kin Gaku Zasshi No. 281, 1919. In Japanese 132. MIYAIRI K, SUZUKI M. (On the development of Schistosoma japonicum .) Tokyo Iji Shinshi No. 1836, pp 1-5, 1913. In Japanese. Abstracted in 205 133. MIYAIRI K, SUZUKI M. (Der Zwischenwirt des Schistosomum japonicum Katsurada.) Mittheilungen aus der medizinischen Fakultät der kaiserlichen Universität Kysush u Fukuoka 1: 187-197, 1914 Partly translated in 84 134. MOSLER KF. Ueber einen Fall von Helminthiasis. Archiv für pathologische Anatomie und Physiologie und für klinsiche Medicin (Virchow) 18: 242-250, 1860 135. MOSLER KF. Helminthologisch e Studien und Beobachtungen, A Hirschwald, Berlin, pp 89, 1864 136. MÜLLER OF. Vermium terrestrium et fluviatilium, seu animalium infusorium , helminthocorum et testaceorum, non marinorum, succincta historia. Volume 1, Infusoria, Havniae et Lipsiae, pp 135, 1773 137. MUTO M. (Biologische Studien über die Cercarien und die encystierten Cercarien de s Metagonimus yokogawai.) Kyoto Igaku Zasshi 14: 79-100, 1917. In Japanese, wit h German summary, pp 54-56 138. MUTO M. Ueber den ersten Zwischenwirt von Clonorchis sinensis . Verhandlungen der japanischen pathologischen Gesellschaft, Tokyo 8: 151, 1918. Abstracted in Tropica l Diseases Bulletin 17: 49, 1921 139. MUTO M. (On the primary intermediate host of Clonorchis sinensis .) Chuo Igakkai Zasshi 25, No. 3, 49-52, 1918. In Japanese. Translated in 84. 140. NAKAGAWA K. (A preliminary report on the discovery of the intermediate host of the human lung fluke.) Tokyo Iji Shinshi, No. 1910, 1915. In Japanese 141. NAKAGAWA K. The mode of infection in pulmonary distomiasis. Certain freshwate r crabs as intermediate hosts of Paragonimus westermanii . Journal of Infectious Diseases 18: 131-142, 1916 142. NAKAGAWA K. Human pulmonary distomiasis caused by Paragonimus westermani . Journal of Experimental Medicine 26: 297-323, 1917 143. NAKAGAWA K. On the life cycle of Fasciolopsis buski , Lankester. Kitasato Archives of Experimental Medicine 4: 159-167, 1921 144. NAKAGAWA K. The development of Fasciolopsis buski (Lankester). Journal o f Parasitology 8: 161-165, 1922 145. NAUNYN B. Ueber die zu Echinococcus hominis gehörige tänie. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin, pp 412-416, 1863. Translated in 84 146. NEEDHAM JT. Observations upon the generation, composition and decomposition o f animal and vegetable substances. Phil osophical Transactions of the Royal Society, volume 44, 1750. Cited in 31 147. NICHOLL W, MINCHIN EA. Two species of cysticercoids from the rat flea ( Ceratophyllus fasciatus). Proceedings of the Zoological Society of London 1: 9-13, 1911

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148. NITZSCH CL. Seltame Lebens- und Todesart eines kleinen bisher unbekannte n Wasserthierchens. In, Kilian. Georgia, der Der Menschen im Leben und im Staate, p p 257-262, 281-286, 1807 149. NITZSCH CL. Beitrag zur Infusorienkunde, oder Naturbeschreibung der Zerkarien und Bazillarien. Neue Schriften der naturforschenden Gesellschaft zu Halle 3: 1-128, 1817 150. von NORDMANN A. Mikrographische Beiträge zur Naturgeschichte der wirbellose n Thiere, G Reimer, Berlin, two volumes, pp 268, 1832 151. OKEN LH. Cited and partly translated in 24 152. OKEN LH. Cited and partly translated in 181 153. OLIVER JH. Cited in Seventh Annual Report of the Sanitary Commissioner (1870) of the Government of India, Calcutta, pp 82-83, 1871 154. ONJI Y, NISHIO K. (General observations on new intestinal flukes.) Igaku Chuo Zasshi 14: 875-883, 1915. In Japanese 155. ORIBASIUS. Cited in 2 156. ORIHEL TC, MOORE P JJ. Loa loa: experimental infection in two species of African primates. American Journal of Tropical Medicine and Hygiene 24: 606-609, 1975 157. ORIHEL TC, PACHECHO G. Brugia malayi in the Philippine macaque. Journal o f Parasitology 54: 1234-1235, 1968 158. PALLAS PS. Bemerkungen über die Bandwürmer in Menschen und Thieren. Neu e nordische Beyträge Physikalische und Geographische Erd- und Vokerbeschriften 1 : 39-112, 1781. Partly translated in 116 159. PALLAS PS. Einige Erinnerungen die Bandwürmer bettrefend: in Beziehung auf da s zwölfte und vierzehnte stück des Naturforschers. Neue nordische Beytrage Physikalische und Geographische Erd- und Vokerbeschriften 1: 113-131, 1781 160. PARACELSUS. De natura rerum, liber primus de generationibus rerum naturalium . Saemtliche Werke, K Sudhoff (Editor), München, 14 volumes, 1922-1923. Partl y translated in 77 161. PARÉ A. Les oeuvres d'Ambroise Paré etc., Paris, 1561. Partly translated in 77 162. PASTEUR L. Mémoire sur les corpuscles organisés qui existent dans l'atmosphère . Examen de la doctrine des générations spontanées, Société Chimique, Paris, 1861 163. PERRONCITO E. On the tenacity of life of the cysticercus in the flesh of oxen and on the rapid development of the corresponding Taenia mediocanellata in the human body. The Veterinarian 50: 817-818, 1877 164. PLANCK M. Wissenschaftliche Selbstbiographie, Johann Barth, Leipzig, 1955. Partl y translated in 55 165. POUCHET FA. Hétérogonie, Paris, 1859. Partly translated in 31 166. POUCHET, VERRIER. Expériences sur l es migrations des entozoaires. Comptes Rendus Hebdomadaires des Séances de la Académie des Sciences 54: 958-963, 1862. Translated in Quarterly Journal of Microscopical Science 2: 171-175, 1853 167. POWER H, SEDGEWICK LW (Editors). The New Sydenhams Society's lexicon o f medicine and the allied sciences, The New Sydenham Society, London, five volumes , 1881-1894 168. PROMMAS C, DAENGSVANG S. Preliminary report of a study on the life-cycle o f Gnathostoma spinigerum . Journal of Parasitology 22: 180-186, 1936 169. REDI F. Esperienze intorno alla generazione degl'insetti, Carlo Dati, Firenze, pp 177 , 1668. Experiments on the generation of insects, translated from the 1688 edition by M Bigelow, Opencourt Publishing Co., Chicago, pp 160, 1909 170. RHIND W. A treatise on the nature and cure of intestinal worms of the human body , Samuel Highley, London, pp 153, 1829 171. ROSEN F. Recherches expérimentales sur le cycle évolutif du Dibothriocephalus latus . Bulletin de la Société Neuchâteloise des Sciences Naturelles 42: 29-49, 1917. Partl y translated in 84 172. RUDOLPHI CA. Entozoorum sive vermium intestinalium historia naturalis, Treuttel et Würtz, Paris, two volumes, pp 1370, 1808-1810

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173. SCHREIBER. Cited in 25 174. von SIEBOLD CT. Helminthologische Beiträge. Archiv für Naturgeschichte 1: 45-84 , 1835 175. von SIEBOLD CT. Zur Entwicklungsgechichte der Helminthen. In, Die Physiologie als Erfahrungswissenschaft (KF Burdach, editor), 2 Aufl. v. 2, Buch 4, pp 183-213, 1837 176. von SIEBOLD CT. Bericht über die Leistungen im Gebiete der Helminthologie während des Jahres 1842. Archiv für Naturgeschichte 9: 300-335, 1843 177. von SIEBOLD CT. Parasiten. In, Handwörterbuch der Physiologie mit Rücksicht au f physiologische Pathologie, R Wagner (Editor), 2: 650-676, 1844 178. von SIEBOLD CT. Expérience sur la transformation des vers vésiculaires ou cysticerques in taenia. Annales des Sciences Naturelles, series 3, 17: 377-381, 1852 179. von SIEBOLD CT. Ueber die Verwa ndlung des Cysticercus pisiformis in Taenia serrata. Zeitschrift für wissenschaftliche Zoologie 4: 400-408, 1853. Translated in Quarterl y Journal of Microscopical Science 2: 255-263, 1854 180. von SIEBOLD CT. Ueber die Verwan dlung der Echinococcus-brut in Taenien. Zeitschrift für wissenschaftliche Zoologie 4: 409-425, 1853. Partly translated in 84 181. von SIEBOLD CT. Über die Band- und Blasenwürmer nebst einer Einleitung über di e Entstehung der Eingeweidewürmer, W Engelmann, Leipzig, pp 115, 1854. On tape and cystic worms, with an introduction on the origin of intestinal worms, translated by T H Huxley, pp 88; bound with volume 2 of F Küchenmeister's "Manual of parasites", Th e Sydenham Society, London, 1857 182. von SIEBOLD CT. Cited in 112 183. SINGER CT. A history of biology to about the year 1900, Abelard-Schuman, revise d edition, London, pp 580, 1960 184. SPALLANZANI L. Saggio de osservazione microscopiche concernanti il sistema della generazione de' Signori de Needham e Buffon, Modena, 1755. Also; Upuscoli de fisica animale e vegetabile, Modena, 1766 185. SPIGELIUS A. De lumbrico lato liber etc., L Pasquati, Patavii, pp 88, 1618 186. STEENSTRUP JJ. Om Fortplantning og Udvikling gjennem vexlende Generation s Raekker en saeregen Form for Opfostringen i de lavere Dyreklasser, CA Reitzel , Kjøbenhavn, pp 76, 1842. On the alternation of generations, or, the propogation an d development of animals through alternate generations: a peculiar form of fostering th e young in the lower classes of animals, translated by G Busk from the German version of CH Lorenzen, The Ray Society, London, pp 132, 1845 187. von STEIN F. Beiträge zur Entwickelungsgeschichte der Eingeweidewürmer. Zeitschrift für wissenschaftliche Zoologie 4: 196-214, 1852 188. STUNKARD HW. The morphology and life history of the cestode, Bertiella studeri. American Journal of Tropical Medicine 20: 305-333, 1940 189. SWAMMERDAM J. Historia insectorum generalis etc., M van Dreunan, Utrecht, pp 49, 1669. Also; The Book of nature; or the history of insects....illustrated with coppe r plates....with the life of the author by H Boerhaave, translated from the Dutch and Latin original edition by T Flloyd, revised and improved by notes from Reamur and others, by J Hill, London, 1758 190. THOMAS AP. Report on experiments on the development of the liver fluke ( Fasciola hepatica). Journal of the Royal Agricultural Society of England 17: 1-28, 1881 191. THOMAS A P. Second report of experiments on the development of the liver fluk e (Fasciola hepatica). Journal of the Royal Agricultural Society of England 18: 439-455, 1882. Abstracted in British Medical Journal ii: 1001-1002, 1882 192. TUBANGUI MA, PASCO A. The life history of the human intestinal fluke, Euparyphium ilocanum (Garrison, 1908). Philippine Journal of Science 51: 581-603, 1933 193. TURKHUD TA. Report of the Bombay Bacteriological Laboratory for the year 1913 , presented by WG Liston, Government Central Press, pp 14-16, 1914 194. TYSON E. Lumbricus latus, or a discourse read before the Royal Society, of the joynted worm, wherein a great many mistakes of former writers concerning it, are remarked; its

Origin and Migration of Worms

195. 196. 197.

198. 199.

200. 201.

202.

203. 204.

205. 206. 207. 208.

209. 210. 211.

212.

69

natural history from more exact observations is attempted; and the whole urged, as a difficulty against the doctrine of univocal generation. Philosophical Transactions of th e Royal Society 13: 113-144, 1683 TYSON E. The Lumbricus Latus (Abstract). Memoirs of the Philosphical Transactions of the Royal Society pp 122-130. Abstract of 194 la VALETTE de ST. GEORGE A. Symbolae ad trematodorum evolutionis historiam , Berlin, pp 38, 1855 VALLISNERIUS (VALLISNIERI) A. Opera fisico-mediche stampate e manoscritte . Raccolte da Antonio suo figliuolo, S Coleti, Venezia, three volumes, pp 1696, 1733 . Partly translated in 37 VILLANOVANUS (de VILLENEUVE) A. De lumbricus et ascaridibus. In, Opera omnia, Basileae, 1585. Original edition c. 1300. Cited in 37 VIRCHOW R. Die Cellularpathologie in ihrer Begründung auf physiologische un d pathologische Gewebelehre, A Hirschwald, pp 440, Berlin, 1858. 1859. Cellula r pathology as based upon physiological and pathological histology, translated from th e second edition by F Chance, J Churchill, London, pp 511, 1860 VIRCHOW R. Futterungsversuch mit Trichina spiralis. Deutsche Klinik 11: 430, 1859 VIRCHOW R. Recherches sur le développement de la trichina spiralis (Ce ver devien t adulte dans l'intestin du chien). Comptes Rendus Hebdomadaires des Séances d e l'Académie des Sciences 49: 660-662, 1859 VIRCHOW R. Helmintholgische Notizen. 3. Ueber Trichina spiralis. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 18 : 330-345, 1860. Abstracted in British and Foreign Medico-Chirurgical Review 26 : 515-516, 1860 VOGEL H. Der Entwicklungszyklus von Opisthorchis felineus (Riv.) nebst Bemerkungen über Systematick und Epidemiologie. Zoologica 33: 1-103, 1934 WAGENER H. Beiträge zur Entwickelungs-Geschichte der Eingeweidewürmer . Naturkundige Verhandelingen van de Hollandsche Maatschapij der Weteschappen t e Haarlem, pp 112, 1857 WARREN K S. Schistosomiasis: the evolution of a medical literature. M.I.T. Press , Cambridge, Mass., pp 1307, 1973 WILMS. Anchylostoma duodenale und Angullula intestinalis . Schmidt's Jahrbücher der in-und ausländischen gesammten Medicin 256: 272, 1897 WOTTON E. Edoardi Wuottoni Oxoniensis, De differentiis animalium, Lutetia e Parisiorum, 1552 WYKOFF DE, HARINASUTA C, JUTTIJUDATA P, WINN MM. Opisthorchis viverrini in Thailand - the life cycle and comparison with O. felineus, Journal of Parasitology 51: 207-214, 1965 YOKOGAWA S. (A new parasite involving trout as its intermediate host and its ne w generic name.) Okayama Igakkai Zasshi No. 279, 1912. In Japanese YOKOGAWA S. (Schistosoma japonicum in Formosa, especially on its intermediat e host.). Taiwan Igakkai Zasshi 149: 178-183, 1915. In Japanese. Abstracted in 205 YOKOGAWA S. (Paragonimus ringeri . Study of stages from the crab and points o f difference distinguishing it from similar cysts occurring there.) Taiwan Igakukai Zasshi No. 175, pp 298-307, 1917. In Japanese. Abstracted in Tropical Diseases Bulletin 12 : 173-174, 1918 ZENKER FA. Ueber die trichinen-Krankheit des Menschen. Archiv für pathologisch e Anatomie und Physiologie und für klinische Medicin (Virchow) 18: 561-572, 1860 . Translated in 84

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Table 2.1. Landmarks in the understanding of the origin and transmission of worms ___________________________________________________________________ BC 1668

1673 1698 1700

1750+ 1766 1780

1781 1787

1790 c.1800 1810-19 1817 1818 1819 1831 1835 1835 1837 1842

1851 1851 1852 1853

The spontaneous generation of certain animals was generally accepted Redi showed by experiment that maggots in rotten meat developed not b y spontaneous generation but from eggs deposited by flies. He conceded, however, that intestinal worms may be generated spontaneously Leeuwenhoek began to publish the results of his observations using a microscope of the microbiological world Bidloo discovered eggs of Fasciola Andry in his textbook declared that all parasitic worms were bred by means of a "seed" introduced from the external envi ronment. He believed that he had observed the eggs of tapeworms Buffon and Needham defended staunchly the theory of spontaneous generation Spallanzani showed that heated, sealed infusions were sterile and concluded that "animalcules" were carried in by the air The Royal Academy of Science in Copenhagen set a prize essay on "The origins of parasitic worms". First and second prizes were won by Bloch and Goeze , respectively, both of whom believed in spontaneous generation. Pallas injected Dipylidium caninum eggs into the abdominal cavity of a dog and concluded erroneously that they developed into adult worms Linnaeus believed incorrectly that certain specific, parasitic worms develope d from morphologically similar, immature free-living helminths that were ingested in food and water. The principle, however, was correct Abildgaard fed stickleback fis h containing immature cestodes to a duck and found them living in the gut three days later The discovery that many cysts were verminous in nature yet had no reproductive organs seemed to support the idea of spontaneous generation Rudolphi (1810) and Bremser (1819) in their textbooks of helmintholog y continued to support the theory of spontaneous generation Nitzsch noticed the resemblance between cercariae and flukes, and discerned the encystation of cercariae Bojanus discovered that cercariae w ere generated within organisms (rediae) within snails Chamisso described the alternation of generations of marine animals belonging to the family, Salpae Mehlis observed larvae (miracidia) hatch from fluke eggs von Siebold observed rediae released from disintegrating miracidia in water von Siebold discovered larvae with hooklets within tapeworm eggs von Siebold found that certain cercariae encysted inside snails Steenstrup published his book on the "Alternation of Generations" in which h e proposed a unifying hypothesis to explain the life cycles of certain trematodes and other organisms Herbst found Trichinella spiralis larvae in dog muscles after feeding them with infected badger flesh Küchenmeister fed Cysticercus pisiformis of the rabbit to foxes and recovere d adult tapeworms (Taenia pisiformis ) from the gut Küchenmeister gave Cysticercus fasciolaris of mice to a cat and recovered adult tapeworms (Taenia taeniaeformis ) Küchenmeister reared adult tapeworms in dogs fed with cystic worms from sheep: Taenia hydatigera from Cysticercus tenuicollis and T. multiceps from Coenurus cerebralis

Origin and Migration of Worms 1853 1854 1855 1855 1855

1857 1857+ 1859 1860

1860

1861 1862 1865 1867 1870 1870 1877 1877 1881 1881-3

1886 1886 1887 1889 1892

71

von Siebold discovered Echinococcus granulosus adult worms in the intestines of dogs after feeding hydatid cysts to them van Beneden generated Cysticercus cellulosae by feeding Taenia solium eggs to pigs Küchenmeister reported the recovery of immature Taenia solium after feeding Cysticercus cellulosae shortly before execution to a condemned murderer Humbert ingested Cycsticercus cellulosae and three months later began to pas s Taenia solium proglottids in his stools la Valette de St. George showed that certain encysted cercariae but no t non-encysted cercariae developed into adult flukes when ingested by birds o r animals Wagener witnessed the metamorphosis of Distoma cygnoides miracidia into rediae in snails Pasteur showed that a bacterial ferment soured milk and that yeasts or mould s were necessary for the making of wine from grapes Virchow discovered adult Trichinella spiralis in the gut of a dog after feeding it with trichinous meat Zenker discovered adult Trichinella spiralis in the bowel at the post-morte m examination of a young woman who had died of a typhoidal illness after recently eating trichinous pork Küchenmeister repeated his experime nt on a condemned murderer. The incubation period was several months and this time he recovered Taenia solium tapeworms up to 1.5 m long Pasteur showed that air contained bacteria which caused putrefaction in steril e infusions Leuckart fed Taenia saginata proglottids to calves and generated Cysticercus bovis Leuckart and his students swallo wed Enterobius vermicularis eggs and developed patent infections Leuckart generated hydatid cysts in pigs after feeding them with Echinococcus granulosus ova Oliver may have produced a patent Taenia saginata infection in a human afte r feeding Cysticercus bovis to a man Fedchenko reported that Dracunculus medinensis larvae developed with the body of Cyclops (crustacean) Perroncito recovered an adult Taenia saginata from a human 4 months afte r ingestion of Cysticercus bovis Manson discovered that Wuchereria bancrofti microfilariae metamorphosed i n certain mosquitoes Thomas and Leuckart independently discovered that Lymnaea snails were the intermediate hosts of Fasciola hepatica Braun showed that certain freshwater fish were the second intermediate hosts of Diphyllobothrium latum by feeding infected fish to dogs and humans the n recovering adult worms Calandruccio produced a patent infection with Trichuris trichiura in himself after swallowing eggs Leichtenstern produced patent infections with hookworm in humans afte r administering infective larvae orally Grassi showed that Hymenolepis nana could be transmitted directly from on e definitive host to another Grassi and Rovelli reported that Dipylidium caninum larvae developed in fleas Grassi and Rovelli showed that Hymenolepis diminuta developed in a variety of arthropod intermediate hosts

72 1892 1897 1898 1900 1901 1901-2 1907 1909 1911 1911 1911 1913 1913

1913 1914 1914 1915 1915

1916 1917 1917 1917 1917-19

1918 1921 1922 1922

A History of Human Helminthology Lutz fed Fasciola cysts to guinea pigs then recovered adult flukes Wilms infected a human by administering Strongyloides stercoralis larvae orally Looss first claimed that hookworm infective larvae penetrated the intact skin Low reported thatWuchereria bancrofti infective larvae were found in th e mouthparts of mosquitoes that had been filariated by Thomas Bancroft Looss showed by histological examination of an amputated leg that hookwor m larvae applied before amputation penetrated the skin van Durme showed that Strongyloides larvae penetrated the skin Leiper recovered immature Dracunculus medinensis from a monkey 6 month s after feeding it water containing infected Cyclops Fujinami and Nakamura demonstrated that Schistosoma japonicum infection in cows was acquired via the skin Looss reported the development of a patent hookworm infection 71 days afte r percutaneous infection of a human Yokogawa discovered that trout were the second intermediate hosts o f Metagonimus yokogawai Kobayashi recovered adult Clonorchis sinensis from the biliary system of cat s after feeding them with fish infected with certain encysted, immature flukes Leiper reported that tabanid flies ( Chrysops) were the vectors of Loa loa Miyairi and Suzuki discovered that Oncomelania snails were the intermediat e hosts of Schistosoma japonicum , described the larval stages of the parasite, and recovered adult worms from mice infected percutaneously with cercariae released from these snails One out of five persons given infected Cyclops to drink by Turkhud develope d dracunculiasis one year later Fülleborn showed that Strongyloides stercoralis larvae applied to the ski n developed into adult worms in the gut of dogs Nakagawa showed that crabs of the genus Potamon were the second intermediate hosts of Paragonimus westermani Onji and Nishio found that certain fishes were the second intermediate hosts o f Heterophyes heterophyes Leiper and colleagues showed that miracidia from terminal-spined egg s (Schistosoma haematobium) developed in Bulinus snails, described the intermediate stages, then recovered adult worms after infecting mic e percutaneously with cercariae obtained from these mice Leiper proved that miracidia derived from lateral-spined eggs developed i n Biomphalaria snails and were a different species ( S. mansoni) Muto reported that Semisulcospira snails were the first intermediate hosts o f Metagonimus Ciurea discovered that certain fishes were the second intermediate hosts o f Opisthorchis felineus Janicki and Rosen discovered that certain crustaceans ( Cyclops) were the first intermediate hosts of Diphyllobothrium latum Ando, Kobayashi, Miyairi, Nakagawa and Y okogawa all concluded independently that Melania (= Semisulcospira) snails were the first intermediate hosts o f Paragonimus Muto showed that Bithynia (= Parafossarulus) snails were the primar y intermediate hosts of C. sinensis Nakagawa reported that Segmentina snails were the first intermediate hosts o f Fasciolopsis buski Nakagawa showed that Fasciolopsis cercariae escaped from the snails an d encysted on grass, then fed them to dogs and recovered adult worms Connal and Connal provided detailed descriptions of the development of Loa loa

Origin and Migration of Worms 1926 1927 1928 1931 1933 1934 1936 1949 1952 1953 1955 1966 1968 1971 1972 1975 1979

73

in Chrysops Blacklock discovered that Simulium blackflies were the vectors of Onchocerca volvulus Dyce Sharp showed that Culicoides midges were the vectors of Mansonella perstans Asada described the snail intermediate host of Heterophyes heterophyes Cameron observed that certain snails were intermediate hosts of Dicrocoelium dendriticum Buckley found that Culicoides was the vector of Mansonella ozzardi Vogel found that Bithynia snails were the first intermediate hosts of Opisthorchis felineus Prommas and Daengsvang described the first and second intermediate hosts o f Gnathostoma spinigerum Chardome and Peel showed that Culicoides was the vector of Mansonella streptocerca Krull and Mapes showed that Dicrocoelium dendriticum larvae encysted in certain ants Edeson and his colleagues infected a human with Brugia pahangi using Mansonia mosquitoes Mackerras and Sandars reported that slugs were the intermediate hosts o f Angiostrongylus cantonensis Wykoff and colleagues described the first and second intermediate hosts o f Opisthorchis viverrini Orihel and Pachecho produced patent infections in monkeys with B. malayi Morera and Ash described the slug vector of Angiostrongylus costaricensis Cross and his colleagues found that Capillaria philippinensis infection was acquired by ingesting infected fish Orihel and Moore transmitted Loa loa to subhuman primates Cross and his colleagues successfully infected monkeys with Wuchereria bancrofti

___________________________________________________________________

74

A History of Human Helminthology

Chapter 3

THE DISCOVERY AND DEVELOPMENT OF ANTHELMINTICS

TRADITIONAL REMEDIES Men have undoubtedly tried to rid themselves of worms infecting their bodies for almost as long as they have recognized them. As discussed elsewhere in this book, only a very small number of parasitic helminths were known during most of recorded history. These were certain visible worms that enjoyed a wide geographical distribution and were extruded from time to time from the gastrointestinal tract, i.e. tapeworm proglottids or segments (Taenia and Diphyllobothrium species), the common roundworm (Ascaris lumbricoides) and the pinworm or threadworm (Enterobius vermicularis). In addition, Guinea worm (Dracunculus medinensis) was found in certain restricted localities but its verminous nature was a matter of some controversy. Most attention, therefore, was paid to the common intestinal worms. Plants were the major therapeutic sources. Herbal products that were believed to have specific vermicidal or vermifugal properties were often combined with purgatives (to flush the worms out) and various sweeteners or diluents. In the Egyptian Papyrus Ebers (c.1500 BC), for example, castor oil and senna were recommended as purgatives and anthelmintics were often administered together with honey, sweet beer or dates126. While it is true that certain preparations did have some therapeutic efficacy, the coincident, spontaneous passage of senescent worms often led to anthelmintic properties being ascribed erroneously to many concoctions. The development of herbal products depended upon the local botanical flora with the result that different remedies tended to develop in different parts of the world. Nevertheless, in some instances, the same or related plants were used over wide geographical areas. Thus, the pomegranate (Punica granatum) was utilized in countries ranging from Egypt to China. For convenience, however, major traditional remedies are reviewed in relation to different regions of the globe.

THE MEDITERRANEAN REGION Many different anthelmintics were used in the countries abutting the Mediterranean Sea in the centuries before the birth of Christ. The Egyptian 75

76

A History of Human Helminthology

Papyrus Ebers (c.1500 BC) mentions various purgatives such as castor oil, colocynth and senna as well as specific vermifuges such as pomegranate 126. Clay tablets found in the library of Asur-bani-pal (c.650 BC) in Assyria refer to mint, coriander seeds, onion, colocynth, myrrh, turpentine, pomegranate and cassia as anthelmintics79. These agents, as well as extracts of Artemisia, acacia gum, anise seed, fennel, garlic, mulberry, olive oil, pepper, scammony seed, spearmint and male fern root found their way into the materia medica of ancient Greece and Rome. Extraordinarily complicated combinations of drugs and directions for their administration were evolved. Thus, Celsus (c.25 AD) wrote: For the flat worms, there should be given as draughts, a decoction of lupins, or of mulberry bark, to which may be added, after pounding, either hyssop or a vinegar cupful of pepper, or a little scammony. Alternatively, on one day let him eat a quantity of garlic and vomit, then on the next day take a handful of fine pomegranate roots, crush them and boil them in a litre and a half of water down to one-third, to this add a little soda, and drink it on an empty stomach. At three hours interval, let him take two further draughts; but with the addition of half a pint of sea water or strong brine; then on going to stool, sit over a basin of hot water. Again, for the roundworms...., both the same remedies may be given and some milder ones, such as pounded-up seeds of nettles or of cabbage or of cummin in water, or mint in the same of a decoction of worm-wood or hyssop in hydromel or cress-seeds pounded up in vinegar. It is also of service either to eat lupin or garlic, or administer into the lower bowel a clyster of olive oil.28

Many of these drugs maintained their popularity over the next two thousand years. Pomegranate The roots or bark of the pomegranate (Punica granatum) have been used as an anthelmintic for millenia. Perhaps the earliest record is in the Egyptian Papyrus Ebers: to kill roundworm: root of pomegranate 5 ro (1 ro = 15 ml), water 10 ro, remains during the night in the dew, is strained and taken in one day.126

Pomegranate continued to be popular with the physicians of ancient Greece and Rome for the treatment of both roundworm and tapeworm infections and was still being recommended around 1,000 AD by the Arabian, Avicenna6. Nevertheless, pomegranate bark was little valued in northern Europe until the beginning of the nineteenth century when the Englishman, Buchanan, introduced it from the the East Indies. The alkaloid, pelleterine, was isolated as the active principle26 and pomegranate decoctions remained a standard remedy until well into the twentieth century. Male fern (filix mas, oleoresin of Aspidium) Male fern, otherwise known as filix mas or oleoresin of aspidium, is derived

Anthelmintics

77

from the powdered rhizomes of Dryoptera filix mas. These plants are spread widely throughout the northern hemisphere. The efficacy of this extract in the treatment of tapeworm infections was recorded long ago by the Greek, Theophrastus of Eresus (370-c.285 BC) who wrote: Of male fern, no part but the root is useful and it has a sweet astringent taste. It expels the flat worm. It has no seed nor juice; and they say it is ripe for cutting in the autumn.165

Likewise, the Roman, Pliny (23-79 AD), recommended powdered root of male fern as an anthelmintic24. Filix mas has maintained its popularity in one form or another for centuries. One classic example of its use was as the major constituent of Madame Nouffer's "Tapeworm Cure" in the late eighteenth century. The French king, Louis XVI, was somewhat peeved to find this in 1776 after he had handed over 18,000 francs for the formula. Madame Nouffer's technique was described by Davaine46. Three drachms of the pulverized root in four ounces of infusion were administered followed by a bolus of calomel, scammony and gamboge after two hours. When vomiting occurred, the remedy was repeated and strong coffee was given to prevent sickness. If the worm was not fully expelled in four hours, an ounce of magnesium sulphate in warm water was then drunk. The general practice was to collect rhizomes of the plant in autumn, free them from roots and dead parts, then soak them in ether for 48 hours. This was then filtered out, leaving a dry, oily residue, oil of aspidium. Male fern was added to the British Pharmacopoeia in 1863. Beginning with the work of Boehm in 1897 14 , a number of phloroglucinol compounds have been isolated as active principles. The major anthelmintic constituent is filicic acid (= filicin)26. Male fern remained popular in the treatment of tapeworm infections until more effective and less toxic drugs became available in the middle of the twentieth century. Semen-contra-vermes (Santonin) Semen-contra-vermes (semen against worms) is so-named because of its fancied resemblance to semen. It consists of the dried, unexpanded flower heads obtained from several species of the genus Artemisia (= Santonica), especially A. cina. It was mentioned by the Roman, Dioscurides Anazarbeus, in the first century AD as being indicated for the treatment of ascariasis and enterobiasis 50. It remained popular for centuries and was mentioned by Avicenna (980-1036) 6. According to Davaine in 186046, it was most effective against Ascaris, moderately active against tapeworms, and less efficacious against Enterobius. Semen-contra-vermes was added to the British Pharmacopoeia in 1863. The active principle is santonin, a sesquiterpene lactone27. The drug was abandoned in the early twentieth century when more effective and less toxic agents became available.

78

A History of Human Helminthology

Chrysanthemum Flowers of Chrysanthemum have been used for centuries as anthelmintics. The active constituents of pyrethrum powder obtained from these plants are pyrethrins; these substances are also powerful insecticides. Modern studies have given conflicting reports on the effectiveness of pyrethrins against cestodes26 and there is some evidence that they are partially active against intestinal nematodes27. Tin Metallic tin has been used to treat tapeworm infections for centuries. Their use was praised by Paracelsus (1493-1541) 127 and tin filings were commonly prescribed until the first half of the nineteenth century. This was somewhat dangerous, however, as tin preparations often contained traces of lead or arsenic that led to poisoning. "Cestodin", a combination of metallic tin, tin oxide and tin chloride was used until recent years.

AFRICA Anthelmintics used traditionally by people living along the Mediterranean littoral have been described earlier. Little is known of practices in Africa south of the Sahara. An important remedy in northeastern Africa, however, was kousso. Kousso (kosso) Tapeworm infections have been particularly common for many years among people living in Ethiopia as a result of the habit of eating raw beef. Consequently, there was also considerable interest in that country in developing taenicides. The most popular of these was kousso which was derived from the blood-red flowers and seeds of the tree Hagenia abyssinica (= Banksia abyssinica = Brayera anthelmintica). One of the earliest records of its use is the indication by a sixteenth century monk that Bitole, the fourth Golla chief, adopted the habit of taking it during his term of office from 1546-1554 124. The drug attracted the attention of Spanish and Portuguese Jesuit missionaries in the early seventeenth century. They observed that it was prepared by steeping a handful of seeds of flowers in two quarts of beer all night then the bitter potion was drunk in the morning. Little interest in this preparation was shown in Europe, however, until the Frenchman, Dr Brayer, publicized its effectiveness in the 1820's125. In 1845, his compatriot, Rochet d'Héricourt brought enough drug for 40,000 doses to Paris. Its effectiveness was confirmed by several French medical authorities and it became popular not only in France but also in

Anthelmintics

79

Britain. A major problem initially was its expense but, with increasing availability, its price fell. Kousso was finally given a place in the British Pharmacopoeia in 1863. The active principles were identified as phloroglucinol derivatives, kosin and kosotoxin, related to filicic acid of male fern26. Its popularity waned in Europe in the latter part of the nineteenth century but it is still widely used in Ethiopia today.

ASIA As in the West, herbal remedies were popular in the Orient. Traditional anthelmintics still in use in India at the beginning of the present century were derived from the leaves of Clerodendrum infortunatum, fruits of Embelia ribes, juice of the leaves or the head of the wild date palm (Phoenix dactylifera, and from the leaves of Costus speciosus as well as the root of the pomegranate (Punica granatum). Likewise in China, there was little change in the products used over a period of 2,000 years78. The most popular plants were "Lei-wan" (Mylitta lapidescens), "Ho-shih" (Carpesium abrotanoides), "Shih-chun-tze" (Quisqualis indica), "Ping-lang" (Areca catechu = betel nut), "Shih-liu-p'i" (Punica indica = pomegranate) and Mallotus philippinensis (= kamala). In addition, a number of substances of mineral and animal origin were used. Among the former were included sulphur, lead, tin, mercury and arsenic. Animal products with supposed vermifugal properties included chicken faeces, pig's blood, ash of human hair, baked toad and snake skin. Several examples of Chinese anthelmintic prescriptions are listed below. a. For Ascaris: Han period (c.220 AD): "Decoct 2 liang (1 liang = 36 gram) of Kan-ts'ao (= Glycyrrhiza glabra) in 3 sheng (1 sheng = 1 litre) of water until 2 sheng of the fluid is left. Then discard the sedimented particles and add to the fluid 1 liang Fen (lead carbonate) and 4 liang Mi (honey). Stir thoroughly and decoct the mixture again to a solution like congee, 1 sheng of which taken warm, will effect an immediate cure."30 b. For Enterobius: T'ang dynasty (c.650 AD): "Take one ball of human hair about the size of an egg burned into ashes. Mix the above, after sifting, with bitter wine, and take the entire solution after rising in the morning."159 c. For tapeworm: T'ang dynasty (c. 752 AD): "Suan-shih-liu-ken, root of Punica granatum (pomegranate) one handful of its branches directing eastwards, 3 liang Wu-i (Ulmus macrocarpa) and one half liang powdered Ch'ien-niu-tzu seed (Ipomoea hederacea). Decoct the first two drugs in 6 sheng of water. Then filter and divide the total solution into three equal parts. Admix the powder of the seed of Ipomoea when the drug is to be taken. Take successive doses at intervals equal to the time required for a five-li walk. All the worms will be killed and passed out.176

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Betel nut (Areca) Betel nuts are seeds of the palm, Areca catechu, which is widespread in southern and eastern Asia. According to Liu102, the chewing of betel nut has been practised for at least 1400 years and has built up a reputation as a taeniafuge. It may also be administered in the form of a decoction obtained from the dried, powdered nut. Such a technique is described by Sun Szu-Miao in the T'ang dynasty (c.650 AD): Grind 14 pieces of Ping-lang (Areca catechu) into powder and sift. Then boil the shells of Ping-lang in 2.5 sheng of water until half a sheng of the liquid is left. After filtration, put the powder into the liquid. Drink the solution from time to time and lie in bed and keep warm. The worms will come out.159

The active principle is the alkaloid, arecoline26. Kamala Kamala is a resin derived from the glands and hairs covering the fruits of Mallotus philippinensis (= Rotteria tinctoria) which is widespread in Asia and has been used as a folk remedy for centuries. It became popular in Europe for the treatment of tapeworm in the nineteenth century and was entered into the British Pharmacopoeia in 1863, decoctions being prepared in alcohol. Like male fern and kousso, the active constituents are ploroglucodins such as rottlerine which paralyse the cestodes26. Its popularity waned with the appearance of more efficient agents in the twentieth century.

THE AMERICAS A number of plants have been held in some traditional regard as vermifuges. These include a legume (Mucuna pruriens), the cebadilla (Spigelia anthelmintica) in tropical America as well as Fucus helmintocorton, a seaweed from the west of Argentina78. The most important American plant products, however, were pumpkin seeds, oil of chenopodium and leche de higueron. Pumpkin seeds Pumpkin seeds, particularly Cucurbita pepo, have been used in tropical America for centuries as a treatment for tapeworm infections. From there, the popularity of this remedy spread to Europe. Tyson in England, for example, recommended consumption of pumpkin seeds for taeniasis in 1683171. The seeds were generally minced into a paste and swallowed. The active component, cucurbitine, has been isolated and identified as an amino acid, 3-amino-3-carboxy pyrrolidin26.

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Oil of chenopodium The most widely used indigenous plant anthelmintic from the Americas is oil of chenopodium derived from Chenopodium ambrosioides, popularly known as American wormseed, Mexican teak, Jerusalem oak and "epazote" or "paico"89. This aromatic herb is found as an annual weed in locations varying from Argentina in the south to Canada in the north. Archaeological and ethnological studies suggest that it has been used for many centuries. Wild plants have been found growing in association with long-abandoned Pueblo ruins while the pre-Columbian Maya of Yucatan in Mexico called it "lucum xiu" meaning "worm-plant"139. The plant was illustrated in a sixteenth century codex concerned with the Aztecs49. In the early eighteenth century, Peter Kalm (1715-1779), a Swedish botanist and traveller, reported that it was used by both the indigenous inhabitants as well as European settlers in the American colonies for the treatment of Ascaris 83. In 1723, plants were taken to Europe, cultivated widely, and were soon in common use. The leaves, seeds and flowering tops have all been used to produce decoctions. The extracted oil of chenopodium, usually prepared by boiling, became the common form of the drug throughout the nineteenth century and during the first half of the twentieth century. The active principle, ascaridol, a volatile terpene, was isolated and eventually synthesized 27. Although Baumler (1881) and Breton (1905) in the United States of America had tried oil of chenopodium without success in ancylostomiasis, Bruning began to use it successfully in 190917 then this was confirmed by Schüffner152. In view of its easy availability and cheapness, oil of chenopodium was employed with considerable success by the Rockefeller Foundation in hookworm campaigns in the Dutch East Indies (Indonesia), Malaya (Malaysia) and Fiji in the 1920's and then in Brazil in the 1930's. Toxic reactions including gastrointestinal upsets, headache, deafness, tachycardia and rarely death were recognized with increasing frequency, however, and this together with the development of other safe, effective anthelmintics led to its official abandonment. Moreover, a recent study of traditional village use of Chenopodium extracts has cast doubts on its efficacy89. Nevertheless, it continues to be used by millions of urban and rural people in the third world for the treatment of intestinal worm infections. Leche de higueron The inhabitants of equatorial South America and Central America have long used the sap of the figs, Ficus glabrata and F. laurifolia, as an anthelmintic. The milky fluid (latex) has been called leche de higueron or lait d'higueron. Wucherer remarked in 1866 that it was effective in the treatment of hookworm infection180 then in 1912 Berrio reported that it was useful for trichuriasis 12. The active principle, ficin, is a protease related to papain27.

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Table 3.1. Major anthelmintics listed by Rudolphi140 ____________________________________________________________________ Mechanical irritants Stannum purum et granulatum (tin) Purgatives Salina, Glaubers, ammonia etc. (Glaubers' salts etc) Olea expressa Olea ricina (castor oil from Ricinus species) Oleum nucum Scammoneum (scammony from Convolvulus scammonia) Helleborum (hellebore from Helleborus species) True anthelmintics Stizolobium (from cowhage, Macuna pruriens) Aqua frigida (ice water) Oleum Chaberti (Chabert's oil) Oleum animali Dippelis Oleum terebinthicae (turpentine from Pistacia terebinthus) Petroleum Oleum cajeputi (from Melaleuca) Camphora (from Camphora officinarum = Laurus camphora) Artemisiae judaicae sive cinae semen (semen-contra-vermes) Tanaceti vulgaris semina Helminthocorton Goeffroeae surinamensis cortex (bark of Geoffroea surinamensis) Polypodii (Aspidii) filicis maris radix (root of male fern) Spigelias ____________________________________________________________________

NINETEENTH CENTURY When Clericus in Geneva reviewed human helminthology in his book in 1715, he tabulated the substances believed to have an anthelmintic action that were known in Europe at that time36. Of these, 379 were vegetable in origin, 27 were derived from animal products, and 13 were minerals. Those that were considered to be of greatest value were listed by Rudolphi at the beginning of the nineteenth century (Table 3.1). He divided these agents into three groups "purgatives" which expelled helminths from the gut by increasing intestinal secretions and stimulating peristalsis, "mechanical irritants" which were supposed to cause the worms to relax their hold upon the gut mucosa so that they could be expelled more readily by purgatives, and "true vermifuges" which poisoned the parasite. Those substances that really were important anthelmintics are all traditional remedies and have been described already.

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FIRST QUARTER OF THE TWENTIETH CENTURY One major advance in the chemotherapy of helminth infections was made during the first quarter of the twentieth century. This was the discovery that antimony compounds when administered intravenously were effective in the treatment of schistosomiasis. In addition, a number of other compounds with some anthelmintic efficacy were described. Antimonials In 1918, Christopherson reported that the antimony compound, tartar emetic (antimony tartaratum, potssium antimony tartrate) was extremely effective in human infections with Schistosoma haematobium and S. mansoni 31. His serendipitous discovery of the use of this drug for schistosomiasis while treating a patient with kala azar is detailed in chapter 8. Pentavalent antimonials were found to be ineffective in schistosomiasis but a number of trivalent organic antimony compounds including sodium antimony tartrate, stibophen (fouadin), lithium antimony thiomalate (anthiomaline), sodium antimony gluconate (triostam) and sodium antimony dimercaptosuccinate (stibocaptate, astiban), were developed. The relative advantages and efficacies of these compounds are discussed further in chapter 8. Antimony therapy of schistosomiasis was taken up enthusiastically and, despite some toxicity, remained the cornerstone of treatment for these infections for the next forty to fifty years. Betanaphthol Betanaphthol is a synthetic naphthalene derivative which was first used as a treatment for hookworm by Bentley in 190411. Its side-effects, particularly in causing haemolysis and renal damage, led to its falling into disfavour. Bismuth Bismuth carbonate was used by Loeper in 1921 for the treatment of enterobiasis but did not enjoy wide favour104. Carbon tetrachloride In 1921, Hall reported that carbon tetrachloride was a useful anthelmintic in animals with intestinal nematode infections70. Having swallowed some himself without ill-effect, he suggested its use in the treatment of human hookworm infection71. The effectiveness of this drug in ancylostomiasis was soon confirmed7,99 and it was also reported to be useful in tapeworm infections143 . Doubts soon arose about its toxicity when a number of people died of liver

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failure158, however, and it fell rapidly into disuse.

SECOND QUARTER OF THE TWENTIETH CENTURY The pace of discovery quickened considerably during the second quarter of the twentieth century. These drugs influenced many helminth infections and ranged from the introduction of tetrachlorethylene in the treatment of hookworm infection to the use of lucanthone for the therapy of schistosomiasis and diethylcarbamazine for filariasis. Arsenicals Arsenical compounds were introduced by Erlich for the treatment of trypanosomiasis and syphilis at the dawn of the twentieth century. In 1905, Blair had claimed that sodium arsenite produced clinical improvement in dogs with heartworm infection but produced no supporting parasitological details. Neoarsphenamine was soon tried in bancroftian filariasis with disappointing results. In 1940, Hawking noted that phenyl arsenoxide derivatives were microfilaricidal in vitro but little attention was paid to this observation because of the distractions of war74. A few years later, Otto and Maren noticed an action of arsenicals against both adult worms and microfilariae of Litomosoides 121 and Dirofilaria immitis 122. The most effective preparations were arsenamide and several melarsen derivatives. Arsenamide (thiacetarsamide) was used in humans infected with Wuchereria bancrofti 166 amd Onchocerca volvulus 122. Melarsenoxide was used against W. bancrofti by Culbertson 41 and found to be moderately effective but dangerous. A soluble derivative, melarsenoxide potassium dimercaptosuccinate (Mel W) was also tried in bancroftian filariasis106 and onchocerciasis 62 a few years later. Unfortunately, these drugs may be highly toxic, particularly to the liver, kidney and brain. They therefore fell into disrepute for the treatment of filarial diseases since these conditions, although they may produce significant morbidity, rarely cause death. For similar reasons, arsenicals have been little used in intestinal nematode infections although acetarsol was employed in enterobiasis by Perrin in 1927132 and diphetarsone was tried in trichuriasis by Junod83. Cashew nut oil (oil of anacardium) Cashew nut oil is obtained from Anacardium occidentale, a tree indigenous to tropical America. The oil was shown to be effective in canine ancylostomiasis then was used with some effect in human hookworm infection53.

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Chloroquine Chloroquine was introduced in the 1940's as an antimalarial agent. In 1949, Basnuevo used it with some success in patients with fascioliasis 9. Subsequently, Chung and colleagues claimed some value for the drug in the treatment of paragonimiasis 32 while others believed it had a place in the management of opisthorchiasis 142. Diethylcarbamazine In 1947, Hewitt and his colleagues showed that the piperazine derivative, diethylcarbamazine, was active against Litomosoides carinii in cotton rats and against Dirofilaria immitis in dogs76. This anthelmintic was the result of a research programme initiated because of the large number of American veterans who had acquired filariasis during World War II. Later in the same year, Santiago-Stevenson described the use of diethylcarbamazine in humans with bancroftian filariasis and noted that it produced a dramatic fall in the numbers of circulating microfilariae144. Subsequent observations, however, revealed that these effects were not sustained. Within a year or two, a number of investigators reported that diethylcarbamazine produced some clinical improvement in patients with loiasis154,156. The majority of these patients did not have microfilaraemia, however, and it took some little time for it to become clear that the reduction in microfilaraemia was transient. Likewise, the effects of diethylcarbamazine in onchocerciasis were soon examined. In 1948, Mazzotti and Hewitt found some reduction in the numbers of microfilariae in the skin after diethylcarbamazine treatment but observed living adult worms in extirpated nodules113. Mazzotti then noted that microfilarial numbers in the skin built up again to pre-treatment levels over the next few months112. In contrast to all of these conditions, Danaraj in 1958 observed that the ill-defined filarial infection, tropical pulmonary eosinophilia, responded dramatically and permanently to diethylcarbamazine treatment45. Although diethylcarbamazine has been used primarily in filarial infections, it has also been used for the treatment of gastrointestinal nematode infections. Hewitt and colleagues in 1948 observed that it was effective in canine ascariasis77 then in the following year Oliver-Gonzalez and others showed that it was reasonably effective in humans infected with Ascaris lumbricoides 120. While diethylcarbamazine was thought to be moderately valuable in ancylostomiasis 44, it was noted to be ineffective in enterobiasis 105. Gentian violet and related dye-stuffs Gentian violet is a dye-stuff composed of a mixture of variable proportions of the tetra-, para- and hexylmethyl derivatives of rosaniline. Kudiche showed in 1925 that the related compounds, crystal violet and fuchsin, killed Strongyloides

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stercoralis infective larvae in vitro 91. In 1928, de Langen reported that oral administration of gentian violet in conjunction with intravenous injection of tartar emetic was effective in strongyloidiasis 97 but in the following year he acknowledged that his patients had relapsed98. Faust, on the basis of experiments in monkeys, believed that adult worms were killed in situ 56 then in 1932 claimed that 95% of patients were cured by oral gentian violet57. Palmer123 gave gentian violet by slow intravenous injection in this condition then Schreiber 151 extolled its value when given by duodenal intubation. Nevertheless, the preponderance of opinion was that the drug was of little value in the treatment of strongyloidiasis. Wright and Bray in 1938 used gentian violet for the treatment of enterobiasis179 but much more effective drugs are now available. Hexylresorcinol Hexylresorcinol is a phenol which was shown by Lamson and his colleagues in 1931 to be effective in the treatment of ascariasis 95. Shortly afterwards, Maplestone and Mukerji reported that it was active againt Taenia saginata 110. It then became the treatment of choice for hymenolepiasis until recent times. Likewise, hexylresorcinol has been used in fluke infections such as fasciolopsiasis108. Lucanthone and hycanthone Lucanthone (miracil D, nilodin) was the first schistosomicidal drug which was metal-free and orally active. Its efficacy in experimental schistosomiasis was first shown by Kikuth and colleagues during World War II2 then this was reported several years later88. Experimental and clinical studies indicated that it was most active against Schistosoma haematobium, less active against S. mansoni and had little effect on S. japonicum. It was shown eventually by Rosi and co-workers that the active form was an hydroxymethyl derivative now known as hycanthone138. This drug was then used clinically as hycanthone methanesulphonate (etrenol)35. Concern was expressed about possible mutagenic effects, however, and it was eventually replaced by more effective and less toxic agents. Mepacrine (quinacrine, atebrin, atabrine) Mepacrine was originally synthesized as an antimalarial compound in 1932. In 1939, Neghme reported that it was useful in the treatment of Taenia saginata and T. solium infections118. Ruikka showed in 1951 that it was also effective in diphyllobothriasis 141. Mepacrine became a very popular treatment for tapeworm infections until the introduction of niclosamide.

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Phenothiazine The anthelmintic properties of phenothiazine were first recognized by Harwood and colleagues who reported in 1938 that it eliminated ascarids from the intestines of swine73. Manson-Bahr then showed in 1940 that it was effective in humans infected with Enterobius vermicularis 109. However, less toxic agents soon became available for the treatment of intestinal nematode infections. Piperazine (diethylenediamine) In 1942, Giroud noted that a patient infected with Enterobius was cured when treated with piperazine. This observation was taken up by Mehrez who in 1947 confirmed its effectiveness 115. Two years later, Fayard described its efficacy in ascariasis58. This drug was so superior to all previously available agents for the treatment of ascariasis and enterobiasis that Bueding and Swartzwelder in 195718 considered its discovery to be one of the most important turning points in development of the chemotherapy of helminthiasis. Piperazine was prepared in a number of forms including the hydrate, citrate, adipate and phosphate compounds. Piperazines were shown rapidly to be ineffective in the other major intestinal nematode infections but they are still widely used in many countries as inexpensive, popular anthelmintics. Suramin (antrypol) Suramin was introduced in 1921 for the treatment of trypanosomiasis. In 1945, van Hoof and his colleagues, during experimental infections on trypanosomiasis in volunteers, fortuitously discovered that it also acted upon Onchocerca volvulus adult worms (cited in177). This action was then confirmed by Ashburn and colleagues 4. Subsequently, Thooris showed that it killed Wuchereria bancrofti adult worms as well170. It was observed, however, that this drug may cause serious toxic effects, particularly to the kidney, and it has not found a place in the treatment of filariasis and its role in the management of onchocerciasis remains doubtful. Tetrachlorethylene Tetrachlorethylene was introduced by Hall and Shillinger in 1925 for the treatment of hookworm infection72 four years after the advent of carbon tetrachloride. Its effectiveness was confirmed by Schapiro and Stoll148. In 1929, Lamson and colleagues showed that this drug was significantly less toxic than carbon tetrachloride 96. Although it still had significant toxicity, it remained a very popular anti-hookworm therapy for several decades.

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THIRD QUARTER OF THE TWENTIETH CENTURY Wide ranging advances in anthelmintic therapy occurred in the third quarter of the twentieth century. A number of new drugs were developed for the treatment of schistosomiasis, niclosamide became available for the therapy of tapeworm infections, and the benzimidazole series of anthelmintics appeared. Bephenium In 1958, Copp and his colleagues reported the discovery of quaternary ammonium compounds effective against intestinal nematodes; of these, bephenium was the most interesting37. In the same year, the drug was reported to be an effective agent against Ancylostoma caninum and Toxocara canis in dogs and T. cati in felines21 then was shown to be superior to tetrachlorethylene in the treatment of human ancylostomiasis 66,184. Moreover, the drug was noted to be effective also against Ascaris lumbricoides 66 and to be variably effective in trichostrongyliasis 68 and heterophyiasis117 but ineffective in enterobiasis and strongyloidiasis. Bithiniol Bithiniol was described originally as a bactericidal and antifungal agent but in 1957 Sawada reported that it was active against the chicken tapeworm Raillietina kashiwarensis 147. It was then shown to expel Taenia saginata 183 and Diphyllobothrium latum 116 from humans. Dichlorophene This halogenated hydroxyphenylmethane was shown in 1946 to be active against tapeworms in dogs40. Its use in human Taenia saginata infections was first suggested in 1956114,153. Dithiazanine Dithiazanine iodide is a dicarbocyanine dye which was demonstrated as having anthelmintic properties in experimental animals by MacCowen and colleagues in 1957107. They showed that it was effective against Ascaris, Ancylostoma and Trichuris infections in cats and dogs. These actions in human intestinal infections were confirmed in the same year. The distinctive feature of dithiazanine in contrast to earlier anthelmintics was that while it had limited activity in ascariasis, ancylostomiasis and enterobiasis, it was active against Trichuris trichiura 63,160 and Strongyloides stercoralis 160. Likewise, encouraging reports appeared of its value in taeniasis175 and clonorchiasis 181. Unfortunately, at least eight deaths due to dithiazanine administration occurred1,137,157 and the drug was

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withdrawn from the market. Hetol (chloxyl) This chlorinated benzene derivative (1,4-bis trichloromethylbenzene) was shown to be effective in the treatment of fascioliasis in various animal species by Lämmler in 196094. Some success attended its use in human fascioliasis 133, clonorchiasis 182, paragonimiasis 33 and opisthorchiasis 134. Hexachlorophene Hexachlorophene was tried in clonorchiasis with mixed success by Chung and colleagues 34 and by Liu103. Metrifonate Metrifonate is an organophosphate compound. These substances have been used as insecticides since the 1950's. Their use as anthelmintics in veterinary medicine was first described by Levine and colleagues in 1958100. In 1960, Da Cruz Ferreira and co-workers reported on its use in ancylostomiasis but it was variably effective and caused some intolerance 43. Two years later, Cerf and others showed that it was moderately effective against both Ascaris lumbricoides and Schistosoma mansoni 29. In 1963, Talaat and colleagues confirmed this observation and also showed that metrifonate was active against S. haematobium 163. Subsequent experience indicated that this drug was particularly useful for S. haematobium infections and it was not used for other forms of schistosomiasis 59. Niclosamide In 1960, Gönnert and Schraufstätter described a new molluscicide, niclosamide (molluscicide Bayer 73). Screening studies showed that it was active against Hymenolepis diminuta in rats65. World-wide clinical trials followed and it was shown that it was active against practically all the tapeworms of man42,90. Niclosamide remains one of the drugs of choice for the treatment of tapeworm infections. Niridazole In 1964, Lambert reported that niridazole was active against Schistosoma mansoni infections in mice92. In the following year, Lambert and Da Cruz Ferreira showed that it was effective in humans with urinary schistosomiasis in Portuguese Guinea (Guinea Bissau)93. Further observations revealed that in humans, niridazole was more active against S. haematobium than S. mansoni

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and least active against S. japonicum 145. Niridazole held pride of place in the treatment of urinary schistosomiasis for a short period but has now been largely displaced by less toxic drugs, especially praziquantel. Oxamniquine In 1973, Foster and colleagues reported that oxamniquine was active against Schistosoma mansoni in rodents and monkeys although it was inactive against S. haematobium and S. japonicum 60. In the same year, Katz and his colleagues tested the efficacy of the drug when given by oral and intramuscular routes to humans with schistosomiasis in Brazil and observed that the latter route was preferable85. Subsequent studies indicated that oxamniquine was more active against South American than African strains of S. mansoni 162. Oxantel Oxantel is an analogue of pyrantel that was shown to be effective in trichuriasis by Lim in 1974101 but has little effect on ascariasis and hookworm infection. It has therefore been used sometimes in combination with pyrantel. Paromomycin Paromomycin is an antibiotic with antibacterial and amoebicidal properties. Ulivelli reported in 1963 that it was effective in humans with taeniasis172. Pyrantel In 1966, Austin and colleagues reported that pyrantel was an effective broadspectrum anthelmintic in domestic animals5. Three years later, Bumbalo and co-workers showed that it was useful in human enterobiasis 19 then in 1970 Desowitz and others found that it was effective in ascariasis and hookworm infection but not in trichuriasis 48. Stilbazium The anthelmintic actions of stilbazium iodide in infected animals were first escribed by Burrows and colleagues in 196122. In the following year, Swartzwelder and co-workers reported that it was effective in humans infected with Ascaris lumbricoides, Enterobius vermicularis and Trichuris trichiura but was of little value in ancylostomiasis 161. This drug has not found a permanent place in the therapeutic armamentarium.

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Tetramisole and Levamisole In 1966, Thienpont and his colleagues described tetramisole as a potent broadspectrum veterinary anthelmintic 167. Later in the same year, Do Nascimento and colleagues showed that it was effective in humans with ascariasis 51. Subsequent observations, however, revealed that its activity was relatively poor in hookworm infection, trichuriasis and strongyloidiasis. In 1969, Thienpont and his collaborators showed that the levo-isomer of tetramisole, levamisole, was more active against Ascaris lumbricoides than the racemate and was useful in hookworm infection and possibly in strongyloidiasis but was not effective in trichuriasis or enterobiasis 166. Thiabendazole, Mebendazole, Albendazole and other Benzimidazoles Thiabendazole was introduced in 1961 when Brown and his colleagues showed that this agent had broadspectrum activity against intestinal nematodes in pigs and horses15. Later that year, Gordon indicated that it was highly effective against nematode infections of the gastrointestinal tract of sheep67. The drug was then tried in human infections and was found to be variably effective in 61,173 ascariasis81, enterobiasis54 , ancylostomiasis81,173 and strongyloidiasis but inactive in trichuriasis. Mebendazole was introduced in 1971 by Brugmans and colleagues who showed that it was effective in enterobiasis16. It was soon noted to be also active in ascariasis 64,129, trichuriasis64,129 , ancylostomiasis8,64 , trichostrongyliasis3 and capillariasis 155 but to be of doubtful efficacy in strongyloidiasis. In addition, mebendazole was shown to be of some value in intestinal taeniasis87,119. Subsequently, experimental studies in animals suggested that it may be of value in echinococcosis 75 then it was used with partial success in humans with hydatid infections by Bekhti and colleagues in 197710. The activity of albendazole against certain trematode, cestode and nematode infections in animals was described by Théodoridès and colleagues in 1976164. It was shown to be effective in a number of human gastrointestinal nematode infections including enterobiasis, ascariasis, trichuriasis and ancylostomiasis by Pene and co-workers in 1981130 but to be of variable effectiveness in strongyloidiasis 38. More recently, it has been suggested that albendazole may be better than mebendazole in the treatment of infections with Echinococcus granulosus and E. multilocularis 128. Cambendazole was used in strongyloidiasis with good effect by Martirani and Rodrigues in 1976111 but the drug has since been withdrawn from the market. Flubendazole, a fluorine analogue of mebendazole, was reported to have similar activity to that compound by Schenone and colleagues 149.

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Viprynium (Pyrvinium) Viprynium pamoate is a cyanine dye. In 1953, both Hales and Welch69 and Weston and others178 showed that it had anthelmintic activities in animals. It was then shown in the same year to be of some value in human hookworm infection by Perez-Santiago and colleagues131 but its main role came to be in the treatment of enterobiasis.

FINAL QUARTER OF THE TWENTIETH CENTURY The last quarter of the twentieth century is only halfway through but already two valuable new drugs, ivermectin and praziquantel, have appeared. Ivermectin Studies on the fermentation broth of the actinomycete, Streptomyces avermitilis, revealed that it was active against Nematospiroides dubius in mice. In 1978, Blair and Campbell reported that a purified product of this broth, ivermectin, was active against Ancylostoma caninum 13 and Dirofilaria immitis 25 in dogs. Subsequently, it was observed that ivermectin had extraordinary potency against a wide range of nematodes and arthropods. In 1984, Coulaud and colleagues reported that it was useful in the treatment of humans with onchocerciasis 39. Praziquantel Praziquantel was identified from a group of heterocyclic pyrazino-isoquinolines and found to have unusually broad anthelmintic activity. In 1975, Thomas and his colleagues reported its efficacy against intestinal tapeworms 169. In 1977, Espejo showed that it was valuable in the treatment of infections with Hymenolepis, Taenia solium and Diphyllobothrium pacificum 55 while Bylund and colleagues documented its use in D. latum infections23. In 1979, a number of reports appeared describing its use in the three major schistosome infections of man47,80,86,146. Subsequently, its value in clonorchiasis135 , fasciolopsiasis20 , fascioliasis 150 and paragonimiasis 136 was reported.

CONCLUSION It is only fifty years since the sulphonamides first appeared then penicillin ushered in the dawn of antibiotic therapy of bacterial infections. In that short time, a variety of antibiotics have been developed for the treatment of the vast majority of bacterial infections. In contrast, cures for worms have been sought

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for millenia. Although remarkable advances have been made in recent times, many helminthiases, particularly nematode and cestode infections of the tissues, remain refractory to therapy. They offer a continuing challenge for parasitologists, pharmacologists and physicians.

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153. SEATON DR. A short way with Taenia saginata. Lancet i: 808-809, 1956 154. SHOOKHOFF HB, DWORK KG. Treatment of Loa loa infections with hetrazan. American Journal of Tropical Medicine 29: 589-593, 1949 155. SINGSON CN, BANZON TC, CROSS JH. Mebendazole in the treatment of intestinal capillariasis. American Journal of Tropical Medicine and Hygiene 24: 932-934, 1975 156. STEFANOPOULO CJ, SCHNEIDER J. Essais de traitement de la filariose à F. loa par la 1-diethylcarbamyl 4-methylpipérazine. Comptes Rendus Hebdomadaires des Séances de l'Académie de Biologie 142: 930-931, 1948 157. STEMMERMAN GN, NAKASONE N. Strongyloides stercoralis infestation: malabsorption defect with reaction to dithiazanine iodide. Journal of the American Medical Association 174: 1250-1253, 1960 158. STRAUB M. Tetrachloorkoulstofvergiftigi ng in twaalf gevallen. Geneeskundig Tijdschrift vor Nederlandsch-Indië 65: 624-645, 1925 159. SUN SZU-MIAO (One thousand golden prescriptions.) About 650 AD. In Chinese, partly translated in 78 160. SWARTZWELDER JC, FRYE WW, MUHLEISEN JP, MILLER JH, LAMPERT R, PEÑA CHAVARRIA AA, ABADIE SH, ANTHONY SO, SAPPANFIELD RW. Dithiazanine, an effective broad spectrum anthelmintic. Journal of the American Medical Association 165: 2063-2067, 1957 161. SWARTZWELDER JC, MILLER JH, LAMPERT R, PEÑA CHAVARRIA A, ABADIE SH, FRYE WW, MUHLEISEN P, LIZANO C. Anthelmintic activity of stilbazium iodide (monopar) against intestinal nematodes in man. Journal of Parasitology 48: 29-30, 1962 162. SYMPOSIUM DE OXAMNIQUINE. Rio de Janeiro, Brasil, Junho, 1973. Revista do Instituto de Medicina Tropical de São Paulo 15, supplement, pp 1-175, 1973 163. TALAAT SM, AMIN N, EL MASRY B. The treatment of bilharziasis and other intestinal parasites with dipterex. A preliminary report of 100 cases. Journal of the Egyptian Medical Association 46: 827-832, 1963 164. THEODORIDES VJ, GYURIK RJ, KINGSBURY WD, PARISH RC. Anthelmintic activity of albendazole against liver flukes, lung and gastrointestinal roundworms. Experientia 32: 702, 1976 165. THEOPHRASTUS. Enquiry into plants, translated by A F Horst, Loeb Classical Library, Heinemann, London, two volumes, 1948-1949 166. THETFORD ND, OTTO GF, BROWN HW, MAREN TH. The use of phenyl arsenoxide in the treatment of Wuchereria bancrofti infection. American Journal of Tropical Medicine 28: 577-583, 1948 167. THIENPONT D, BRUGMANS J, ABADI K, TANAMAL S. Tetramisole in the treatment of nematode infestations in man. American Journal of Tropical Medicine and Hygiene 18: 520-525, 1969 168. THIENPONT D, VAN PARIJS OF, RAEYMAKERS AH, DEMOEN PH, ALLEVWIJN FT, MARSBOOM RP, NIEMEGEERS CJ, SCHELLEKENS KH, JANSSEN PA. Tetramisole (R.8299), a new potent broad spectrum anthelmintic. Nature 209: 1084-1086, 1966 169. THOMAS H, GÖNNERT R, POHLKE R, SEUBERT J. A new compound against adult tapeworms. Proceedings of the Seventh International Conference of the World Association for the Advancement of Veterinary Parasitology, Thessaloniki, Abstract No. 51, 1975 170. THOORIS GC. Le traitement expérimental de la filariose à Wuchereria bancrofti en Océanie française par la suramine (naphuride de sodium). Bulletin de la Société de Pathologie Exotique 49: 311-317, 1956 171. TYSON E. Lumbricus latus, or a discourse read before the Royal Society, of the joynted worm etc. Philosophical Transactions of the Royal Society 13: 113-144, 1683 172. ULIVELLI A. Terapia antibiotica della teniasi (primi favorelli resulti del trattamento con paromomicina). Revista di Clinica Pediatrica 72: 371-383, 1963 173. VILELA M de P, RODRIGUES LD, CAPELL JI, BRANDAO JA, MARTIRANI I, ZACATO M. O emprego di tiabendazole no tratamento de estrongiloidiase de outras

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parasitos humanas. Hospital, Rio de Janeiro 62: 691-710, 1962 174. VOGEL VJ. American Indian medicine, University of Oklahoma Press, Norman, 1970 175. WAGNER ED, LEMON FR, BURNETT HS. The use of dithiazanine in the treatment of helminthiasis in Mexican farm labourers. Transactions of the Royal Society of Tropical Medicine and Hygiene 52: 56-59, 1958 176. WANG T'AO (The private prescriptions of an official.) About 752 AD. In Chinese, partly translated in 78 177. WANSON M. L'hetrazan dans la période d'invasion de l'onchocercose. Annales de la Société Belge de Médecine Tropicale 29: 85-89, 1949 178. WESTON J, THOMPSON P, REINERTSON J, FISKEN R, REUTNER T. Antioxyuricid activity, toxicology and pathology in laboratory animals of cyanine dye 715. Journal of Pharmacology and Experimental Therapeutics 107: 315-324, 1953 179. WRIGHT WH, BRADY FJ. Studies of oxyuriasis. A preliminary note on therapy with gentian violet. Proceedings of the Helminthological Society of Washington 5: 5-7, 1938 180. WUCHERER OE. Sobre a molestia vulgarmente denominada oppilaçao ou cançaço. Gazeta Medica da Bahia 1: 27-29, 39-41, 52-54, 63-64, 1866 181. YAMAGUCHI T, UEHARA K, SHINOTO M, MINEDA H. Dithiazanine iodide as a new anthelmintic for treatment of Clonorchis sinensis. Japanese Journal of Parasitology 10: 697-704, 1961 182. YOKOGAWA M, KOYAMA H, YOSHIMURA H, TSAI CS. Chemotherapy of Clonorchis sinensis infection. Clinical observations on the treatment of patients with 1,4-bis-trichloromethylbenzol. Japanese Journal of Parasitology 14: 526-533, 1965 183. YOKOGAWA M, YOSHIMURA H, OKURA T, SAITO M. The treatment of Taenia saginata with bithiniol. Japanese Journal of Parasitology 11: 39-44, 1962 184. YOUNG MD, JEFFERY GM, FREED JE, MOORHOUSE WG. Bephenium, a new drug active against human hookworm. Journal of Parasitology 44: 611-612, 1958

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Chapter 4

Fasciola hepatica and FASCIOLIASIS

SYNOPSIS Common name: liver fluke; produces sheep liver rot Major synonyms: Distoma hepaticum, Distomum hepaticum Distribution: world-wide Life cycle: The flat, leaf-like hermaphroditic worms, 30 mm long by 13 mm wide, live in the biliary tract and produce eggs which are passed in the faeces. The ova develop in water over two weeks or so, then each miracidium escapes and invades a snail intermediate host of the genus Lymnaea. The miracidium becomes a sporocyst (an elongated sac without suckers or alimentary canal) which in the course of four weeks produces first-generation then second-generation rediae (characterized by the presence of a single sucker and a simple sac-like alimentary canal) and cercariae. The cercariae emerge from the snail, swim about in water, then encyst on aquatic vegetation. After ingestion by a mammalian host, the enclosed metacercaria excysts in the duodenum, migrates through the intestinal wall into the peritoneal cavity, penetrates the liver capsule then migrates through the parenchyma to the biliary tree where it matures over two to three months Definitive hosts: sheep, goats, cattle, pigs, humans etc. Major clinical features: fever, malaise, jaundice, abdominal pain, urticaria in heavy infections Diagnosis: demonstration of eggs in the faeces of patients with patent infections Treatment: bithiniol, praziquantel

DISCOVERY OF THE ADULT WORM IN ANIMALS The name of the person who first found liver flukes and knowledge of when the observation was made have been lost in the sands of time. The flukes wer e probably found independently by numerous people in diverse places over many years. The first recorded reference to these worms was made by a Frenchman, Jean de Brie, in 1379. de Brie, who was known as "Le bon berger", meaning "The good shepherd", had been commissioned by Charles V of France to write a treatise on the proper management of sheep and the production of wool . Although he did not describe the morphology of the parasite, was uncertain of its precise nature, and appears to have been somewhat confused as to whether the worms were the cause of, or the consequence of sheep rot, there is littl e

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doubt that he recognized the worm we now know as Fasciola hepatica. He believed that the consumption by sheep of a herbivorous leaf known locally as "la dauve" (probably Ranunculus species) corrupted the liver to produce "a type of worm which putrefaction does eat and destroy the entire liver of th e animal"15. The parasites were discussed again in 1523 by the English lawyer, Anthony Fitzherbert (1470-1538), who, in the section on sheep rot in the book on animal husbandry traditionally ascribed to him, referred to "flokes" (flukes) in the livers of afflicted animals 32. This name is thought to have been derived from the old Anglo-Saxon word "floc", meaning a flounder (i.e. type of fish) 18. Twenty four years later (1547), the Italian physician, Hieronymous Gabucinus, referred to worms resembling pumpkin seeds that he had often found in the livers o f sheep and goats 34. In 1551, Conrad Gesner mentioned "duva" or liver flukes in his monumental book, Historia Animalium 36. They were discussed again by the Dutchman, Cornelius Gemma, in his 1575 accoun t of an epidemic of fascioliasis which had occurred in Holland in 1562 35. He was followed by Fromma n (1663)33, Faber (1670), Leeuwenhoek (1679), Wepfer, Borel and others. The worms were, of course, well-known to the butchers of the time, those i n Florence referring to them as "Biscioule", those in Holland calling the m "Bottiens", and those in Provence naming them "Dalbères". The afore mentioned authorities, however, were frequently as ignorant as th e butchers, often considering the flukes to be leeches or cucurbitini (tapewor m proglottids). The first person to investigate and illustrate these parasites further was th e Italian physician, Francisco Redi, when he recovered them from the liver of a castrated ram in 1668 68. He encountered them again in 1684 in a hare whic h also harboured large numbers of "hydatids" (pr esumably Cysticercus pisiformis ) in the mesentery and in the perit oneal cavity. He observed 18 worms swimming in the bile and remarked that their shape resembled somewhat the fish calle d sole. Because of the concurrence of the two forms, he wondered: whether the aqueous swelling, shaped like the seeds of a melon or gourd could possibly be the embryos, so to speak, of the worms which dwell in the bile, and whether they, upon growing and perfecting themselves, become such. However, I would not affirm this with certainty.69

In order to test this possibility, he took fluid from the vesicles and boiled it . Since it did not coagulate as did fluid in eggs found in the ovaries of quad rupeds, he concluded by this doubtful process of reasoning that this possibility was unlikely. A study of these worms was then taken up in earnest by the Dutchman , Godefridus Bidloo. In a letter dated 21 March 1698, he wrote to the celebrated microscopist, Antony van Leeuwenhoek, detailing his findings; this wa s published as a memoir in that year 8, then was included in the Dutch and English editions of the Select works of A. van Leeuwenhoek . He provided illustrations of the parasite, noted its size and shape (which he compared with sole an d

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flounder), colour, the transparent skin and discussed its motion. He was rather confused about parts of the internal anatomy, however, giving the wor m non-existent eyes, liver, heart and circulatory system. Nevertheless, he di d discern correctly a bowel, discovered eggs, and recognized that the creature s were hermaphroditic. Concerning the ova, he recounted that he had found: an innumerable quantity of oval particles, hundreds of which, taken together, are not equal to the size of a grain of sand. They are of a pale red colour, and I take them to be the spawn or eggs.8

and with respect to the sexuality of the flukes, he noted: Notwithstanding my most diligent examination of these creatures, I could never discover any difference of the sexes; and its seem to me most probable that they are of that species called Hermaphrodites, or everyone equally prolifick. 8

Even though Fasciola had been known for many years, there was an imperfect perception of its structure and confusion as to its zoological position. Thus , Gabucinus, Redi, Malpighi and Borel seem to have equated the fluke wit h cucurbitini (Taenia), while Bonamicus, Fromann and Wepfer regarded it as a kind of leech. In fact, Linnaeus appears at various times to have considered it as a leech, a planarian, and a cestod e. More than 100 years were to pass before the details of the fluke's anatomy were worked out correctly by a number o f investigators including Mehlis (1831) 56, Emile Blanchard, Rudolf Leuckart , Sommer and Macé.

IN HUMANS Although this fluke had been found many times in animals, infection wa s rarely recognized in humans. Passing references to human infection wer e made in the seventeenth century. According to Clericus, Pierre Borel noted that he had seen flukes, which he called insects, in all sorts of animal s including humans and pigs, writing, "mihi asseruit in omnibus animalibu s insecta haec reperiri et se in hominibus, porcis etc., eos vidisse" 11. Similarly, Marcus Malpighi claimed that cucurbitine worms occurred frequently in th e livers of humans and animals, especially in cattle and wrote: "In hepat e frequentes occurent vermus cucurbitini in homine et brutis, praesertim i n bove"53. Again, Bidloo recalled having seen, in human livers, worms similar to those commonly encountered in the livers of sheep and cattle 8, while Wepfer claimed to have often found the bile ducts of humans filled with "hirudinibus" (leeches). The first person to clearly describe finding these flukes in a human, however, was Pallas who in 1760 recounted observing worms in the hepatic ducts of a female patient during an autopsy in Berlin 66. He was followed a century later by Bucholz in Weimar who found a large number of flukes in the gallbladder of a convict who had died from a "putrid fever" 17. Although Bucholz's case wa s accepted by Davaine 24, Küchenmeister46 noted that Bremser had later examined some of the worms which had been preserved and thought that they were really

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Distoma lanceolata (= Dicrocoelium dendriticum ). Some years later, Chabert claimed to expel great numbers of flukes from a twelve year old girl with the aid of his empyreumatic oil 19. NOMENCLATURE Linnaeus at first regarded the fluke as a slug, but eventually created the genus Fasciola in his group Intestina of his Class Vermes and named the parasit e Fasciola hepatica in 175851. The generic name is derived from the Latin word "fasciola" meaning "fillet" or "small b andage". Goeze believed that the organism was a planarian and at one time called it Planaria latiuscula. In 1786, Retzius needlessly changed the name of the genus to Distoma, meaning two openings (as opposed to the Monostoma - worms with a single opening - and Polyostoma - worms with multiple openings) 70,71, then Abildgaard designated the fluk e Distoma hepatica 1. This nomenclature was followed by Zeder (1800) , Rudolphi (1808-1810) and Dujardin (1845), while Diesing (1849-1851) called it Distomum hepaticum, with the result that the disease was known for man y years as distomiasis. With the establishment of the law of priority i n nomenclature in the early part o f this century, however, the Linnean designation regained pride of place through Opinion 84 of the International Commission on Zoological Nomenclature 41.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND SNAIL INTERMEDIATE HOSTS Early students of Fasciola suggested all manner of means by which the worms were produced and propagated, ranging from generation by putrified o r decaying substances to the eff ects of excessive wetness or heat. Bidloo in 1698, however, no doubt girded by his discovery of eggs in the flukes, asserted tha t these suggestions were but "ideal tales" and "senseless imaginations". He laid: it down as a certain truth, that these, as well as other small living creatures, are produced from their like, by the means of eggs, seed or spawn, according to the nature implanted in them at their first creation.8

Bidloo thought it most probable that the worms bred in moist earth then were swallowed together with their eggs in water by herbivorous animals such a s sheep, stags, calves and wild boars. He did not believe, however, that the adult worms forced their way from the gut into the gall bladder and biliary system . Rather, he reasoned that the eggs might be carried into the biliary passages , become fixed there, then nourish themselves on the bile and develop. Bidloo's correspondence with Antony van Leeuwenhoek encouraged th e Dutch microscopist to investigate the manner of transmission of this infection. Being conversant with the general view that infection was acquired by animals feeding on contaminated pastures, he examined green sods from the meadows

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on which some infected sheep had fed seeking microscopical creatures re sembling the adult flukes. Sadly, he communicated his failure to find any such animals to the Royal Society of Londo n, but being convinced that infection must be acquired by ingestion, he speculated that when the worms reached: the beginning of the guts, where the bladder of the gall doth empty itself, these animals being pleased with the taste of the gall, swim against it. 47

and thus enter and lodge in the biliary system. Both Bidloo and Leeuwenhoek were close to the truth, but nearly 200 years were to pass before the life cycle of Fasciola hepatica was finally elucidated. During this period, many author ities strayed far from the mark. As late as 1837, Youatt in his book on sheep claimed that: Rot is caused simply by the extrication of certain gases or miasmata during the decomposition of vegetable matter, under the influence of moisture and air. 94

An understanding of the mode of development of Fasciola hepatica took so long to achieve for several reasons. Not only was the life cycle of this parasite extremely complex, but the concepts involved were unknown in the eighteenth century and were appreciated only gradually during the nineteenth century . Fasciola hepatica was the first fluke of human importance to be discovered, and also the first one in which the life cycle was worked out. The way in which this was achieved, however, can only be und erstood when viewed in a wider context encompassing discoveries with various non-human parasites. In 1773, OF Müller discovered microscopic organisms, which we now know to be the larval stages of trematodes, living free in water 58. He regarded them as independent adult creatures, consi dered them to be Infusoria, and gave them the generic name, Cercaria. A study of these organisms was then taken up by CL Nitzsch, a professor in Halle, (now East) Germany, in the early part of th e nineteenth century. He noticed that many of these cercariae transformed into a "pupa" or "encysted" on foreign bodies, but was of the opinion that this process merely signified the termination of life 60. Nitzsch also recognized that cercariae were not Infusoria, and came some way towards realizing that they wer e trematodes. He noticed the resemblance of the anterior part of the body of a cercaria to a fluke (Distomum). As a result of such observations, he concluded in 1817 that a cercaria was a combination of a Distomum with a Vibrio which he believed provided the characteristic tail of the cercaria 61. The origin of these cercariae was a puzzle. They did not appear to have any sexual organs so many authorities invoked the doctrine of spontaneous generation to explain their existence. In 1818, however, the Prussian, Ludwig Bojanus, a professor at Wilno (now Vilnius) in present-day Lithuania made a momentous discovery. While dissecting some snails from a fresh-water pond, h e noticed that cercariae crept out of s acs in the viscera of the snails and concluded that they were probably generated within them. He called these sacs "roya l yellow worms" (or "king's yellow worms"): When the Lymnaea (snails) were taken from the dish, a large number of royal yellow, living, but in movement very indolent, cylindrical worms (Distomata?) were found in many of them....In the yellow worm one saw, under the microscope, active movement

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which came from the enclosed winding animals....Some of the enclosed animals succeeded, finally, at various places, in breaking through. All those that slipped out by themselves had the appearance of the previously described cercariae. 10

These yellow royal worms were given the generic name Redia by de Filippi in 1837 in honour of Francesco Redi 30; de Filippi later accepted the view that the redia was a larval stage and recommended that the name be no longer used to designate a genus31. It caused much astonishment that cercariae were no t derived from parents resembling themselves, but came from these peculiar , animated, worm-shaped sacs. Oken, in whose journal Bojanus published hi s discovery, remarked that "observations of this kind make one dizzy" 64 and added that "one might lay a wager that these cercariae are the embryos o f distomes"63. This observation of Bojanus was confirmed by CE von Baer i n 1827. The story was taken a stage further in 1831 when Karl Mehlis, a medica l practitioner in Clausthal in (now West) Germany, not only discovered th e operculum (lid) of each fluke ovum, but also saw an infusorian-like ciliate d embryo slip out of many eggs of the flukes, Monostomum flavum and Distomum hians 56. Several years later (1837) Friedrich Creplin (1788-1863), a medical practitioner and zoologist in Greifswald, (now East) Germany, showed that the eggs of Fasciola hepatica likewise hatched a ciliated larva 23. Again it caused some surprise that the embryo, later to be called a miracidium, meanin g "youthful person" by Braun 12 should be so different in appearance from th e parent worm. The discovery of these motile worms led von Nordmann to point out that the ability of the flukes' progeny to swim about in water suggested that hosts were unlikely to become infected by passively ingesting eggs, but rather that the swimming embryos might seek out their hosts themselves 62. Nevertheless, it was not until Simonds showed in 1852 that not a single fluke was found nor were any traces of liver rot present in sheep fed fluke eggs, that the old hypothesis that infection was acquired by ingestion of eggs was finally laid to rest 78. Meanwhile, Carl von Siebold had linked the embr yos released from fluke eggs with rediae and cercariae. While District Medical Officer in Heilsberg (no w known as Lidzbark) in East Prussia (present-day Poland), he had occasion t o examine large numbers of the fluke Monostomum mutabile which lived in the orbital cavities of geese. He noted the hatching of ciliated larvae from the eggs and watched them swimming around in the water. After a while, they died and disintegrated, each one releasing from its interior a motile, cylindrical body with two short lateral processes and furnished with a pharynx and simple gut. These he recognized as being identical with certain cercaria-sacs that he had seen in snails. Although he was not able to actually witness the process, he theorize d that the adult trematode worms produce e ggs from which the larvae hatch, swim around to find an appropriate snail, penetrate the tissues of the new host, then die releasing cercaria-sacs (rediae) 75. This hypothesis was eventually prove n correct when G Wagener observed the metamorphosis of the miracidium o f

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Distoma cygnoides of the frog into a redia in 1857 88. The fate of the cercariae thus produced remained uncertain although von Siebold reported in 1837 that some cercariae such as C. echinata encysted in snails. Despite the observations and hypotheses mentioned above, most authorities held that Cercaria, Redia and Distoma were unrelated organisms, eac h deserving and occupying separate generic sta tus in the schemes of classification. To others, however, all these seemingly irregular phenomena constituted a complete chaos which appeared to break down all the known laws of anima l existence and propogation. It was at t his point that the Danish scholar, Johannes Steenstrup, entered the scene. He succeeded in evolving a certain plan out o f this confusion by the discovery of a hidden, underlying law of nature throug h which all the phenomena that had seemed devoid of plan could be brought t o order. He synthesized many reports in the literature with his own observations, then in 1842 he published a book in which he promulgated his doctrine of the "Alternation of Generations" 81. This term had already been used in 1819 by the German poet and navigator, A von Chamisso, who had shown that in the Salpae, a form of marine animal, free individuals and individuals bound together i n chains alternated with one another in each successive generation. In his work, Steenstrup gave an account of the evolution of coelenterates (Medusae an d claviform polyps), of pelagic tunicates (Salpae), and of trematodes, and found a phenomenon common to all of them that he summarized in the followin g terms: An animal bears young which are, and remain, dissimilar to their parent, but bring forth a new generation, whose members either themselves, or in their descendants, return to the original form of the parent animal. 81

Thus, just as the polyp originating from the eggs of a medusa represented a n alternate generation, so did the royal yellow worm (cercaria or redia) derive d from the ciliated embryo of a fluke. The consequences of this statement wer e that cercariae were the progeny of trematodes, that these worms passed part of their existence in a state of freedom, and that whole divisions of families must be abolished because they included only undeveloped forms. Steenstru p observed that in some of the Trematoda the latter generations remained within the earlier forms until they attained their full development whereas other s forsook them earlier to become free-swimming then underwent a complet e metamorphosis. He conjectured fur ther that cercariae might penetrate into other animals, lose their tails and become adult flukes. Steenstrup knew that C. echinata encysted in snails so he extracted parasites from the cysts after various periods and showed that they contained typical fluke-like forms. His view s required both correction and completion, particularly in his supposition tha t final maturation occurred in the body of the snail, but they provided a n indispensable principle upon which the details of the life cycles, not only o f trematodes but also of cestodes, could be fleshed. Although some investigators such as von Siebold (1844) 76 and van Beneden (1852) 7 seized upon this idea of alternation of generations, other authoritie s

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remained obstinate. Thus, Diesing in his major work of 1849-1851, Systema Helminthum, still considered cercariae to be adult trematodes and erected a suborder for them25. Later (1858), he came to accept the larval nature o f cercariae although he continued to use generic names for them 26. Immediately after the appearance of Steenstrup's book, von Siebol d expressed the opinion that encysted cercariae must migrate, i.e. needed to b e transmitted with the bearers on or in which they were encysted into other hosts, before they could mature 76. In this view he was supported by de Filippi31 , la Valette de St. George87 and Pagenstecher 65. La Valette de St. George provided important information when he showed that if tailed, non-encysted cercaria e were administered to experimental animals, they failed to develop. He the n went on to show, however, that when certain encysted cercariae wer e ingested, the larvae escaped in the stomach and matured in the gut. Thus , Cercaria echinifera was converted very rapidly in the intestine of warm blooded animals and slowly in that of cold-blooded species into Distoma echinifera, and C. flava became transformed into Monostomum flavum of finches and sparrows 87. When Küchenmeister came to review the probable life cycle of F. hepatica in 1855 he speculated, therefore, that although it was still unknown how th e miracidium became metamorphosed, into what redia it was converted, where the rediae lived, whether their offspring were tailed or tail-less, or whether the y encysted themselves, it seemed likely that herbivores and omnivores, including humans, infected themselves with encysted worms by devouring infected snails hidden in grass or vegetables, or possibly by drinking contaminated water 46. These views were modified by the Ger man zoologist, David Weinland, in 1875. During studies of the molluscan fauna of the Swabian Alps, he found rediae in the livers of Limnea (= Lymnaea) truncatula. He noted further that whe n cercariae were released they showed a strong inclination to leave the water and climb up onto foreign objects. He speculated, therefore, that they might encyst on grass in order to be ingested by sheep, and suggested that they could be the intermediate forms of F. hepatica 91. This was the scene in 1880 when the young Englishman, Algernon Thomas turned his attention to the problem, and when Rudolf Leuckart in German y finally began to have some success with his endeavours. For many years , Leuckart had tried in vain to infect the most frequently encountered local snails with miracidia of F. hepatica. Near the end of the summer of 1879, he foun d small snails which he thought were Limneus minutus (= L. truncatula) in the Dresden Botanical Gardens. A few days after placing them in his breedin g vessels, he found that some snails were cover ed with small parasites which were also to be found in the viscera, especially in the lungs. They had the form o f small tubes, but without cilia, and had two eye spots and a head sucker, while their contents consisted of clear cells which were beginning to proliferate. He thought that there was little doubt that these organisms were related to F. hepatica miracidia. Unfortunately, he ran out of snails with which to continue

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his experiments, and a paucity of the molluscs plagued him again in th e following year. In the interim, however, he convinced himself that the snail s were really young L. pereger which he had already failed to infect wit h F. hepatica when they were half-grown or mature. This led him to the idea that F. hepatica miracidia might only be able to develop in very young snails of this species. He believed this t o be proven in the summer of 1881 when he was able to infect hundreds of young snails thought to be L. pereger with F. hepatica. He traced the development of miracidia into rediae containing 5- 8 offspring, but by the time of his report in December 1881, he had been unable to characterize them in any detail 48. In fact, he at first believed incorrectly that F. hepatica rediae contained tail-less larvae 49. He then realized his mistakes, and in 1882 detailed the development of F. hepatica in L. truncatula, his final paper being published in October of that year 50, almost simultaneously wit h Thomas's second report in the Journal of the Royal Agricultural Society o f England. Concurrently with Leuckart and quite independently of him, Thomas was researching the life cycle of F. hepatica in England. A major outbreak of liver rot in 1879-1880 had killed more than three million sheep in Britain. The Roya l Agricultural Society of England provided funds for an investigation of th e problem, particularly regarding t ransmission of the infection. George Rolleston, professor of anatomy and physiology at Oxford University, who had earlie r postulated that the black slug, Arion ater, was the intermediate host, wa s approached to investigate the problem. He declined because of ill-health bu t recommended instead that his former pupil, Thomas, who had just bee n appointed demonstrator in biology at the University Museum be given the task. Thomas took up the challenge and showed first that eggs of F. hepatica would not develop when maintained at internal body temperature (37 oC) or at the lower temperatures obtaining during an English winter. When the eggs wer e kept at 23-26 oC, however, the miracidia developed fully within two to thre e weeks, although some eggs continued to hatch over weeks or even months 83. He observed, further, that the released miracidia lived for only about eight hours in water. Thomas was aware that similar embryos of Distoma nodulosum and D. trigonocephalum developed in the snails Bithynia tentaculata and Paludina species, respectively. In these hosts, the former worm metamorphosed into a sporocyst, and the latter helminth changed into a redia, both ultimately giving rise to cercariae. He assumed, therefore, that a species of mollusc was likely to be the intermediate host of F. hepatica. Consequently, he expose d experimentally "Arion ater, Limax agrestia, Arion hortensis, Limax cinereus, Planorbis marginatus, Succinea amphibia, Limnaeus pereger and Limnaeus truncatulus"83 as well as some small crustacea to F. hepatica miracidia, but without success. Thereupon, he decided to tackle the problem from anothe r angle, and so began to visit a large number of farms near Oxford where there had been severe outbreaks of fascioliasis in 1879-1880. There he examined the fauna, particularly the snails, in great detail in the middle of 1880. The results

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were tantalizing but inconclusive. On 22 December 1880 he found in a field at Wytham, a tiny L. truncatula which was infected with a redia containin g peculiar tadpole-shaped cercariae. Since no-one at that time knew what th e cercariae of F. hepatica looked like, the identity of these worms remaine d uncertain. The only way to be sure was by experimental infection of snails, but by this time, Thomas's source of snails had dried up and such researche s had to await the next season. Nevertheless, he was able to observe the habits of these cercariae. He found that they encysted on surroundings objects , especially plants, and speculated that sheep might be infected wit h F. hepatica by ingestion of grass contaminated with these cysts. Th e following year (1881) proved to be one of intense disappointment. Despit e scouring the countryside, no appropriate snails could be found. Never theless, the absence of an epidemic of liver rot in sheep near Oxford that year consoled him somewhat and convinced him that he must be on the right track. In the meantime, he had reasoned that two species of snails likely to be intermediate hosts were Lymnaea pereger and L. truncatula. These molluscs were two of the eight species of snails on the Faroe Islands where fascioliasis wa s very common, and L. pereger was the only aquatic pulmonate snail on th e Shortland Islands where liver fluke also occurred. Accordingly, he tried onc e more to infect these snails experimentally. In July of 1882, floods in the rive r Isis (Thames) at Oxford result ed in the appearance of vast numbers of L. truncatula. He exposed them to F. hepatica miracidia and was immediatel y successful: The snails were speedily found to have afforded a suitable place for the further development of the embryos, and of those examined up to the present time all have proved to be infected, often containing as many as 80 embryos. 84

Thomas was then able to follow the devel opment of larvae within the snails. He observed that once in the snail: the embryo undergoes a metamorphosis. It loses the external layer of ciliated cells and changes from the conical to an elliptical shape.84

This organism was not a redia, but a sporocyst or brood-sac in which redia e would be formed. Within the sporocy sts, which Thomas found in the pulmonary membrane of the mollusc, balls of cells multiplied and were transformed int o rediae, each with its own pharyn x and intestine. He found that when a redia was fully formed: it breaks through the wall of the sporocyst, and the wound caused by its forcible exit immediately closes up, and there remaining germs continue to develop. 84

These rediae were much more dangerous to the snail than the rather iner t sporocysts, for they were very activ e and migrated from the pulmonary chamber to various tissues, especially the liver, upon which they fed. By 31 days afte r infection, the rediae were approximately 1 mm long by 0.2 mm in width an d contained up to a score of "germs" or " spores" in various stages of development, although it was still not clear what form they would take. By seven weeks , however, he could find cercariae within the rediae. In contrast to Leuckart' s

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assertion of the previous year, each cer caria was endowed with a long tail. What was more, these cercariae and rediae appeared to be identical with those he had seen in the snail collected from the farm at Wytham two years before. H e concluded that: There can be no doubt that the cercariae I found really belong to the liver fluke. The rediae in which they occurred were closely similar to those I have found throughout this examination of the snails I have infected with embryos, and in the same snail with these rediae were sporocysts, still recognisable by the eye-spots and papilla as belonging to F. hepatica. Moreover, all the specimens of L. truncatulus which I have infected have proved to contain larval trematodes, clearly belonging to one and the same zoological species, and as a preliminary precaution a number of snails of the same gathering as those submitted to infection were examined, and all were completely free from larval trematodes.84

Furthermore, Thomas observed that rediae sometim es did not produce cercariae, but generated rediae instead. Indeed, he found as many as four generations o f larval F. hepatica within the same snail, and calculated that a single fluke might give rise to over 1,000 cercariae. He ended his paper by indicating that it was still necessary to elucidate the manner in which sheep were infected wit h cercariae. He noted that this could occur either by consumption of mollusc s containing cercariae, as Leuckart favoured, or as he believed more likely , cercariae might swim about, encyst on grass and then be ingested. Thomas' s second report84 and Leuckart's final paper50 both came out in October 1882 . Thomas then wrote two further papers 85,86 reviewing his findings and comparing them with those of Leuckart. Despite Thomas's confident anticipation that he would soon be able to provide the answer to the last-posed question, another ten years were to elaps e before the Brazilian, Adolfo Lutz, proved that infection was acquired by in gestion of cysts containing metacercariae. In t he interim, Leuckart had also tried to infect rabbits but was unable to find any worms. The reasons for his apparent lack of success were not apparent until Ssinitzin discerned the pathway o f migration in the body of young worms in 1914. Lutz was working in Hawai i where he was the Director of the Leper Hospital in Honolulu. Although h e published his findings as referring to F. hepatica, it has since been suggested that the species he studied was in fact F. gigantica 2. Be that as it may, the findings are equally applicab le. Lutz observed in 1892 that snails infected with Fasciola only liberated cercariae when they were damaged or dead. Thes e cercariae encysted rapidly as soon as they found support, whether a plant o r some other material, and remained viable for up to two months. He infected a kid, a piglet and three guinea pigs with numerous cysts of different ages. The kid died within 20 hours of feeding, probably because it was weaned too early, and worms could not be found in the piglet bec ause its stomach was too full. He had more luck with his guinea pigs. The f irst animal was infected on 23, 24 and 27 December 1891 with about 60 cysts. It was found dead one month later and autopsy revealed numerous small cavities filled with blood clot in the live r parenchyma: 29 flukes ranging in size from 5-9 mm were recovered from this

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organ. In the second guinea pig, which had been fed with about 20 cysts, 1 8 flukes were recovered 32 days later, one of them being in the liver and the rest being located in the peritoneal cavity. Similar findings were obtained with the third guinea pig 52. Finally, Shirai eventually proved that not only were cercariae non-infective, but the cysts were not either until a period of at least twelv e hours had elapsed after encystment 74. Thus, the mode of transmission of the parasite from excretion of eggs in the faeces to ingestion of metacercariae had been determined. What remained to be demonstrated was the route of migration and the processes of maturation o f worms in the definitive host.

STUDIES OF THE MIGRATION AND DEVELOPMENT OF LARVAE AND PATHOLOGICAL REACTIONS IN THE DEFINITIVE HOST Initial conceptions as to the genesis of disease were confused. Jean de Bri e (1379) ascribed a major role to the herb, "la dauve": La dauve is of such a nature that it adheres to and lives in the liver of the sheep or other beasts. And this bad herb does not rise, does not return to the throat of the animal as do other herbs but....corrupt(s)....the liver. 15

de Brie believed that this damage was then compounded by the worms which were generated and ultimately destroyed the entire liver. He found it necessary to explain that the reason why sheep died was because "the liver is one of the three principal places where life lies....therefore the sheep cannot live" 15. Fitzherbert (1523) described the morbid anatomy of infected sheep ver y graphically. Moreover, he comprehended the connection between flukes, liver disease, jaundice and ascites: whane thou hast kylde a shepe his belly woll be full of water yf he be sore rotten: and also the fatte of the flesshe wolle be yellowe if he be rotten and also and thou cut the lyver therin wyll be lytell quykena lyke flokes and also the lyver will be full of knotts and whyte blysters yf he be rotten.32

Many persons believed that the flukes were situated in the portal veins. John Faber in 1670 was apparently the first to state that liver flukes were located in the bile ducts28. Willius in 1674, in describing an epidemic in cattle in Zeeland, wrote that not only were the worms in the branches of the portal veins, but that large numbers of flukes were also present in the biliary and hepatic ducts 92. Redi emphasized the biliary location of worms further in 1684 69 as did Bidloo in 1698. The latter wrote that they are found: only (in) the vessels, tubes and channels wherein the gall is formed and collected, though most commonly in the liver, and here they may be said to swarm, producing grievous swellings, callosities, contortions and sinuses in the part: and cavities which will be often found an inch and a half in diameter. In these parts the noxious animals are found in heaps and the places where they lie become hard and cartilaginous. In the small gall-ducts they lie longitudinally, and sometimes rolled or curled up together. 8

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Bidloo further realized that the numbers of worms varied enormously: in one liver he recovered 870 worms plus ma ny fragments, whereas in other livers he found but ten or twelve flukes. He postulated a number of mechanisms b y which they might cause ill-effects, including distension, destruction an d inflammation of the biliary passages following obstruction of the biliar y circulation by worms and their products, inf lammation and necrosis of the liver by worm toxins, and competition by the worms with the organs for nutrien t juices. Once the location of worms in the biliary tree was identified correctly, the logical assumption seemed to be that they reached that site via the opening of the bile duct into the duodenum. For over 200 years this remained accepte d dogma. In 1880, Thomas made an observation which could have put him on the right path, but he failed to interpret it properly. In September of that year, he was sent a liver which contained over 2 00 small, immature flukes. He noted that: no flukes of any kind could be found in the larger ducts. By far the largest number were in the smaller branches of the bile ducts or in centres of destroyed hepatic tissue. They occurred especially near the surface of the liver. The young fluke on entering the liver by the duct appears to push its way onwards into smaller ducts where some remain whilst others penetrate the walls of the ducts and crawl forwards to the surface, causing the destruction of the parenchyma as they proceed. Arrived at the surface of the liver, they may pass along beneath the peritoneum, or....pierce the peritoneum and set up perihepatitis.83

Furthermore, Thomas had seen flukes in the peritoneal cavity of a rabbit and had been told of worms in the mesentery and uterus of a sheep that had died of the rot. Thus, Thomas made the correct observations, but his interpretation was exactly opposite to the actual route of migration. Leuckart made similar observations and also arrived at the same misconception. Lutz (1892) made the same mistake. In one of his experimental guinea pigs, the vast majority of young flukes were in the peritoneal cavity, but he concluded erroneously that: the invading flukes soon go to the periphery of the liver and when the normal bile passages become too narrow, they burrow further....through the soft parenchyma. Having reached the surface, they perforate the capsule and thus can reach the peritoneal cavity where they live perhaps for some time, but probably do not reach full development.52

It fell to Dimitry Ssinitzin (also known as Sisintsin) in Moscow in 1914 to demonstrate what is generally accepted as being the true pathway of migration. He put the reasoning behind his experiment in a very entertaining fashion a few years later: I am now a cercaria which has just emerged from its cyst and has found itself in the intestinal tract....On me are poured smart, biting fluids from the digestive glands and I wish nothing more than to escape this horrib1e place....What am I to do? If I were smaller, I should penetrate into a blood vessel but I am too big for that. Dr. Leuckart advises me to look for the opening of the gall duct in the duodenum, but while I am listening to him I am transported far behind this opening and how can I, in such a spacious hollow filled with moving food, find that commended spot? I do not accept

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this advice; I hasten to conceal myself in any place; I work my way into the bottom, between the folds of the epithelium and penetrate through the intestinal wall. 79

Ssinitzin infected rabbits with metacercariae and found that the young worms had escaped from the cyst walls within two to three hours of reaching th e intestine. He then observed that they penetrated the intestinal wall and passed into the peritoneal cavity where they remained for up to two weeks. They then attached themselves to the surface of the liver by the mouth suction cap, penetrated into the liver parenchyma with the aid of hard, pointed spines, the n passed further into the biliary passages every day. He noticed that they fed on erythrocytes during their travels and emphasized the large haemorrhages they left in their tracks behind them. Final ly, they reached the larger branches of the biliary system and mature worms bega n to pass eggs two months or more after infection80. Ssinitzin's findings were confirmed in guinea pigs by Shirai in 1927 74 and then in rabbits by Krull and Jackson in 1943. Suzuki in 1931 provide d confirmation in another manner. He freed young worms from their cysts b y artificial digestion then inject ed them directly into the abdominal cavity, portal vein and bile duct of goats, rabbits and guinea pigs. He claimed success for the portal but not the biliary routes. Nevertheless, he did not believe that th e former pathway was really relevant in natural infections, considering instead that some of the young worms penetrated the intestinal wall to enter th e abdominal cavity 82. The duration of infection is uncertain, but three patients have been reported with longlasting infections, suggesting that in humans, worms may live for at least nine years 3.

RECOGNITION OF THE CLINICAL FEATURES IN ANIMALS Fitzherbert provided a masterly description of the clinical manifestations of liver rot in sheep, paying particular attention to jaundice (best noted in th e eye), the appearance of the sk in and the condition of the wool. To Sir Anthony Fitzherbert, a judge of the Court of Common Pleas, has traditionally bee n ascribed authorship of A Boke of Husbondrye published in 1523 but it wa s probably written by his brother, John: Take both your hands and twyrle upon his eye: and if it be ruddy and have reed strands in the whyte of the eye than he is sounde. And if the eye be whyte lyke talowe; and the strindes darke coloured than he is rotten: and also take the shepe and upon the wole on the syde and if the skynne be ruddy colour and drie thane he is sounde: and if he be pale coloured and watry than he is rotten....take a lytell of the wole between thy fynger and thy thombe and pull it a lytell and yf it stycke fast he is sounde and yf it come lightly of he is rotten.32

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This description has hardly been improved upon since.

IN HUMANS One of the earliest detailed descriptions of subacute fascioliasis was recorded during the severe epidemic of sheep rot in Britain in 1879-1880. I n November, 1879, a 52 year old labourer at Corfe Castle in Dorset, Englan d complained of vomiting and upper abdominal pain of two months' duration . Examination revealed that his abdomen was distended with gas and that h e was intensely tender in the epigastrium. Soon after admission to hospital, he became febrile and developed increasing pain in the right hypochrondrium , diarrhoea, and began to cough. His rectum became blocked transiently, bu t was cleared and he passed a stinking slough 3x5 inches in size per rectum . Fistulous abscesses developed around the rectum and he died four month s later. At post-mortem examination, the upper rectum was thickened and narrowed, with sinus tracks opening into it. The liver was greyish-red and tense; the hepatic ducts were considerably thickened and enlarged and contained 26 fully developed F. hepatica 40. Despite the severe complications which could occur, as in this patient, it was recognized that many infected people were either asymptomatic or had onl y minor symptoms. Perhaps unexpectedly in view of the fact that flukes live in the bile ducts, jaundice was not a common feature, occurring in only three of sixteen patients reported up to 190227. This was confirmed during a small outbreak of fascioliasis in six patients in England in 1958, none of whom wer e jaundiced29, and in a subsequent epidemic involving 44 people a few year s later in the same country39. The dominant features in these patients were malaise, fever, weight loss and right upper quadrant pain and tenderness of th e abdomen. Many of them had transient episodes of urticaria, but the liver was rarely much enlarged. Very infrequently, immature flukes have been found in ectopic sites. One of the earliest recorded examples of this concerns a woman who presented i n 1848 with a painful sole which she had had for several months; surgica l exploration revealed the presence of an immature F. hepatica 37. Naturally enough, this experience (in 1848) suggested to some commentators that fascioliasis might be acquired by migration of cercariae through the skin 46. In 1895, the case was described of a French naval officer who after three weeks of a pulmonary illness which included pain at the base of his right lung , paroxysmal coughing and slight haemoptysis, finally coughed up a living F. hepatica 38. This was said to be the first recorded case in which the parasite had been lodged in the lungs, but as will be discussed later, some subsequent commentators have believed that this worm was really F. gigantica. Finally, adult F. hepatica has been said to cause "halzoun" or oedema of the

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buccopharyngeal mucosa by becoming attached to the lining of the oral cavity when ingested45. Nevertheless, Azar was unable to reproduce this when he fed infected raw liver to 92 volunteers 6.

DEVELOPMENT OF DIAGNOSTIC METHODS For many years, a diagnosis of fascioliasis was difficult to prove. The rar e patient passed flukes in the faece s or brought them up in the vomitus. The first person who considered the diagnosis in and proved it in a living patien t appears to have been Dr. San Pedro Marti n de la Calle in the late 1880's (cited in4 ). His patient remained undiagnosed for four months until it suddenl y occurred to Martin de la Calle that many sheep had been dying for the past few months from a disease called locally "con vulia", and that these sheep had many signs somewhat reminiscent of those present in his patient. He examined the carcasses of some of these sheep and found flukes in the biliary system. The clue being thus obtained, he set abo ut looking for flukes in the patient's faeces; nothing was found at first, but eventually an adult fluke was passed after the patient had been treated with castor oil. Surprisingly, no attempt was apparently made to examine the faeces microscopically for ova, despite the fact that it was well-known to veterinarians that eggs were common in the faeces of infected shee p. Indeed, the first person who diagnosed a patient in this way seems to have been Ward in 1911 89. Martin and his collaborators found eggs in the bile in 1944 54; it is likely that this will become more common now that upper gastrointestinal endoscopy is bein g practised widely. A clue to the infection may be provided by finding an eosinophilia; this was also first recorded by Ward 89. The possibility of diagnosing fascioliasis serologically by a complement fixation test was first demonstrated in sheep b y Weinberg in 1909 90, then this assay was improved and used in a human patient by Servantie in 1921 73. Skin tests, both by scratch testing and by intradermal injection, were used by Morenas with the former technique being mor e accurate57.

THE SEARCH FOR EFFECTIVE TREATMENT It is only in recent times that effective therapy for fascioliasis has becom e available. Many years ago, Chabert claimed to effect the passage of flukes with his empyreumatic oil 19. Küchenmeister (1855) despaired of treatment, bu t recommended that calomel and mineral waters or oil of turpentine with sulphuric ether be tried 46. Subsequent putative remedies included extract of mal e fern, antimony compounds, carbon tetrachloride and thymol, but evidence for

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the efficacy of these drugs was lacking. Kouri and Arenus introduced treatment with emetine in 1932 45 and this became adopted widely even though no controlled trials verified its efficacy . Subsequently, chloroquine was evaluated, but it failed to cure the infection 29. Bithiniol was thought to be of value by Yoshida and his collaborators (1962) who used it in two patients 93. This drug was also claimed to be effective b y Ashton and colleagues, although convincing evidence for this was not pre sented5. Again, good results were claimed i n a small number of patients treated with metronidazole 59. Recently, it has been shown that praziquantel is effective in fascioliasis 72.

UNDERSTANDING THE EPIDEMIOLOGY Jean de Brie in the fourteenth century made an epidemiological observation of the profoundest importance by linking the acquisition of infection to feeding animals on certain types of pasture at particular times of the year: The good shepherd should be extremely careful in the month of March not to lead his animals to pasture in marshy regions that are low and damp for there grows a very dangerous herb with a small, round, green leaf that is called la dauve, which the sheep like very much to eat, but which is very harmful and damaging to them. 15

These points were expounded 150 yea rs later by Fitzherbert, who, having described several grasses called "sperewort", "penny grasse" and "myldew e grasse" remarked that "All manner of grasse that the lande flode ronneth over is yll for shepe" 32. In 1562, a very severe epidemic of sheep rot broke out in Holland. This was described by the Dutch physician and astronomer, Cornelius Gemma wh o ascribed it to a manifestation of divine justice as were earthquake, flood and pestilence35. This episode was followed by a large outbreaks in Holland i n 167492 and again in Germany in 168 3. The problem was so widespread and so well-known that Shakespeare alluded to it in his play "Titus Andronicus" (Act 4 Scene 4): I will enchant the old Andronicus With worms more sweet, and yet more dangerous, Than baits to fish, or honey-stalks to sheep, When as the one is wounded with the bait, The other rotted with delicious feed.

It gradually became clear that infection was most likely to occur when sheep and other animals were fed on moist ground in warm weather. This was most probable in low-lying marshes and swamps, but could happen upland if there was sufficient moisture. In his studies on the transmission of fascioliasis , Thomas (1881-1882) made a number of observations which helped to clarify the epidemiology of this infection. Firstly, he defined the environmenta l conditions necessary for ripening of the eggs. Secondly, he showed that eggs

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continued to hatch over weeks or months, thus prolonging the period of transmission. Thirdly, he indicated that outbreaks of fascioliasis in sheep wer e associated with similar epidemics in rabbits and that these animals greatl y facilitated the dispersion of ova. Fourthly, he confirmed that Weinland' s observation of cercarial cyst formation on grass 92 was applicable to F. hepatica, and thus helped to explain the mod e of acquisition of infection 83,84. Finally, his and Leuckart's discovery that certain speci es of snails were the intermediate host made the epidemiology of fascioliasis comprehensible. The potentia l magnitude of transmission was emphasized by their calculations that eac h fluke produced at least 40,000 eggs, and that a single miracidium might generate over 1,000 cercariae. Militating against this, however, was the fact that environmental conditions generally prevented the majority of miracidia an d cercariae from finding their intended hosts. It was now clear that epidemic s were common in wet years because moisture both enhanced the development of F. hepatica eggs and favoured the multiplication of molluscan intermediate hosts. Sheep were likely to be infected by eati ng grass contaminated with cysts, perhaps by ingesting infected snails, and possibly by drinking adulterate d water. During this century, studies have defined the species of Lymnaea and related genera that are intermediate hosts of this parasite in different regions of the world. Despite the ravages of rot in sheep, it was recognized that fascioliasis was rare in humans 4. Indeed, by 1915, it was said that only 28 cases had been recorded in the literature up to that time, although it must be said that man y hundreds of such infections have since been reported. There was considerable discussion for many years as to whether it was safe for humans to eat the flesh of sheep with this infection. With the demonstration of Simonds (1850) that feeding F. hepatica eggs did not result in infection, and with the delineation of the life cycle by Thomas and Leuckart (1 881-1882), it became apparent that the dangers of such a practice were not at all that great. Nevertheless, thi s possibility was in the back of t heir minds when Humble and Lush in 1881 discussed how their patient had become infected. After discounting this as a possibility, for the patient had not been in the habit of eating sheep's livers , they remarked that "we can throw no light on the question, how the patien t contracted the disease" 40 but did mention that "he frequently ate th e watercress" 40. It subsequently became accepted that infection could be acquired by eating plants contaminated with cysts, particularly watercress ( Nasturtium officinale), or by drinking polluted water. The role of the former wa s emphasized when a small outbreak of fascioliasis occurred in six patients in Hampshire, England in 1958-1959; all of them were in the habit of eatin g watercress frequently29. It was shown even more dramatically in a larg e outbreak in Monmouthshire, England in 1968-1969 in which 44 patients were infected, all of whom admitted to have eaten watercress from the same be d

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which also was located near some infected cattle and sheep 39.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The possibility of preventing fascioliasis in sheep has been known for mor e than 600 years. de Brie in 1379 concluded his dissertion on rot in sheep b y reminding his readers that "the s hepherd should take care not to lead his sheep near marshy places where la dauve grows all summer long" 15. Fitzherbert (1523) emphasized this, recommending that the sheep "may nat well be lette out of the fold tyll the sonne have domynacion to drie them away" 32. Thomas amplified preventive measures by recommending that infecte d sheep be destroyed, infected livers disposed of, and manure from infecte d sheep be collected and eggs hindered from developing by the addition of coal tar or by being spread over, dry, well-drained ground. Further, he emphasized the value of draining the land and destroying snails with a dressing of lime or with salt83. To these measures were added during this century, adequat e chemotherapy of infected animals and t he introduction of newer molluscicides. Understanding the epidemiology and the frequent incrimination of water cress as the vehicle by which human infections were acquired, led to repeated calls for education of the public concerning the dangers of eating wild watercress, and recommendations that watercress be grown commercially unde r controlled conditions.

OTHER SPECIES OF FASCIOLA F. GIGANTICA The adult fluke was discovered in the liver of a giraffe and named Fasciola gigantica by Spencer Cobbold in 1855 21. The life cycle of this parasite and the pathology and clinical features it induces parallel those of F. hepatica, but different species of snails are the intermediate hosts. In 1895, de Gouvêa in Rio de Janeiro, Brazil published an account of a French naval officer who had recently been in Senegal and who had presented with fever and haemoptysis, then had coughed up a fluke 2.5 cm long 38. There have been differences of opinions as to the identity of this parasite. According to Brumpt16, Railliet considered that it was the liver fluke, F. hepatica var augusta while Raphael Blanchard identified it as F. gigantica. In 1927, Pigoulewsky described F. gigantica infection in a child in Tashkent, USSR. The diagnosis was based only upon the appearances of eggs found in th e faeces67. The first clearcut case of fascioliasis gigantica was reported b y Codvelle and his colleagues in 1928 22.

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REFERENCES 1. ABILDGAARD PC. Almindelige Betragtninger over Involde-Orme, Bemaerkninger ved Hundsteilens Baendelorm, og Beskrivelse med Figurer af nogle nye Baendelorme. Skrivter af Naturhistorie-Selskabet Kjøbenhavn 1: 26-64, 1790 2. ALICATA JE. Observations on the life history of Fasciola gigantica, the common liver fluke of cattle in Hawaii, and the intermediate host, Fossaria ollula. Bulletin 80 of the Hawaii Agriculture Experimental Station, pp 22, 1938 3. d'ALLAINES F, LAVIER G, GANRILLE. Une petite epidémie de distomatose hépatique à Fasciola hepatica. Diagnostiquée rétrospectivement. La Presse Médicale 50: 738-739, 1942 4. ANONYMOUS The rot in sheep. Lancet i: 924, 1880 5. ASHTON WL, BOARDMAN PL, D'SA CJ, EVERALL PH, HOUGHTON AW. Human fascioliasis in Shropshire. British Medical Journal ii: 500-502, 1970 6. AZAR JE. An unsuccessful trial on production of parasitic pharyngitis (Halzoun) in human volunteers. American Journal of Tropical Medicine and Hygiene 13: 582-583, 1964 7. van BENEDEN PJ. Mémoires sur les vers intestinaux. Supplement to Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences, Tome II, Paris, pp 376, 1858 (written, 1852; couronné par l'Institut, 1853) 8. BIDLOO G. Brief van G Bidloo, aan Antony van Leeuwenhoek, wegens de dieren, welke men zomtyds in de lever der schaapen en andere beesten vind, H van Kroonevelt, Delft, pp 34, 1698. In, The select works of Anthony van Leeuwenhoek containing his microscopical discoveries in many of the works of nature, translated by S Hoole from the Dutch and Latin editions, Henry Fry, London, 1798 9. BLANCHARD E. Recherches sur l'organisation des vers. Annales des Sciences Naturelles, Zoologie, Series 3, 7: 87-149, 271-341, 1847 10. BOJANUS LH. Kurze Nachricht über die Zerkarien und ihren Fundort. Isis (Oken's), Oder Encyclopädische Zeitung, Jena, pp 729-730, 1818 Partly translated in 43 11. BOREL P. Cited in 20 12. BRAUN M. Vermes. In, Klassen und Ordnungen des Tierreichs, HG Bronn (Editor), CF Winter'sche Verlagshandlung, Leipzig, volume 4, pp 209-925, 1879-1893 13. BRAUN M. The animal parasites of man: a handbook for students and medical men, third edition, translated by P Falcke and brought up to date by LW Sambon and FV Theobald, John Bale, Sons and Danielsson, London, pp 453, 1906 14. BRAUN M, SEIFERT O. Die Tierischen Parasiten des Menschen, Verlag von Cürt Kabitzsch, Würzburg, volume 1, pp 559, 1915 15. de BRIE J. Le bon berger ou le vray régime et gouvernement des bergers et bergères. Composé par le rustique Jehan de Brie le bon berger (1379), Isidor Liseux, Paris, pp 160, 1879 (reprinted from the edition of 1541). Partly translated in 43. 16. BRUMPT R. Précis de parasitologie, Masson et Cie, éditeurs, Libraires de l'Académie de Médecine, Paris, pp 1011, 1913 17. BUCHOLZ. Cited in 42 18. CAMERON TW. The internal parasites of domestic animals, A&C Black Ltd., London, pp 292, 1934 19. CHABERT JX. Another case of tapeworm "about 30 yards long" associated with specimens of Distoma hepaticum. Boston Medical and Surgical Journal 47: 173, 1853 20. CLERICUS D (LE CLERC). Historia naturalis et medica latorum lubricorum intra hominem et alia animalia, nascentium. Ex variis auctoribus propriis observationibus, Fratres De Tournes, Genevae, pp 449, 1715. A natural and medicinal history of worms bred in the bodies of men and other animals etc., translated by J Browne, printed for J Wilcox at the GreenDragon, Little Britain, pp 436, 1721 21. COBBOLD T S. Description of a new trematode worm (Fasciola gigantica). Edinburgh New Philosophical Journal, new series, 2: 262-267, 1855 22. CODVELLE, GRANDCLAUDE, VANLANDE. Un cas de distomatose humaine à Fasciola gigantica (Cholécystite aigue distomienne avec lésions particulières de la paroi

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24. 25. 26.

27. 28. 29. 30. 31. 32.

33.

34. 35. 36. 37. 38. 39. 40. 41.

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vésiculaire). Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris 52: 1180-1185, 1928 CREPLIN FC. "Distoma". In, Allgemeine Encyklopädie der Wissenschaften und Künste, JS Ersch und JP Gruber (Editors), Leipzig, Sect. 1, Part 29: 309-329, 1837 Partly translated in 43 DAVAINE CJ. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, second edition, J-B Baillière et fils, Paris, pp 1003, 1877 DIESING CM. Systema helminthum, Wilhelmum Braumüller, Vindobonae, two volumes, pp 1267, 1849-1851 DIESING CM. Berichtigungen und Zusätzen zur Revision der Cercarien. Sitzsungsberichte der Akademie der Wissenschaften in Wien. Mathematische-naturwissenschaftliche Klasse 31: 239-290, 1858 DUFFEK E. Distomum hepaticum beim Menschen. Wiener klinische Wochenschrift 15: 772-776, 1902 FABER J. Note in G J Sach's Scholium to T. Bartholin's "Sanguis verminosus", Lipsiae, p 147, 1670 FACEY RV, MARSDEN PD. Fascioliasis in man: an outbreak in Hampshire. British Medical Journal ii: 619-625, 1960 de FILIPPI F. Descrizione di nuovi entozoi trovati in alcuni molluschi d'aqua dolce. Bibliotheca Italiana, an 22, 87: 333-340, 1837 de FILIPPI F. Mémoire pour servir à l'histoire génétique des trématodes. Memorie della Reale Accademia delle Scienze de Torino, second series, 15: 331-358, 1854 FITZHERBERT A. The boke of husbondrye. Here begynneth a newe tracte or treatyse moost profytable for all husbande men: and very frutefull for alle other persons to rede, pp 65, 1523. Formerly attributed to Sir Anthony, but really written by John, his brother FROMMAN JC. De verminoso in ovibus et juvencis reperto hepate. Miscellanea Curiosa Sive Ephemeridum Medico-Physicarum Germanicarum Academiae Naturae Curiosorum (1675-1676), pp 245-252, 1688 GABUCINUS H. De lumbricis alvum occupantibus, ac de ratione curande eos, qui ab illis infestantur, commentarius, H Scotus, Venetiis, pp 56, 1547 GEMMA C. De naturae divinis characterismis seu raris et admirandis spectaculis, causis, indiciis, proprietatibus rerum in partibus singulis universi, Antverpiae, pp 225, 1575 GESNER C. Historiae animalium liber I. Qui est de quadrupedibus viviparus, Tiguri, pp 1104, 1551-1558 GIESKER, FREY H. Helminthologische Beitrag. Mittheilungen der naturforschenden Gesellschaft in Zurich 2: 89-95, 1850 de GOUVÊA H. La distomatose pulmonaire par la douve du foie, L Bataille et Cie, Paris, pp 46, 1895. Abstracted in British Medical Journal i: 932, 1895 HARDMANN EW. Fascioliasis - a large outbreak. British Medical Journal ii: 502-505, 1970 HUMBLE WE, LUSH WV. A case of Distoma hepaticum (liver-fluke) in man. British Medical Journal ii: 75-76, 1881 INTERNATIONAL COMMITTEE ON ZOOLOGICALNOMENCLATURE. Trematode, Cestode and Acanthocephala names placedin the official list of generic names (Opinion 84), Smithsonian Miscellaneous Collections, Smithsonian Institution, Washington, DC, Publication 2830, 73: 11-12, 1925. Also, Nature 117: 414, 1926 JÖRDENS JH. Entomologie und Helminthologie des menschlichen Körpers etc., GA Grau, Hof, pp 473, 180-1802 KEAN BH, MOTT JE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 KHOURY A. Le halzoun. Archives de Parasitologie 9: 78, 1905 KOURI P, ARENAS R. La distomatosis par Fasciola hepatica L. en Cuba. Especial referencia sobre so tratamiento. Possible accion especifica de la emetine. Vida Nueva 28: 553-579, 1932 KÜCHENMEISTER F. Die in und am dem Körper des lebenden Menschen Vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und

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52. 53. 54.

55. 56.

57.

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59. 60.

61. 62. 63. 64. 65. 66. 67.

68.

69.

A History of Human Helminthology pflanzischen Parasiten des Menschen, two volumes, BG Teubner, Leipzig, pp 486, 1855. On animal and vegetable parasites of the human body. A manualof their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 van LEEUWENHOEK A. Part of a letter from Mr. Antony van Leeuwenhoek concerning worms observ'd in sheeps livers and pasture grounds. Philosophical Transactions of the Royal Society 24: 1522-1527, 1704 LEUCKART R. Zur Entwickelungsgeschichte des Leberegels. Zoologischer Anzeiger 4: 641646, 1881. Translated in 43 LEUCKART R. Zur Entwickelungsgeschichte des Leberegels (Distomum hepaticum). Archiv für Naturgeschichte 1: 80-119, 1882 LEUCKART R. Zur Entwickelungsgeschichte des Leberegels. Zweite Mittheilung. Zoologischer Anzeiger 5: 524-528, 1882 LINNAEUS C. Systema naturae, per regna tria naturae, secundum, classes, ordines, genera, species, cum characteribus differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 LUTZ A. Zur Lebensgeschichte desDistoma hepaticum. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 11: 783-796, 1892. Partly translated in 43 MALPIGHI M. Opera posthuma. Quibus praefixa est vita, a seipso scripta, A et J Churchill, Londini, pp 187, 1698 MARTIN R, LE ROY, SUREAU B, BABOUOT P, BOURCART N. Un nouveau cas de distomatose hépatique: diagnostic précoce par le tubage duodénal. Bulletin de la Société de Pathologie Exotique 37: 359-363, 1944 MARTIN de la CALLE SP. Abstracted in, Distomiasis in man, Lancet ii: 1340-1341, 1890 MEHLIS CF. Novae observationes de entozois, auctore Dr Fr Chr H Creplin. . . Angezeigt und mit Bemerkungen begleiter von Dr E Mehlis. Isis (Oken's), Oder Encyclopädische Zeitung, Jena, pp 68-99, 166-199, 1831 MORENAS L. Les réactions d'allergie cutanée dans la distomatose humaine àFasciola hepatica: cuti et intra-dermo-réaction. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 137: 563-565, 1943 MÜLLER OF. Vermium terrestrium et fluviatilium, seu animalium infusorium, helminthocorum et testaceorum, non marinorum, succincta historia. Vol. 1, Infusoria, Havniae et Lipsiae, pp 135, 1773 NIK-AKHTAR B, TABIBI V. Metronidazole in fascioliasis. Report of four cases. Journal of Tropical Medicine and Hygiene 80: 179-180, 1977 NITZSCH CL. Seltsame Lebens- und Todesart eines kleinen bisher unbekanntnen Wasserthierchens. In, Kilian. Georgia, oder Der Menschen im Leben und im Staate, pp 257-252, 281-286, 1807 NITZSCH CL. Beitrag zur Infusorienkunde, oder Naturbeschreibung der Zerkarien und Bazillarien. Neue Schriften der naturforschenden Gesellschaft zu Halle 3: 1-128, 1817 von NORDMANN A. Mikrographische Beiträge zur Naturgeschichte der wirbellosen Thiere, G Reimer, Berlin, two volumes, pp 268, 1832 OKEN L. Cited in 13 OKEN L. Cited in 77 PAGENSTECHER HA. Trematodenlarven und Trematoden, Helminthologischer Beitrag, Heidelburg, pp 56, 1857 PALLAS PS. Dissertatio medica inauguralis de infestis viventibus intraviventia, Lugduni Batavorum, 1760 PIGOULEWSKY SW. (Un cas de Fasciola gigantica Cob chez un enfant Usbék en Vieux Tashkent. Pensée Médecine d'Usbekistane.) In Russian, pp 59-61, French summary, p 131, 1927. Republished in German in Archiv für Schiffs- und Tropen-Hygiene 32: 511-512, 1928 REDI F. Esperienze intorno alla generazione degl'insetti, Carlo Dati, Firenze, pp 177, 1668. Experiments on the generation of insects translated from the 1688 edition by M Bigelow, Opencourt Publishing Co., Chicago, pp 160, 1909 REDI F. Osservazioni intorno agli animal viventi che si trovano negli animali viventi, Piero

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Matini, Firenze, pp 244, 1684. Partly translated in 43. 70. RETZIUS AJ. Lectionibus publicae de vermibus intestinalibus imprimis humanis quas habuit in musaeo rev. nat. acad. Ludensis d. xviii Martii et seq., 1784, Holmiae, pp 55, 1786 71. RETZIUS AJ. Lectionibus publicae de vermibus intestinalibus, imprimis humanis, quas habuit in musaeo rev. nat. acad. Ludensis d. xviii Martii et seq. 1784. In. J P Frank, Delectus oposculorum medicorum, Ticini, 9:1-92, 1790 72. SCHIAPPACASSE RH, MOHAMMADI D, CHRISTIE AJ. Successful treatment of severe infection with Fasciola hepatica with praziquantel. Journal of Infectious Diseases 152: 1339-1340, 1985 73. SERVANTIE L. Recherche de la déviation du complement dans la distomatose humaine. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 84: 699, 1921 74. SHIRAI M. The biological observation on the cysts ofFasciola hepatica and the route of migration of young worms in the final host. Scientific Reports of the Government Institute of Infectious Diseases, Tokyo, 6: 511-523, 1927 75. von SIEBOLD CT. Helminthologische Beiträge. Archiv für Naturgeschichte 1: 45-84, 1835 76. von SIEBOLD CT. Parasiten. In, Handwörterbuch der Physiologie mit Rücksicht auf physiologische Pathologie, R Wagner (Editor), Braun Schweig, 2: 650-676, 1844 77. von SIEBOLD CT. Über die Band- und Blasenwürmer nebst einer Einleitung über die Entstehung der Eingeweidewürmer, W Engelmann, Leipzig, pp 115, 1854. On the tape and cystic worms with an introduction on the origin of intestinal worms, translated by TH Huxley, pp 88, bound with volume 2 of F Küchenmeister's Manual of Parasites, The Sydenham Society, London, 1857. 78. SIMONDS JB. The rot in sheep; its nature, causes, treatment and prevention, fifth edition, John Murray, London, pp 100, 1880 79. SISINTSIN DF. Methods I have followed in my research. Journal of Parasitology 13: 84-86, 1926 80. SSINITZIN DF. Neue tatsachen über die Biologie der Fasciola hepatica L. Zentralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 74: 280-285, 1914 81. STEENSTRUP JJ. Om Fortplantning og Udvikling gjennem Vexlende Generations Raekker, en saeregen Form for Opfostringen i de lavere Dyreklasser, CA Reitzel, Kjøbenhavn, pp 76, 1842. On the alternation of generations, or, the propogation and development of animals through alternate generations: a peculiar form of fostering the young in the lower classes of animals, translated from the German version of CH Lorenzen by G Busk, The Ray Society, London, pp 132, 1845 82. SUZUKI S. (Researches into the life history of Fasciola hepatica and its distribution in Formosa, especially on the determination of the first intermediate host and some experiments with larvae freed from their cysts artificially.) Taiwan Igakkai Zasshi volume 30, no 12. In Japanese, with English summary 30: 97-100, 1931 83. THOMAS AP. Report on experiments on the development of the liver fluke (Fasciola hepatica). Journal of the Royal Agricultural Society of England 17: 1-28, 1881 84. THOMAS AP. Second report of experiments on the development of the liver fluke (Fasciola hepatica). Journal of the Royal Agricultural Society of England 18: 439-455, 1882. Abstracted in British Medical Journal ii: 1001-1002, 1882 and Lancet ii: 849, 1882. 85. THOMAS AP. The rot in sheep, or the life history of the liver fluke. Nature 26: 606-608, 1882 86. THOMAS AP. The life history of the liver fluke (Fasciola hepatica). Quarterly Journal of Microscopical Science, new series, 23: 99-133, 1883 87. la VALETTE de St. GEORGE A. Symbolae ad trematodum evolutionis historiam, Berlin, pp 38, 1855 88. WAGENER GR. Beiträge zur Entwickelungs-Geschichte der Eingeweidewürmer. Naturkundinge Verhandelingen van de Hollandsche Maatschapij der Wetenschappen te Haarlem, pp 112, 1857 89. WARD GR. Hepatic distomiasis (sheep rot) in man. British Medical Journal i: 931-935, 1911

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90. WEINBERG. Recherches des anticorps spécifiques dans la distomatose et la cysticercose. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 66: 219-221, 1909 91. WEINLAND D. Die Weichthierfauna der schwäbischen Alp, Stuttgart, p 101, 1875 92. WILLIUS JV. Vernichtung des Viehstandes auf Abrahamstrup in Seeland durch Blasenwürmer. In, Th. Bartholinus, Acta medica et philosophica, Hafniansa, Library of Useful Knowledge, London, 5 volumes, 1673-1680 93. YOSHIDA Y, MIYAKE K, NAKANISHI Y, NISHIDA K, YAMASHIKI Y, ISHIKAWA T, FUJISAKA K, TANAKA A, EBARA S. (Two cases of human infection withFasciola sp. and the treatment with bithiniol). Japanese Journal of Parasitology 11: 411-420, 1962. In Japanese 94. YOUATT W. Sheep, their breeds, management, and diseases, London, pp 568, 1837

Table 4.1. Landmarks in fascioliasis _________________________________________________________________ 1379

First recorded reference to worms in sheep by de Brie, who also linked infection with feeding animals in certain types of pastures at particular times of the year 1523 Fitzherbert gave an accurate clinical description of fascioliasis in infected sheep 1670 Faber observed that worms were located in the biliary tree 1690 Bidloo discovered eggs and recognized that the worms were hermaphroditic 1758 Linnaeus named the worm Fasciola hepatica 1760 Pallas gave the first detailed account of human infection (earlier allusions had been made by Borel, Malpighi and Bidloo) 1882 Leuckart and Thomas described independently the development of miracidia through to cercariae in the snail, Lymnaea truncatula 1892 Lutz demonstrated that adult worms developed after ingestion of encysted metacercariae 1911 Ward diagnosed human fascioliasis by finding eggs in faeces 1914 Ssinitzin demonstrated the pathway of migration of flukes in the definitive host 1985 Schiappacasse and colleagues reported that praziquantel was effective in human fascioliasis ___________________________________________________________________

Chapter 5

Fasciolopsis buski and FASCIOLOPSIASIS.

SYNOPSIS Common name: giant intestinal fluke Major synonyms: Distoma crassum, Distoma Buskii Distribution: Asia, especially eastern Asia Life cycle: The elongate-ovoid hermaphroditic worms, 20-75 mm in length, 8-20 mm in breadth and 0.5-5 mm in thickness live in the small intestinal lumen attached to the duodenal and jejunal mucosa. They produce eggs which are passed in the faeces. The ova develop in water over 3-7 weeks then each miracidium escapes and invades snail intermediate hosts of the genera Segmentina and Hippeutis. The miracidium becomes a sporocyst which passes through first and second generation rediae to produce cercariae after a few weeks. The cercariae emerge from the snail and encyst on aquatic vegetation including caltrop and water chestnut. People become infected by peeling off the outer covering of the plants with their teeth before swallowing the raw nut. The metacercariae excyst in the duodenum, attach to the small intestinal wall and mature in about three months. Definitive hosts: humans, pigs, (dogs) Major clinical features: diarrhoea, abdominal pain and urticaria in heavy infections Diagnosis: demonstration of eggs in faeces Treatment: hexylresorcinol, dichlorophen, praziquantel

DISCOVERY OF THE ADULT WORM While performing in 1843 an auto psy on a Lascar (i.e. a sailor from the eastern part of India) who had died in the naval hospital Dreadnought in Greenwich, England, the English surgeon, George Busk, found 14 flukes in the duodenum. This finding was not reported until 1852 when, based upon informatio n supplied by Busk, it was described briefly by George Budd in his book , Diseases of the Liver. It was noted that these flukes, which were not present in the gall bladder or bile ducts: were much thicker and larger than those of the sheep, being from an inch and a half to near three inches in length. They resembled the Distoma hepaticum in shape, but were like the Distoma lanceolatum in structure; the double alimentary canal, as in the latter variety, being not branched, and the entire space between it towards the latter part of the body being occupied by the uterine tube. 8

This discovery was cited again in 1857 by ER Lankester in appendix B to his translation of Küchenmeister's textbook, On animal and vegetable parasites

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of the human body. After speculating about the possible life cycle of th e parasite, he went on to say that: In the absence of any other distinguishing name for this species, I have called it, after the name of its discoverer, Distoma Buskii.19

Busk, however, objected to this designation. M oreover, Cobbold considered the name invalid on the ground that Lankester had not provided a sufficien t description of the parasite. Cobbold therefore asked Busk to suggest a ne w name, and the latter thereupon proposed the appellation, Distoma crassum (derived from the Latin "crassus" meaning "thi ck" or "gross"). This was adopted by Cobbold when he redescribed the worm in his Synopsis of the Distomidae communicated to the Linnean Society in London in June 1859 and published in its journal in the following year10. This was to cause confusion subsequently, with some authors calling the worm D. crassum Busk and others referring to it as D. crassum Cobbold. Cobbold himself used the former term in his original description. To complicate matters more, the name Distoma crassum had already been used in 1836 by von Siebold for a fluke found in a house martin. This nomenclature was rejected by C obbold for the same reason that he had set aside D. buskii, i.e. the naming was not accompanied by an adequat e description. Cobbold's redescription w as based on one of Busk's original flukes which had been kept in the museum of the Royal College of Surgeons i n London. He subsequently sent the worm to Leuckart who concurred wit h Cobbold's view and described it as D. crassum in his textbook in 1863 23. Weinland and also Davaine14, however, were misled by the inaccurate original description of the uterine coils and transferred the worm to the genu s Dicrocoelium. The parasite was not recognized again until the northern spring of 1874. A missionary and his wife who had been resident in China for about four year s consulted Dr George Johnstone in London concerning persistent diarrhoea . They were referred to Cobbold who treated them with aloes and asafoetid a without any improvement. Eventually, however, twelve worms were expelled spontaneously. When Cobbold showed them to Busk, "he at once recognised them as referrable to the species he had long ago discovered" 11. Meanwhile, Dr JG Kerr, the founder of the Hospital for the Insane i n Canton, China, had sent another worm to Professor Gross in the Unite d States of America, remarking that it had been vomited by a 15 year ol d Chinese boy. He added that at one time, a four year old English girl ha d passed nine of these worms. The parasite passed into the hands of Josep h Leidy who exhibited it at the Academy of Natural Science in Philadelphia i n October 1873. Leidy described its external morphology but said nothing of its internal organization and misdi agnosed it as Fasciola hepatica 20. He corrected the error 18 years later, merely to commit another when he equated it with F. magna 21. In 1887, J Poirier began the fashion of giving new specific names to variant specimens of F. buski when he described the worm passed by a 35 year ol d

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Chinese woman at the Catholic Mission in Zi-kawei, China, and which ha d been sent to him by Father Rathouis in Shanghai. Since the woman had a chronic liver complaint, Poirier concluded that the parasite must have come from the bile ducts and named it D. rathouisi 33. At the outset, Leuckart was sceptical and considered that it was probably identical with the D. crassum of Busk24. He was supported in this view by Odhner 30 but contradicted by Ward 38 and by Railliet and Henry34. Ward's opinion was based on a study of 11 specimens obtained from two cases by FW Goddard in 1907 and forwarded to him by Dr WH Jeffreys of Shanghai. Included in this batch of worms were fiv e helminths that had minor morphological differences: Ward named these F. goddardi 38. In 1908, an eight year old girl in Hong Kong vomited a fluke; it was brought to DM Heanley by Dr Kwan King-Hung. Heanley thought tha t this was an undescribed species and it be came known as Kwan's fluke 16. Leiper later showed that it was merely F. buski that had been macerated by th e action of gastric juices before being vomited 22. In 1909, another Laskar from Calcutta was admitted to the Seaman's Hospital in Hamburg, Germany, with a provisional diagnosis of typhoid fever. He passed several flukes in his faeces, and E Rodenwaldt, considering them to be a new species, named it F. fülleborni 35. Finally, Brown in 1917 examined 118 specimens preserved i n alcohol that had been collected in Shaohsing, and believing erroneously that F. buski did not have cuticular spines, proposed naming those with spines F. spinifera 7. All this confusion and proliferation of names was brought to an end in 1919 by FW Goddard of the Christian Hospita l in Shaohsing, China. He studied 433 specimens then cut histological sections from 17 worms that conformed to the description of F. buski, F. rathouisi and F. goddardi. He concluded that: the parasite showed great variation in morphology but withal such gradation in variation as to justify including the forms now described as F. rathouisi and F. goddardi in the species F. buski. On account of the close similarity of F. fülleborni it would appear desirable to subject this species also to further investigations. 15

Meanwhile, this species had been transferred to another genus by Odhner in 190230. He examined flukes in the Zoological Museum in Copenhagen tha t were contained in two glass jars dated Dec. 20, 1890 and Jan. 1, 1891. They had been obtained by Dr Deuntzer in Bangkok f rom a 13 year old boy who had had a typhoid fever-like illness and had expelled flukes after the administration of calomel. Odhner improved on the description of the worm and transferred it to the genus Fasciolopsis that had been erected by Looss in 1899 25. This name is derived from a combination of th e Latin "fasciola" meaning "fillet" and the Greek (OPSIS) "meaning resemblance", to indicate the similarity of this worm to F. hepatica. Odhner named the worm Fasciolopsis buski, spelling the specific name with one "i" 30 instead of with two (buskii) as in the original of Lankester; it has generally retained this designation since that time, although some authors have labelled it as F. buskii.

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ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND SNAIL INTERMEDIATE HOSTS When he named the parasite F. buski in 1857, Lankester speculated about the life cycle of this worm. He surmised that the usual host was probably som e species of lower animal living in the tropics and that humans were likely t o acquire the infection in a fashion similar to the way in which they becam e infected with F. hepatica 19. The means by which the latter worm was transmitted was not known at that time, although speculation that snails wer e involved was rife. When this was confirmed by Thomas and Leuckart in 1882 (see chapter 4), it gave credence to the idea that fasciolopsiasis was trans mitted likewise. Lankester's suppositions were substantiated further when i t was discovered that pigs in certain endemic areas were infected not infre quently with F. buski. The only other observation of significance that wa s made during the nineteenth century was the discovery of the operculum of the F. buski egg. Although Cobbold had desc ribed the appearance and dimensions of these ova in 1875 11, he apparently failed to see the operculum. This wa s eventually discovered by an anonymous commentator who examined a specimen submitted to the British Medical Journal by JH Walker in Sandakar , North Borneo in 1891 1. This, therefore, was the background when Koa n Nakagawa in Formosa (Taiwan) in 1915 turned his attention from the study of the life cycle of Paragonimus westermani to investigate that of F. buski. Human infections with the parasite were almost unknown on that island, but fasciolopsiasis was ver y common in pigs, so he obtained his specimens from that source. He pursued his experiments over five years, finally publishing his results in 1921 28 and again with more details in the following year 29. He noted that when eggs were deposited in water during the warmer months, they developed over the nex t two to three weeks, then hatched miracidia which swam about freely in th e water. He incubated these miracidia with a number of species of snail s collected from local ponds and brooks but obtained either negative o r confusing results. Realizing that he had to have snails that were free of an y naturally-acquired infection (there being at least 17 different forms of cercariae present on Taiwan), he tried to raise s nails artificially from eggs in aquaria. He finally succeeded in cultivating what he considered to be two species of snail, Plan-orbis coenosus and Segmentina largillierta (now both known as Segmentina hemisphaerula ). These snails proved susceptible to infection, for when he placed them with F. buski miracidia in an aquarium in April 1920, the snails: were soon found covered by swarming miracidia which tried to bore into the head, foot, tentacles, mantle etc. They left their ciliated coats as they penetrated into the snail.28

In the tissues of the snails, he observed that the miracidia transformed int o sporocysts, grew and migrated, especially into the mantle and walls of the ali-

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mentary canal. By the seventh day of infection, rediae could be seen in th e sporocysts, and by 35 days, young cercariae could be discerned within th e rediae. Moreover, in some instances, daughter rediae (second generatio n rediae) developed within parent redi ae. He then noticed that after the cercariae were liberated from the snail 38 days or so after infection, they soon attached themselves to grass and encysted. Furthermore, the cercariae were identical in appearance to those he had seen in 1918 in naturally infected snails collected from a small pond near Shinchiku where fasciolopsiasis in pigs was ver y common. Nakagawa thus: concluded that the intermediate hosts of Fasciolopsis buski are Planorbis coenosus Benson and Segmentina largillierta Dkr. in Formosa28

Nakagawa then attempted to infect experimental animals with these cysts. On 19 June 1920, he infected a young dog with 40 cysts, then three days later he gave it another 50 encysted cercariae. The animal was killed on 16 July 1920 and 59 young distomes 2-3 mm long were found squirming around in th e duodenum and jejunum. Thereupon, he repeated the experiment with a young pig and returned similar results. A third experiment was then undertaken with another pig being infected on June 1920 then killed 90 days later; in thi s animal, 23 worms, definitely F. buski, 13-15 mm in length, were found in the small intestine. Nakagawa had thus completed the life cycle and conclude d that: the mode of infection with F. buski is very simple. The only means of being infected is to eat raw water plants, which carry the encysted cercariae, or to drink the water containing them.29

The next person to apply his mind to the problem of fasciolopsiasis wa s Claude Barlow, an American missionary at Shaohsing Christian Hospital i n Chekiang Province, China. He reported the results of some of his invest igations in a number of journals over several years, then brought all th e available information together in a monograph of nearly 100 pages published in 19255. Fasciolopsiasis was a common and serious problem in the are a around Shaohsing, occurring frequently in humans but almost never in pigs, the opposite situation to that pertaining in Taiwan. Thus, Barlow's observ ations were made on F. buski derived from human sources. Before the life cycle of F. buski was understood, Barlow swallowed egg s (late 1918) and living adult flukes (early 1920) in order to establish the time required for stools to become free of ova after treatment and to determin e whether infection could be acquired by ingesting adult worms. When he swallowed eggs in gelatine capsules, they appeared in the faeces on either the same day or on the following day, then disappeared within eight days; they did not seem to be damaged in the process. On the first occasion that he swallowe d living adult worms, eggs were not seen at any time. He then ingested thre e more flukes, one of which lodged in t he intestines with the result that ova were discovered in the stools 28 hours later. Fertile eggs continued to be excreted by this single fluke until it was expelled by an anthelmintic one year later 2.

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In 1922, following publication by Nakagawa of the details of the life cycle of F. buski, Barlow reported in a preliminary note that human infection wa s acquired by eating water chestnut ( Eliocharis tuberosa) and water caltrop (Trapa natans) on which the cercariae encysted. The red water caltrop wa s particularly incriminated, with as many as 40 cysts being found on a single nut. Furthermore, he indicated that no cases of infection in pigs had been discovered, even in the areas of greatest infection of humans around Shaohsing, thus suggesting that there may be differences be tween the porcine and human forms of the parasite3. These findings were then reported in greater detail in th e following year when he also recorded the results of his next experiment . Barlow had determined to confirm that Nakagawa's observations on the infection of pigs and dogs exposed to pig-derived F. buski were also applicable to humans infected with cercariae emanating from human sources. Secondary objectives were to characterize the species of snail susceptible to the loca l strain of the parasite and to discern the symptoms induced by infection. Initially, Barlow developed the procedu res necessary for establishing the life cycle of the parasite in the laboratory. He found that two species of aquati c snails that were commonly associated with the water caltrop, Planorbis schmakeri (now known as Hippeutis cantori) and Segmentina nitidellus (= S. hemisphaerula), were susceptible to infection. He reared the snails in th e laboratory and followed the course of infection when they were exposed to F. buski miracidia hatched from eggs in human faeces. Like Nakagawa, he observed the transformation of miracidia i nto sporocysts and the growth of rediae within them, then noted the escape of rediae from ruptured sporocysts , beginning eight days after infection. In fact, he continued to see rediae being released for as long as 254 days after infection of the snail, and thought tha t this probably indicated multiple generations of rediae. He found that cercariae formed within daughter rediae began to emerge between 25 and 30 days after infection of the snail, but that instead of leaving the host immediately through the mantle or pulmonary orifice, they usually remained in the liver or in th e lymph space around the heart for from a few hours to a couple of days while completing their maturation. He descri bed the process of encystation carefully, indicating that it began within a few min utes of the cercariae coming in contact with plants, and was completed within one to three hours. Now that he had a sure and defined source of F. buski cysts, this intrepid investigator was ready to enter the n ext phase of his investigation. On 27 November 1922, having first ascertained that his stools were free of eggs, Barlow swallowed 98 cysts collected from water caltrop in the fields nearby. Th e following day, he ingested another 35 cysts obtained from aquarium-reare d snails. Thirty one days after the initial infection, ova appeared in his faeces. On 23 February 1923, following the administration of an anthelmintic (carbo n tetrachloride), he passed a total of 124 ad ult F. buski in his stools 4. His graphic account of the clinical manifestations induced by infection will be recounted shortly.

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RECOGNITION OF THE CLINICAL FEATURES AND VIEWS O N PATHOGENESIS An association between infection with F. buski and diarrhoea was moote d early. This symptom was the major complaint of the missionary and his wife who were treated by Spencer Cobbold on their return from China. Whethe r coincidentally or not, the diarrhoea resolved when the flukes were expelled , and Cobbold was left in no doubt as to there being a causal relationshi p between the two events. Nevertheless, he had a remarkably naive and immature view of the symptomatology of this infection, for when discussing th e condition several years later, he commented that: Savages of the untutored races in the matter of symptoms, suffer much less from the presence of intestinal worms than their civilised fellow-men do. 12

Several of the first reported patients had a typhoid fever-like illness an d passage of the worms was associated with resolution of the complaint. Thi s led, naturally enough, to speculation that the febrile state was a consequence of the fluke infection, but it was realized subsequently that the worms wer e merely co-existent and that the unfav ourable environment induced by the fever caused them to be expelled. That fever was not a feature of fasciolopsiasis was recognized in 1919 b y Goddard who described three phases in the clinical picture 15. During the period of latency, a few flukes generally caused no inconvenience except for a mild asthenia. The period of diarrhoea was characterized by persistent passage of frequent, offensive stools containing poorly-digested food material, plus a profound anaemia. The final phase was the period in which severe anaemi a was complicated by the appearance of massive oedema beginning in the abdomen and genitals, then progressing t o involve the whole body. Although this description was based upon observation of many patients, the study was uncontrolled, and it is difficult to disentangle the role of F. buski in engendering these features from the multitude of other infectious agents and non-infectious conditions which might produce similar effects in people with coinciden t F. buski infections. The clinical features of fasciolopsiasis were placed on a more defined basis when Barlow infected himself with F. buski 5, although even here, they must be viewed with some circumspection since t he possible causes of diarrhoea for someone living in China at that time were legion. Barlow noticed no particular ill-effects when the infection became patent 31 days after he had swallowe d 132 cysts. Two weeks later, however, he began to develop increasing hunger and epigastric pain before meals. Nearly ten weeks after infection, he started having symptoms even more reminiscent of duodenal ulceration: hypogastric pain became severe and lasted from four o'clock in the morning till food was taken. It was griping in nature and continued for half an hour after eating then subsided entirely. It was of daily occurrence and came on only in the early morning. 5

At the same time, he became troubled with diarrhoea, there being mucus but

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no blood in his stools. On 13 February 1923, 77 days after infection: a severe diarrhoea, with six movements during the 24 hours, began and lasted till the 20th of February, with from four to six movements daily, accompanied with severe griping pain which was irregularly intermittent all day long. The pain was confined to the hypogastrium and seemed to be caused by an increased peristalsis and a large quantity of gas. The pain was so intense that lying on the abdomen was the only way to get relief. During the periods of diarrhoea, there was a marked aversion to food. 5

These problems then subsided somewhat and on 27 February he treated himself with 90 minims (7.5 ml) of carbon tetrachloride in water at 7.30 a.m. At midday, he passed a large, loose stool containing 20 flukes and one ascarid: There was a constant and nauseating eructation of carbon tetrachloride gas and the whole treatment was accompanied by weakness, dizziness, nausea and tinnitus....(the drug) made me feel decidedly ill, but after four stools, this feeling subsided and a comfortable night was passed.5

These four stools contained a further 73 flukes, then another 33 worms were passed on the following day. There was little doubt, therefore, that infectio n with F. buski resulted in diarrhoea, and the absence of anaemia or oedem a could be explained easily enough on the basis that the infection was of either insufficient intensity or duration to induce these effects. Barlow went on t o note that diarrhoea was absent in many patients with this infection, and re marked that anaemia was infrequent. Indeed, he implied that anaemia wa s merely a dilutional consequence of the fluid overload causing ascites an d peripheral oedema. He believed that these complications were most likely to arise if the patient was small and undernourished and at the same time wa s infected heavily. He described such a patient: she was a nine year old gir l suffering from oedema who passed 3,721 flukes after treatment wit h betanaphthol 5. Barlow also described the location of flukes in the small intestine: (They) were all in the duodenum and all fastened to the mucous membrane by their suckers or were buried in mucous secretion. None were loose in the bowel....They may remain attached to the mucosa till little reddened spots appear. 5

It was not surprising that such lesions should induce pain with many of th e features reminiscent of those seen in duodenal ulceration. A number of early authors subscribed to the view that many of the symptoms and signs o f fasciolopsiasis were due to toxins produced by the flukes 5,13,15. If oedema and these other effects are indeed a feature of severe fasciolopsiasis and are due to the liberation of toxins by flukes in the bowel, the toxin or toxins whic h produce them have not yet been identified nor have the mechanisms by which they produce these ill-effects been clarified. Initially, many authors 13,15 took an alarmist view of fasciolopsiasi s considering that the infection "may be fatal unless the parasites are expelled by art or accident" 13. This was based upon the often false assumption that F. buski infection was the cause of the patients' trouble. Thus, Cole wrote that: I had one death....within twenty four hours of admission for bowel troubles, in which the typical ova were demonstrated before death.13

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Nevertheless, it became clear gradually that the severity of infection wa s dependent upon the worm burden and might be grave only in those with extremely heavy infections if left untreated. More recently, the clinical features in 28 infected persons were compared with those in an equal number of uninfe cted control subjects living in the same endemic area of Thailand. No significant differences in symptomatology , growth and development, haematological parameters or screening tests fo r malabsorption were found between the two groups, and it was concluded that F. buski was not responsible for overt clinical disease unless the parasite was present in massive numbers 32.

DEVELOPMENT OF DIAGNOSTIC METHODS It is perhaps remarkable that wh en Cobbold in 1875 found that his patient had fasciolopsiasis, this diagnosis was made only because adult flukes wer e passed in the stools. Apparently he was not in the habit of examining microscopically the faeces of patients whom he suspected of having an helmint h infection, even though such a technique had been described nearly 20 year s earlier. Even had he done so, however, he would not have arrived at the correct diagnosis, as the eggs of F. buski were not described at that time. Nevertheless, observation of their presence would have alerted him to the existence of some intestinal worm in the gastrointestinal tract. The first person to find F. buski eggs in the faeces was JH Walker in British North Borneo in 1891. In a 22 year old Chinese male with beriberi: microscopic examination of the faeces showed that they contained....very numerous eggs of a kind I could not find described in any books at my disposal. 37

He then went on to describe the eggs and provided a figure illustrating one . Walker attempted to ascertain the the adult worm producing these eggs b y treating the patient with a combination of anthelmintics and purgatives; th e patient pronounced himself cured but failed to bring the parasites to th e hospital. He had more luck with a second patient in whose faeces he foun d similar eggs; anthelmintic therapy resulted in the recovery of an adult fluk e which he identified as Distoma crassum. Microscopical examination of the faeces then became standard practice , particularly in the heavily endemic area around Shaohsing in China, wit h Barlow remarking that: in diagnosing fasciolopsiasis there are only two pathognomonic signs; the finding of ova in stool and the vomiting of live flukes. Only in cases of massive infestation does the latter occur, while it is almost impossible to overlook ova in the stool when but one fluke is harboured because of a large number of ova discharged by one adult. 5

although he also claimed that "fluke-harboring individuals are easil y recognized on the streets after one has seen many cases clinically" 5. Stoll and his colleagues took this diagnostic procedure one step further and

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showed that quantification of the number of eggs in the stools was a valuable index of the number of adult worms with which a person was infected. They further demonstrated that each fluke produce d between 15,000 and 48,000 ova per day36.

THE SEARCH FOR EFFECTIVE TREATMENT Walker in 1891 showed that a combination of thymol and santonin togethe r with calomel and senna purgatives was effective against F. buski 37. A traditional Chinese remedy which had some measure of success was areca nu t combined with cathartics. Turpentine and carbon tetrachloride enjoyed transient popularity but they were soon abdandoned because of severe damage to the kidneys and liver, respectively 6. Experience in China then showed tha t betanaphthol was the best available drug, although it had to be given i n repeated small doses in order to reduce the frequency and severity of depression as a side-effect 6,15. In 1937, McCoy and Chu introduced therapy wit h hexylresorcinol. They treated 129 children with this drug and found that when the faeces were re-examined two to three weeks later, that 54% of them were cured and that most of the remainder had a reduction of 80% or more in egg counts26. Tetrachlorethylene also enjoyed som e transient favour. In more recent times dichlorophen has been shown to be relatively effective 17,27. In 1983, Bunnag and his colleagues reported that praziquantel (see chapter 3) wa s effective; they treated 85 children with small doses and all of them wer e cured9. This anthelmintic is likely to become the drug of choice for th e treatment of fasciolopsiasis.

UNDERSTANDING THE EPIDEMIOLOGY Despite the initial paucity of reports, fasciolopsiasis was found to be common in various regions of South and Eastern Asia. One of the most heavily infected areas was the Shaohsing region of China, where Barlow believed that i t occasioned greater economic loss than did hookworm and schistosom e infections put together 5. Between 40 and 50% of the hospital patients were infected, while in some villages, all of the inhabitants carried the fluke. The discovery by Nakagawa of the snail intermed iate host of F. buski and his realization that infection was acquired by ingesting metacercariae encysted on water plants immediately shed light on the epidemiology of fasciolopsiasis . This was extended by Barlow who not onl y confirmed the life cycle of F. buski by deliberate infection of a human, but identified two major types of plants , water chestnut and water caltrop, as the final vehicle of infection to humans. He expounded the reasons why caltrop was so important in transmission: The caltrop is a most acceptable feeding ground for the snails. It has a broad, soft,

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spongy leaf on a fibrous, cellular petiole and the root-stalk is spindle-shaped and cellular. The air cells keep the plant supported on the water, and the rootlets get their food largely from the water, although there is a root which is sent down to the bottom, even though the depth may be 12 or 15 feet. These plants are usually alive with little snails, feeding on the tender skin on the stems, petioles, leaves and nuts. It is not unusual to find more than 20 on a single nut. This obliterates distance for the emerging cercariae and brings encystment where it is more efficacious and dangerous.5

Water caltrop and water chestnut were grown in shallow ponds and infection was enhanced by fertilizing with human night soil. Surveys of these plant s showed that there was an average of 17 cysts for every caltrop nut. Barlow then went on to examine the durability of cysts and found that they were not very resistant to drying, being unable to withstand one day in the hot sun. For this reason, vegetables which were grown on dry soil were not inf ected, even though they were located near ponds containing many infecte d snails. Subsequent experience in other endemic regions indicated that F. buski cercariae were not fastidious but could live on almost any kind of water plant growing in stagnant water near infected snails. Thus, cysts were described on the roots and leaves of lotus, water bamboo, Salvinia natans and Lemna polyrhiza 18. The most common way in which humans acquired infection was by peeling off the outer covering of each nut with teeth, before swallowing the raw food. Likewise, the important snail intermediate hosts in various regions wer e characterized. These snails were somewhat difficult to identify and there was considerable confusion initially. Segmentina hemisphaerula (identical with Nakagawa's S. largillierta and his Planorbis coenosus and synonymous with Barlow's S. nitidellus) and Hippeutis cantori (= Planorbis schmakeri of Barlow) were found to be the major molluscan hosts in eastern Asia, whil e S. trochoideus was identified as the most important vector in northeaster n India. The interaction between the pig and human cycles also caused some con sternation at first. Nakagawa noted that porcine fasciolopsiasis was common in Taiwan, whereas human infe ction was prevalent around Shaohsing. Barlow showed that pigs could be infected with cerca riae derived from human sources, although the parasite appeared to be somewhat smaller 5.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Once he had discovered the life cycle of F. buski, Nakagawa was quick to list various measures designed to reduce the transmission of infection. H e indicated that the eating of raw water pl ants and the drinking of unboiled water should be prohibited, while the consumption of uncooked freshwater fish and

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molluscs which sometimes contain encysted cercariae should be avoided, as should the washing of table utensils in ditches and rivers. Furthermore, h e recommended that faeces contaminated with eggs should be dis -infected , infected domestic waste should be disposed of, and that the intermediate hosts should be destroyed 28. While these measures were simply stated, easy to recommend, and ought to be effective, they were difficult to p ut into practice. In echoing these measures, Barlow noted that: the possibility of control is fairly simple and easily accomplished. With laws effective, living conditions regulated, and customs subordinated, the disease could be blotted out in one season.5

But he was not sanguine about the likely outcome, declaring that: with things as they are, looking with optimism on the problem of control, one may predict that it will take from 10 to 20 years to reduce the disease to the point at which it will cease to be a menace, and 50 years or more to stamp it out completely, unless Chinese officialdom and the common people cooperate in a common plan with the control-man to eradicate it. This is a desideratum hardly to be contemplated. 5

Unfortunately, even this forecast was too optimistic, and in many regions , fasciolopsiasis is still a problem.

REFERENCES 1. ANONYMOUS. A rare parasite. British Medical Journal ii: 1224-1225, 1891 2. BARLOW CH. Experimental ingestion of the ova of Fasciolopsis buski : also the ingestion of adult Fasciolopsis buski for the purpose of artificial infestation. Journal of Parasitology 8: 40-44, 1921 3. BARLOW CH. Life cycle of Fasciolopsis buski : discovery of the means of infestation of human beings. China Medical Journal 36: 546, 1922 4. BARLOW CH. Life cycle of Fasciolopsis buski (human) in China. China Medica l Journal 37: 453-472, 1923 5. BARLOW CH. The life cycle of the human intestinal fluke Fasciolopsis busk i (Lankester). American Journal of Hygiene Monograph Series, No 4, pp 99, 1925 6. BARLOW CH. The treatment of fasciolopsiasis. China Medical Journal 41: 253-265 , 1927 7. BROWN NW. The Fasciolopsinae of China. A study of two species from Chekian g Province. Johns Hopkins Hospital Bulletin 28: 322-329, 1917 8. BUDD G. Diseases of the liver, John Churchill, London, second edition, pp 486, 1852 9. BUNNAG D, RADOMYOS P, HARINASUTA T. Field trial on the treatment o f fasciolopsiasis with praziquantel. Southeast Asian Journal of Tropical Medicine an d Public Health 14: 216-219, 1983 10. COBBOLD TS. Synopsis of the Distomidae. Journal of the Linnean Society, London, Zoological Division 5: 1-56, 1860 11. COBBOLD TS. On the suppos ed rarity, nomenclature, structure, affinities and source of the large human fluke (Distoma crassum Busk). Journal of the Linnean Society 12 : 285-296, 1875 12. COBBOLD TS. Parasites: a treatise on the entozoa of man and animals including some accounts of the ectozoa, J&A Churchill, London, pp 508, 1879 13. COLE AF. Five cases of Fasciolopsis infection, with remarks. Transactions of the Royal Society of Tropical Medicine and Hygiene 14: 93-96, 1921

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14. DAVAINE C, Traité des entozoaires et des maladies vermineuses, de l'homme et de s animaux domestique, J-B Baillière et fils, Paris, pp 838, 1860 15. GODDARD FW. Fasciolopsis buski , a parasite of man as seen in Shaohsing, China . Journal of Parasitology 5: 141-163, 1919 16. HEANLEY CM. A large fluke of man probably not hitherto described; Fasciolopsis buski as a parasite of man in Hongkong; its usual host probably the pig. Journal of Tropica l Medicine and Hygiene 11: 122-123, 1908 17. IDRIS M, RAHMAN KM, MUTTALIB MA, AZAD KHAN AK. The treatment o f fasciolopsiasis with niclosamide and dichlorophen. Journal of Tropical Medicine an d Hygiene 83: 71-74, 1980 18. KUANG WU. Deux nouvelles plantes pouvant transmettre le Fasciolopsis buski . Revue générale. Annales de Parasitologie Humaine et Comparée 15: 458-464, 1937 19. LANKESTER ER. Appendix B. In, F. Küchenmeister's "On animal and vegetabl e parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group entozoa", translated by E Lankester, The Sydenham Society, London, pp 452, 1857 20. LEIDY J. On Distoma hepaticum . Proceedings of the Academy of Natural Sciences , Philadelphia 25: 364, 1873 21. LEIDY J. Notice of entozoa. Proceedings of the Academy of Natural Sciences , Philadelphia, pp 234-236, 1891 22. LEIPER RT. On Kwan's fluke and the presence of spines in Fasciolopsis. Journal of Tropical Medicine and Hygiene 14: 119-120, 1911 23. LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührende n Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sch e Verlagshandlung, Leipzig, volume 1, pp 776, 1863 24. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührende n Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sch e Verlangshandlung, Leipzig, volume 2, pp 897, 1886-1901 25. LOOSS A. Weitere Beiträge zur Kenntnis der Trematoden-Fauna Aegyptens zugleic h Versuch einer naturlichen Gliederund des Genus Distomum Retzius. Zoologische Jahrbücher. Abtheilung für Systema 12: 521-784, 1899 26. McCOY OR, CHU TC. Fasciolopsis buski infection among school children in Shaohsing and treatment with hexylresorcinol. Chinese Medical Journal 51: 937-944, 1937 27. MUTTALIB MA. Dichlorophen in the treatment of Fasciolopsis buski . Bangladesh Medical Journal 7: 45, 1978 28. NAKAGAWA K. On the life cycle of Fasciolopsis buski , Lankester. Kitasato Archives of Experimental Medicine 4: 159-167, 1921 29. NAKAGAWA K. The development of Fasciolopsis buski (Lankester). Journal o f Parasitology 8: 161-165, 1922 30. ODHNER T. Fasciolopsis buski (Lank.) (= Distomum crassum Cobb.) ein bisher wenig bekannter Parasit des Menschen in Ostasien. Centralblatt für Bakteriologie , Parasitenkunde und Infektionskrankheiten, Abteilung originale 31: 573-581, 1902 31. ODHNER T. Was is Distomum rathouisi ? Archives de Parasitologie 12: 573-581, 1909 32. PLAUT AG, KAMPANART-SANYAKORN C, MANNING GS. A clinical study o f Fasciolopsis buski in Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene 63: 470-478, 1969 33. POIRIER J. Note sur une nouvelle espèce de Distome parasite de l'homme le Distomum rathouisi. Archives de Zoologie Expérimentale et Générale 5: 203-211, 1887 34. RAILLIET A, HENRY R. Helminthes du porc receuillis par M. Bauche en Annam . Bulletins de la Société de Pathologie Exotique et de ses Filiales 4: 693-699, 1911 35. RODENWALDT E. Fasciolopsis füllebor ni n. sp. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 50: 451-461, 1909 36. STOLL NR, CORT WW, KWEI WS. Egg-worm correlations in cases of Fasciolopsis

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buski with additional data on the distribution of this parasite in China. Journal o f Parasitology 13: 166-172, 1927 37. WALKER JH. Two cases of beri-beri asso ciated with Distomum crassum , Anchylostoma duodenale and other parasites. British Medical Journal ii: 1205, 1891 38. WARD HB. Fasciolopsis buskii, F. rathouisi and related species in China. China Medical Journal 24: 1-10, 1909

Table 5.1. Landmarks in fasciolopsiasis ___________________________________________________________________ 1843 1857 1891 1918 1920

George Busk discovered the adult worm Lankester named the worm Distoma Buskii Walker diagnosed fasciolopsiasis by finding eggs in faeces Barlow experimentally swallowed eggs Nakagawa hatched miracidia from pig-derived eggs, observed development through to the cercarial stage in snails, noted encystation on plants, then recovered adult worms from experimentally infected pigs 1920 Barlow swallowed adult worms and developed a persistent infection 1922 Barlow swallowed cysts and developed a patent infection 1937 McCoy and Chu introduced treatment with hexylresorcinol 1983 Bunnag and colleagues demonstrated the efficacy of praziquantel __________________________________________________________________

Chapter 6

Clonorchis sinensis and CLONORCHIASIS

SYNOPSIS Common name: Chinese liver fluke Major synonyms: Distoma sinense, D. spathulatum, D. endemicum Distribution: eastern Asia Life cycle: The flat, transparent and spatulate hermaphroditic worms, 10-22 mm long and 3.5 mm wide live in the biliary passages attached to themucosa. They produce eggs which are passed in the faeces. The miracidium hatches only after ingestion of the egg by a suitable species of operculate snail (Alocima, Bulimus, Melanoides, Parafossarulus, Semisulcospira). The miracidia develop into sporocysts then in turn become rediae which produce cercariae. The cercariae emerge from the snail, swim about in the water until they encounter certain freshwater fish (at least 80 species, mostly of the family Cyprinidae are susceptible), attach to the surface, lose their tails, penetrate under the scales, encyst in the skin or flesh, and develop over 3-4 weeks at summer temperatures. When raw, infected fish is eaten by humans, the metacercariae excyst in the duodenum, enter the common bile duct through the ampulla of Vater and ascend to the small biliary passages where they mature in one month Definitive hosts: humans, dogs, cats Major clinical features: fever, jaundice, pain and tenderness in the right hypochondrium, hepatomegaly in heavy infections Diagnosis: demonstration of eggs in the faeces or duodenal aspirate of patients with patent infections Treatment: praziquantel

DISCOVERY OF THE ADULT WORM On 8 September 1874, a 20 year old Chinese carpenter was admitted in a moribund condition to the Medical C ollege Hospital in Calcutta, India. He had been febrile for two weeks and died several hours after admission. A post mortem examination was performed later that morning by James McConnell, professor of pathology and resident physician, who noted that the patient was jaundiced and that: the liver was dark, swollen and tense;....the bile ducts (were) particularly distinct from their large size, and distension with thick yellow bile. O n incising the liver in different directions, it was noticed that small, dark , vermicular-looking bodies escaped onto the table, and on more carefu l 141

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examination these were clearly seen to protrude from the bile ducts, which, on being dissected, were found more or less obstructed by and containing them in large numbers, some lying fr ee, others coiled up and either solitary or in groups of twos or threes within the biliary ducts; all were dead....No distomata were found in the gall-bladder, nor were any ova discovered on microscopical examination of the bile and lining membrane of this sac . Numerous ova and shreds of epithelium were found in the biliary canals. 45 McConnell concluded that the flukes in the bile ducts caused degeneration of the liver, and that the "cholaemic condition" induced by obstruction of th e biliary channels was the immediate cause of death. He then went on to describe the external and internal morphology of the flukes, which were nearl y one inch in length, then compared them with the two flukes well-known i n Europe, Distoma hepaticum (Fasciola hepatica) and Distoma lanceolatum (Dicrocoelium dendriticum), as well as discussing them in relation to Fasciolopsis buski found in China by Kerr and wrongly identified by Leidy a s F. hepatica (see chapter 5). This led McConnell to the conviction that th e flukes that he had found in the liver "not only differ from the ordinary live r fluke (Dist. hepaticum) but constitute an entirely new species" 45. His paper was published in The Lancet on 21 August 1875 then four weeks late r Spencer Cobbold wrote to the editor of that journal remarking that: without doubt the species is new to science, and ought to have som e distinctive name by which it may be recognised amongst th e trematodes. I propose to call it Distoma sinense.11 This name was presumably intended to indicate its discovery in the body of a Chinese person. In the following year, however, Leuckart, in his textbook , labelled the parasite Distoma spathulatum 43. The parasites were encountered again in 1877 by William McGregor i n Port Louis, Mauritius. Eight Chinese persons were suffering from a paralytic illness, and he found the flukes in the three patients who died. Naturall y enough, but quite wrongly, he ascribed the pa ralysis to these worms 47. In 1878, McConnell again found the parasites in a Chinese cook from Hong Kong 46. In the same year, Ishizaka discovered the infection in a farmer in Okayam a Prefecture in Japan31, then Erwin Baelz recovered the worms during th e autopsy of a patient in Tokyo University Hospital in 1883. Baelz recognized two forms of the fluke: he regarded the smaller form as being pathogenic and named it Distoma hepatis endemicum sive perniciosum and the larger type as being nonpathogenic, calling it Distoma hepatis endemicum sive innocuum 3. Ijima, however, believed them to be identical and shortened the name of the parasite to Distoma endemicum 30. In 1895, Raphael Blanchard erecte d the genus Opisthorchis and placed D. sinense in it6. In 1907, however, Arthur Looss created the genus Clonorchis for this oriental liver fluke with branched instead of lobed testes, the nam e being derived from the Greek words (CHLON) and (ORCHIS) meaning "branch" and "testis", respectively 44. He recognized two species ,

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Clonorchis sinensis, a larger form that he believed was found more commonly in China, and C. endemicus, a smaller worm which was thought to be found mainly in Japan and Indochina. In addition, Looss believed that the shapes of the eggs differed between the two forms of the worm. Kobayashi (1912) , however, considering that the size of the adult worm depended upon the nature and size of the host and upon the in tensity of infection, and believing that there were no significant differences in the shape of the eggs, concluded that there was only one species, C. sinensis 36,38.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND INTERMEDIATE HOSTS When McConnell described the adult fluke in 1875, he also described an d illustrated the eggs that he found in the bile. His epidemiological observations allowed him to speculate on the nature of the life cycle of the parasite. H e recalled seeing several patients with clinically enlarged livers who may have been similarly infected. Since these people were Chinese, he surmised tha t they might have become infected by ingestion of certain contaminated fishes or vegetables since: Chinese....are well known to be 'filthy feeders' delighting in putrid messes of half-raw fish, &c; they are bound by no caste prejudices (as the natives of India are) to abstain from any kind of 'flesh, fish or fowl'; they partake, moreover, of all kinds of 'vegetable food'. The sources from whence th e larvae of such parasites may be deri ved are therefore not far to be sought. 45 This idea received further support when M cGregor found the infection in more Chinese, and suggested that the vehicle might be a species of snail, th e "bêche-de-mer" 47 and was reinforced when McConnell found the parasite in yet another Chinese person 46. In 1885, Isao Ijima began to investigate the life cycle of C. sinensis 30. Using those flukes whose life cycle had already been worked out, particularly Fasciola hepatica (see chapter 4) as an analogy, he fixed his attention o n molluscs. He dissected a large number of aquatic snails including species of Anodonta, Corbicula, Cyclas, Lymnea, Melania, Paludina and Planorbis but failed to discern any trace of sporocyst, redia or cercaria in any one of thes e snails. He did, however, describe the appearance of miracidia forced out o f their shells by tapping coverglasses sharply. These embryos were non-motile, and he was unable to hatch them artificial ly, despite keeping them for over five months and placing them in an incubator. This difficulty hindered experimental attempts to investigate the life cycle in the same way that Thomas and Leuckart had recently done for F. hepatica. In noting that he was carrying out suc h experiments, Ijima remarked "I have no expectation of bringing them soon to a close" 30. He then canvassed four possible ways in which humans migh t acquire infection, including drinking of ditch water, ingestion of infecte d

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snails, consumption of vegetables contaminated with cysts, and by eatin g undercooked second intermediate hosts such as shrimps and fishes" 30. The inability to hatch eggs continued to be a bugbear. Saito (1898) developed a mechanical method for expressing the m iracidia and claimed to observe larvae exit from ova spontaneously 63, but this was not the general experience and did not provide sufficient numbers of miracidia for experimental purposes. Similarly, all attempts by Heanley (1908) to hatch eggs failed. He even caused many molluscs to ingest eggs but they were passed in the excreta unhatched. These frustrations led Heanley to adopt the view that: the easiest way of finding out something of the life history of O. sinensis will be to feed animals with food eaten raw by Cantonese....There is a dish frequently eaten which contains uncooked vegetables and fish. Th e freshwater snail (Paludina sinensis) is also eaten more or less cooked, and I was told, sometimes raw. 20 Heanley followed his own advice and fed several dogs with various types of food but failed to achieve any positive result.

DISCOVERY OF THE FISH SECOND INTERMEDIATE HOSTS Heanley's approach was adopte d with success several years later, however, by the Japanese zoologist Harujiro Kobayas hi, while working in Korea. He examined a variety of molluscs, fishes and aquatic arthropods while looking fo r trematode larvae. He found a number of fo rms of cercariae and encysted young flukes, but noted that one particular kind of immature, encysted fluke wa s common in certain freshwater fish that came from the same regions wher e human clonorchiasis was freque nt. Since cats were known to be often infected naturally, he used these animals for experimental studies. They were firs t shown to be uninfected by repeated examination of the faeces then given the flesh of fish containing these cysts. Kobayashi then fed them exclusively on a diet of boiled rice and disinfected milk. Nine kittens and two cats were fed on the fishes Pseudorasbora parva and Leucogobia guntheri. They either died or were killed at varying intervals; all were found to be infected wit h C. sinensis (Kobayashi called the worm C. endemicus) in the bile duct, hepatic ducts, gall bladder, pancreas and duodenum. These findings were first reported by Kobayashi in the form of a short note in Japanese in 1911 35, then appeared in English the following year 37. In 1913, Houghton, a western physician, also claimed to have determined the life cycle of C. sinensis 25. While making some observations in 1910 o n parasites present in foodstuffs commonly eaten in Shanghai, China, where he was working, Houghton noticed the practically constant presence of a larval trematode free in the intestine of a species of fish of the genus Notropis. In view of the possibility that these larvae might parasitize humans or some other mammalian host, he fed them to kittens. In the first experiment, two suckling kittens were fed, one with raw fish, boi led rice and tinned milk, while the other

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received rice and milk only. On killing the animals two months later, he found that the animal fed with fish was infected with C. sinensis whereas the control cat was not. The experiment was repeated and similar results were returned, with hundreds of Clonorchis being recovered. On the third attempt, bot h kittens died of an intercurrent illness after o ne month. Houghton concluded that although his data were scanty, it seemed likely that clonorchiasis was acquired by ingestion of undercooked, sma ll cyprinidine fish. Nevertheless, his findings must be viewed with some scepticism, since the larvae he saw were lying free in the intestines, not encysted in the flesh, nor did subsequent investigator s give any credence to his work. Indeed, Leiper and Atkinson in 1914 made a similar finding in fish near Shanghai and concluded that it had nothing to do with the life cycle of Clonorchis 42. Despite Houghton's claim that th e intestinal larvae were the only trema todes found either in the gut or in the flesh of the fish, it is possible that C. sinensis cysts were present conincidentally in the skin, thus causing him to misinterpret the relationship between th e intestinal larvae and the adult worms that he reared. Meanwhile, Kobayashi continued his studies using cats, dogs, rabbits , guinea pigs and rats, describing his findings in Japanese in 1912 36 and in English in a German journal published on 15 January 1915 38. He observed that cysts were abundant both in the subcutaneous tissues and in the muscles o f fish, particularly in the more superficial parts. In these papers, he showed that another ten species of freshwater fi shes also acted as intermediate hosts. Later, Kobayashi and other workers found further species of freshwater fishes tha t were vectors of C. sinensis, so that by 1965, approximately 80 such species had been identified 40, although only a dozen or so were important sources of human infections 78. Thus, although Kobayashi had demonstrated conclusively tha t experimental animals, and therefore almost certainly humans, acquire d infection with C. sinensis by ingestion of infected fish, the mode of infection of the fish remained unknown. Kobayashi thought it highly likely that a mollusc was involved and suspected Melania species as prime candidates.

DISCOVERY OF THE SNAIL FIRST INTERMEDIATE HOSTS The Japanese pathologist, Masatomo Muto (also known as Shochi Muto) , skirted around the difficulty of obtaining miracidia and solved the riddle of the primary intermediate hosts of C. sinensis in an ingenious manner. Previously, he had been investigating parasites in s nails and had shown that the river snail, Thiara (=Melania) libertina (which Kobayashi had proposed as the likel y intermediate host of C. sinensis) was the primary intermediate host o f Metagonimus yokogawai. Muto thought it unlikely that this species of snai l was also the primary intermediate host of C. sinensis, but while pursuing this line of investigation, came across a new species of snail in Lake Biwa, Koshu, Japan. This snail harboured three species of cercariae. In order to determine

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whether one of these forms was C. sinensis, he used these naturally-infected molluscs to infect experimental, cyst-free fish which were in turn fed t o uninfected mammalian definitive hosts. In his first experiment, he fed tw o small dogs with the fish Pseudorasbora parva which had been incubated in a tank with the snails; C. sinensis ova appeared in the dogs' faeces 18 and 20 days later, then large numbers of adult C. sinensis were found at autopsy. As a control, he fed a third dog with P. parva which had been incubated with T. libertina; Metagonimus but not Clonorchis was recovered from this animal. He repeated this experiment with four guinea pigs, two of which were fed with P. parva incubated with the snails in question, and two of which were given uninfected P. parva to eat; C. sinensis was found in the first two animal s whereas the second two remained uninfected. He summarized his finding s thus: I collected a species of snail ('mametani shi')....and discovered three species of cercaria in the shell. I succeeded in infecting uninfected P. parva with one of these species. After a certain period , I fed the P. parva to small dogs and guinea pigs and confirmed th e existence in these animals of parasitism by C. sinensis. In this way, I proved that the primary intermediate host of C. sinensis is 'mametanishi' - Bulimus striatula var japonica Pilsbury.52 Muto's findings were first presented to the eighth meeting of the Japanes e Pathological Association in April 1918; in this paper, the snail was identified as Bithynia striatula var japonica 51. In his more definitive paper reported later that year, the snail was referred to as Bulimus striatula var japonica52. In 1948, Abbott proposed that the Bithynia striatula of Japan and China should be incorporated into the species Parafossarulus manchouricus which is distributed widely in China, Japan, Korea, Taiwan and probably in Indochina 1. There was little doubt that these sna ils were the primary intermediate hosts of C. sinensis. In order to substantiate this conclusion, however, Muto visited a number of endemic areas and showed that there was a strong correlatio n between the prevalence of clonorchiasis in humans and the presence of these snails. Furthermore, he demonstrated that fishes were a necessary stage in the development of the parasite, for when he infected a rabbit with cercaria e obtained from snails (rabbits having been shown by Kobayashi to be susceptible to infection) adult worms were not found. Finally, Muto obtained a miracidium of C. sinensis and infected a snail with it; when he examined the snail three weeks later, he found a sp orocyst and wrote: "This corroborated my conviction and the results of my experiment" 52. Other species of molluscs were then shown to be intermediate hosts o f C. sinensis in various regions. Melania hongkongensis was found in 1924 to be the vector around Shaohsing, China where cats but not humans were commonly infected12. Faust and Khaw (1927) regarded Bithynia fuchsiana (= Bulimus fuchsianus) as the major vector of C. sinensis in northern China and considered that Bithynia longicornis (= Alocima longicornis) was a less important potential vector 16. The susceptibility of this latter species to infection

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with C. sinensis was confirmed experimentally b y Hsu and Li in 1940 27. Meanwhile, Galliard (1938) found that Bithynia chaperi and Melania tuberculata were the major intermediate hosts of the infection in Vietnam 18. Attempts continued meantime to persuade miracidia to hatch from eg g shells. A variety of mechanical stimuli such as placement of ova in runnin g water34 were deemed to be ineffective. It was eventually shown by Hsu and Li in 1940 that miracidia hatch only in the alimentary canal of susceptibl e snails28. These authors showed that when eggs were ingested by Bithynia fushsiana, miracidia hatched within one hour then penetrated the gut wall to become sporocysts within four hours of infection. The sporocysts the n migrated into the lymph spaces surrounding the intestine and rectum. There, they produced rediae which in turn migrated primarily into the liver, but also into other regions such as the foot and mantle, and produced cercariae within them. Discovery of the snail intermediate host permitted observation of the fate of these cercariae. After escaping from the snail and having a brief free swimming existence, the cercaria e became attached to the fish, discarded their tails, penetrated under the scales and encysted in the subcutaneous tissues or in the muscles. Three or four weeks were required for complete development into metacercariae at temperatures occurring during summer.

STUDIES OF THE MIGRATION AND DEVELOPMENT OF LARVAE AND THE PATHOLOGICAL RESPONSES OF THE DEFINITIV E HOST When Kobayashi discovered that the infection was acquired by ingestion of infected fish, he devised some experiments to ascertain the route by which the parasites migrated in the definitive host. Cats were fed with fish meat containing C. sinensis cysts, then dissected at various intervals. Three hours after ingestion, some of the cysts were found to be empty and the young flukes were creeping about with the aid of their suckers in the gut lumen. Kobayashi was of the opinion that the metacercariae bur st through the cysts walls by their own exertions rather than that the walls were digested by the gastric juices for two reasons. Firstly, the cysts remained undissolved in the gastrointestinal contents for many hours after exit of the parasites. Secondly, when fish flesh wa s crushed and soaked in water, many flukes managed to escape. When two cats were dissected 15 and 24 hours after infection, worms were found both in the gall bladder and in the bile duct. Kobayashi interpreted these results in th e following manner: It is quite natural to infer that after they reach this part they go into th e hepatic duct and in it they cease to travel and grow. 38 The next person to investigat e the route of migration was Takayuki Mukoyama in Japan50. He fed encysted larvae to rabbits, dogs and guinea pigs . Young flukes were found in the bile duct as early as six hours after infection

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(the earliest time at which he looked). The only places in which worms were ever seen were the biliary system, duodenum and stomach. Furthermore, when the bile ducts were ligated, worms were found in the duodenum, but not in the biliary tree, liver or abdominal cavity. Finally, when young flukes were placed directly into the peritoneal cavity of rabbits, the worms failed to migrate to the liver and bile ducts during the three and a half weeks of observation. Thus , Mukoyama concluded that young fluke s were unable to penetrate the intestinal mucosa but migrated directly along the bile duct. Similar conclusions wer e reached several years later by Faust and Khaw who observed that whe n animals swallowed cysts, young flukes attached themselves to the duodena l mucosa, massed in the region of the opening of the common duct, then by 48 hours after infection had all migrated into the biliary tree 15. Since that time, however, some investigators have cast some doubt upon this route o f migration. Nevertheless, the weight of evidence favours the direct lumina l route. Once flukes have reached the biliary system, they may live there for many years. Although Muto found that most worms in infected dogs died during the space of two to three years 53, there are reports of Chinese emigrants continuing to pass eggs after long periods of residence in non-endemic areas, wherea s concomitant infections with other worms such as Ascaris, Trichuris and hookworm disappeared spontaneously. Thus, one person who had live d continuously in Costa Rica for 25 years retained his infection with C. sinensis49. Similarly, C. sinensis ova were found in the bile of a Vietnamese who had lived in New Caledonia for 24 years7 and another Chinese patient still had clonorchiasis after living in Panama for over 40 years 9. Nevertheless, these reports must be viewed with some circumspection, since it is possible tha t infection could have been acquired for example, by ingestion of undercooked fish which had been imported from China. While the route of migration was of great interest to parasitologists, th e consequences of infection were of mor e concern to pathologists and clinicians. When he first found the flukes, McConnell believed that they had played a major part in causing the deat h of his patient 45, and McGregor thought that the flukes produced a paralysis of reflex origin 47. McConnell had doubts abou t this, however, when he reported his second case in 1878 46, and this was echoed a number of years later by Heanley in Hong Kong when he wrote that: The literature of tropical medicine abounds with instances of commo n parasites being mistaken for causes of disease until further investigatio n has shown the parasite to be as common in the healthy population as in the sick.20 Heanley, in fact, reported the first major series of patients with clonorchiasis. He examined 300 unselected livers at autopsy during an 18 month period and found that 109 of them were infected, the number of flukes present rangin g between one and 350, with the average burden in adult persons being of the order of 40-50 worms. He was not impressed by the damage produced b y these worms, remarking that:

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After doing more than 3,000 post mortems in Cantonese, I am still unable to say whether C. sinensis ever produces disease in them, although I a m inclined to think that it in very old people the enlargement of the bile ducts may help in the production of gall-stones. 20 and adding as an addendum to the title of his paper on clonorchiasis, the words "its small pathological importance" 20. Nevertheless, it gradually became clear that serious damage could b e caused by C. sinensis, particularly in heavy infections. Perhaps the mos t massive infection on record is that described by Sambuc and Beaujean i n which 21,000 flukes weighing approximately 300 g were recovered from the liver and biliary system65. In 1920, Mebius gave a detailed pathological study of clonorchiasis seen in Chinese in Indonesia 48. The worms were shown t o induce an epithelial proliferation and crypt formation in the extrahepatic bile ducts, luminal enlargement and thickening of the walls of the intrahepati c ducts, periportal lymphocytic infiltration and fibrosis, and atrophy of live r parenchymal cells. These features were interpreted as indicating hyperplastic cholangitis with chronic fibrosing hepatitis. Similar changes were also noted by Hoeppli (1933) in a series of 66 patients 21. In all of these individuals, the infection was discovered incidentally at autopsy, most patients having die d accidentally, and the conclusion was drawn that bodily damage may b e considerable even though symptoms were abs ent or slight. More recent studies such as those of Hou 23 have defined the incidence of gall-stones, biliar y obstruction, cholangitis and cirrhosis in clonorchiasis, but the absence o f controls has not allowed adequate evaluation of the role of Clonorchis in the genesis of these conditions. Although flukes generally live in the bile ducts, worms have occasionally been found in the pancreatic ducts, the first such patient being described b y Sambuc in 191364. Attempts have been made from time to time to associat e clonorchiasis with cancer. Watson-Wemyss in 1919 reported the coexistence of carcinoma of the liver and clonorchiasis in a Chinese soldier 72, but this association was almost certainly coincidental since both conditions are ver y common in eastern Asia. There may, however, be more substance in the suggestion of a causal relationship between clonorchiasis and carcinoma of th e bile ducts 17.

RECOGNITION OF THE CLINICAL FEATURES Although the first patient reported with clonorchiasis had features clearl y referrable to the hepato-biliary system, having both fever and jaundice 45, these signs could also have arisen as a result of complications of the Clonorchis infection or from a co-existent illness. When he described his second cas e three years later, McConnell remarked that: I am inclined to believe that there do not exist any special symptoms o f liver infection by these flukes - nothing by which the disease can b e

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recognised during life. 46 The question of the clinical manifestations of C. sinensis infection was taken up by Oldt in 1927 in a paper entitled "Is clonorchiasis a health menace i n China?"55. Although he considered that cholelithiasis, Banti's disease, carc inoma and liver disease with ascites were m ore common in patients with Clonorchis infections, particularly in those wi th heavy worm burdens, he concluded from his clinical studies that the presence of flukes did not ordinarily excit e symptoms, and felt that there was no group of symptoms that could properly be called typical of clonorchiasis. Indeed, after considering all the factors, he believed that clonorchiasis was less harmful than ascariasis. Berkowitz working in Korea (1931) believed that the commonest features of clonorchiasis were indigestion and an enlarged liver, but provided no data to support this contention. He also suggested that flukes might cause nigh t blindness, for when flukes were removed by drainage with duodenal tubes left in situ for days, this symptom resolved 5. While it is conceivable that biliar y obstruction by flukes could impede the absorption of vitamin A and thus produce night blindness, it is perhaps more likely that an improved diet while in hospital may have replenished a deficiency of the vitamin. A massive outbreak of clonorchiasis occurred in 1946 in Shanghai, China when 20-30% of 20,000 Jew ish refugees became infected after eating pickled fish. One group was observed from soon after exposure then during the prodromal and acute phases. The onset of illness was variable, with fever sometimes beginning abruptly, sometimes insidiously. This was associated in some patients with enlargement of a tender liver, slight jaundice, splenomegaly and an eosinophilia in 10-40% of them. Eggs were found three to four weeks after exposure39. While these manifestations may have been a consequence of clonorchiasis, there are a multitude of other infectious agents, particularly vira l hepatitis, which occur commonly in refugee camps and could have accounted for most of these effects, and concurrent inf ection with other helminths is likely to have caused an eosinophilia. It certainly seems likely that chronic Clonorchis infection does not cause significant symptoms, particularly if the worm burden is not high. This view is supported by the observations of Strauss w ho compared symptoms in 58 infected Orientals and 48 infected Caucasians in San Francisco, USA, with those in a similar number of uninfected control subjects of both racial groups; n o significant differences were found between infected and uninfected persons 69.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of clonorchiasis was made initially at autopsy. The passage of eggs in the faeces provides a simple method of arriving at the diagnosis. It is not clear who first made use of this technique in the living patient, althoug h Roux and Tardieux (1912) appear to have been amongst the earliest 61. Ova can also be recovered from the upper gastrointestinal tract. Thus, C. sinensis eggs were found in the bile at cholecystostom y71 and in duodenal fluid obtained

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by duodenal intubation 5. Immunodiagnosis has not been of great value. Kuwabara and Muto in 1921 found that the complement fixation reaction was positive in a patient wit h longstanding clonorchiasis but negative in a patient with recent infection 41. In the following year, Ryuji extended these observations in both humans and experimental animals and concluded that the established methods of faeca l examination for ova were both more reliable and easier 62. Radiological investigations such as oral cholecystography and intravenous cholangiography, although not providing an aetiological diagnosis, may give a picture of structural damage consequent upon the infection 57. Functional damage may be indicated by liver function tests, particularly in patients with heavy infections or bacterial complications, but these tests are usually normal in persons with light infections. Choi and his colleagues, for example, found no significant differences between asymptomatic infected persons an d uninfected control subjects 10.

THE SEARCH FOR EFFECTIVE TREATMENT Initial attempts to treat clonorchiasis were based upon the principle of firstly stimulating liver secretions (hopefully) by the administration of such agents as calomel, urotropin and sodium salicylate in order to expel the parasites from the bile duct mechanically, then secondly, obtaining their removal from th e intestines by prescription of purgatives and enemata 61. Needless to say, these measures were not particularly effective. Direct surgical intervention wit h flushing out of flukes by drainage of the gall bladder was also tried o n occasion54,71. Similarly, Bercowitz proposed prolonged duodenal intubatio n and suction in order to remove a dult worms, but the side-effects of such a procedure were somewhat severe 5. A number of specific anthelmintics have been advocated. Some efficac y 14,56 has been claimed for tartar emetic 8, arsphenamine66 , gentian violet , 68 58 29 4 32,59 neostibnal , gold , fouadin , chloroquine , hexachloroparaxylol , and hetol76,77 but the effectiveness of these drugs left a lot to be desired and their toxicity was a serious problem. The recent introduction of praziquantel (see chapter 3) has provided a safer and more effective drug. Although Wang and his colleagues compared praziquantel, amoscanate and hexachloroparaxylol in 98 patients in China and concluded that hexachloroparaxylol was the drug of choice70, subsequent workers have found that praziquantel to be the most effective. Thus, Rim and his colleagues treated 35 patients with three doses of praziquantel on a single day and cured 30 of them; the remaining five patients were cured by a second course of treatment and there were few side-effect s apart from headache and dizziness 60. Similar results have been reported b y other investigators 2,22.

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UNDERSTANDING THE EPIDEMIOLOGY The major factors underlying the epidemiology of clonorchiasis were discerned only gradually. In 1887, Ijima first demonstrated that there was an anima l reservoir of infection when he dissected three cats in Tokyo and foun d C. sinensis in two of them. He concluded that "It thus stands beyong doubt that Dist. endemicum infests not only the human liver but also cats" 30. Subsequently, Kobayashi showed tha t a wide range of carnivorous animals was susceptible to infection 36,38. The importance of cats and dogs in th e maintenance of the life cycle was revealed when it was shown that these animals were heavily infected in central China and that approximately 30% o f them were so infected in northern China 13. Nevertheless, the distribution o f clonorchiasis in animals and humans did not always coincide, the infectio n being infrequent in humans in central China and unknown in northern China, whereas it was common in southern China. The explanation of this phenomenon was furnished by Kobayashi's discovery in 1911 of fish being the second intermediate host of C. sinensis 35, for only in southern China was it the custom of humans to eat fish raw or undercooked. Oldt analysed the prevalence o f infection in this region in detail and showed that 20-30% of humans were infected whereas cats and dogs were only slightly infected55. This was because the price of fish was so high as to preclude its being fed to these animals. For the same reason, the infection was mo re common in the wealthier business people because the poorer classes could not afford to buy the food. The infection was common, however, in the farmers who raised the fish in fresh-water ponds . Amongst towns-people, it was more prevalent in males than in females be cause raw fish were usually eaten in restaurants that women did not patronize. Similarly, custom favoured infection in Vietnam where 1-40% of humans, 11% of dogs and 33% of cats were infected. The Vietnamese commonly ate fish raw. The larger kinds were scaled, cleaned, filletted, cut into pieces 1-4 cm long, carefully dried between two bits of paper, dipped into an acid, salty or sugary sauce, sprinkled with rice or grated sesame, mixed with powdered ginger, wrapped in some aromatic leaf an d eaten. Small fish such as Carassius auratus, however, were placed in a bowl and allowed to swim about, then the feaster when he felt so disposed, f ished for it with a scoop, seasoned it, and ate the fish while it was still wriggling 24. Hsu and Chow investigated the prevalence and intensity of infection with C. sinensis in various species of fish frequently eaten in Canton, the majo r endemic area in China. They found that the number of cysts ranged from none to as many as 300 per fish 26. Finally, when Muto (1918) found the missing link in the chain b y discovering that Bithynia striatula was the first intermediate host, an d subsequent workers defined several other susceptible species of molluscs in limited geographical areas, the restricted distribution of C. sinensis became understandable and fears that clonorchiasis might be introduced and spread in

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new regions were assuaged.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The possibility of preventing clonorchiasis was apparent immediately Kobayashi discovered that fish were the vehicle by which the worm was conveyed to humans. Kobayashi realized this and observed the effects of preparing fish in the standard Japanese ways on the vitality of the enclosed cysts. When whole fish were roasted over live charcoals or boiled in water for 15 minutes an d then fed to cats and rabbits, infection failed to develop, but when the fish were cooked in water at 50-70 oC for 15 minutes, the worms remained viable . Kobayashi found that larvae remained alive for several days when fish wer e refrigerated, but if the fish were kept at room temperature, the young fluke s died when their host became putrid 38. A few years later, Faust also showed that worms survived immersion in strong brine for 54 hours and drying for a similar period 13. It was clear that the infection could be prevented by proper cooking of fish, and many authorities recognized the need for intensive health educationa l campaigns to persuade the populace to reform their eating habits. Thus, one author suggested that public places and schools should be placarded wit h humorous posters24, while in Okayama prefecture, Japan, a leaflet was dis tributed urging that for the good name of the prefecture, river fish should not be eaten unless fully cooked and that no unboiled water be used 67. Other control measures have been suggeste d such as sanitary disposal of human faeces 16 and attempts at snail control 67, but for a variety of reasons, these have not been very successful. Finally, officials of the United States government became concerned about the possibility of importation and spread of clonorchiasis in the USA whe n 20% of Chinese immigrants arriving at San Francisco during World War I were found to be infected 19. Consequently, aliens with clonorchiasis wer e excluded from Hawaii, the condition being classified as a "loathsome an d contagious disease". Since the infection did not spread to humans in th e mainland USA or in Hawaii, and as experiments failed to incriminate native snails as intermediate hosts 73, this restriction on immigration was relaxed i n 1927.

REFERENCES 1. ABBOTT RT. Handbook of medically important mollusks of the Orient and Wester n Pacific. Bulletin of the Museum of Comparat ive Zoology, Harvard College 100: 245-328, 1948 2. AMBROISE-THOMAS P, GOUVILLIER A, WEGNER DG. Le praziquantel dans le traitement des distomatoses hépatiques extrême-orientales à Clonorchis sinensis ou Opisthorchis viverrini. Bulletin de la Société de Pathologie Exotique 74: 426-433, 1981

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3. BAELZ E. Über einige neue Parasiten des Menschen. Berliner klinische Wochenschrift 20: 234-238, 1883 4. BASNUEVO JG. Cloroquina y clonorchiasis. Revista Kuba de Medicina Tropical y Parasitologia 5: 105-110, 1949 5. BERCOWITZ Z. Clinical studies of human infestations with the liver fluke ( Clonorchis sinensis). American Journal of Tropical Medicine 11: 43-60, 1931 6. BLANCHARD R. Animaux parasites (Notice préliminaire). Bulletin de la Sociét é Zoologique de France 20: 217, 1895 7. BORDES FP, CAVALLO A, VAILLANTA, MARTIN M. Distomatose hépatiqu e évoluant plus de vingt ans après l'infestation. Médecine Tropicale 23: 139-142, 1963 8. BRUG SL. Un cas grave de clonorchiase traité par l'émétique. Bulletins de la Société de Pathologie Exotique et de ses Filiales 14: 161-162, 1921 9. CALERO MC. Clonorchiasis in Chinese residents of Panama. Journal of Parasitolog y 53: 1150, 1967 10. CHOI DW, KIM JW, PARKS SB. Laboratory findings in symptomless clonorchiasis. Korean Journal of Parasitology 8: 8-12, 1970 11. COBBOLD TS. The new human fluke. Lancet ii: 423, 1875 12. FAUST EC. Notes on larval flukes from China. II. Studies on some larval flukes from the central and south coast p rovinces of China. American Journal of Hygiene 4: 241-301, 1924 13. FAUST EC. Some recent aspects of the epidemiology of Clonorchis infection in China. China Medical Journal 39: 287-296, 1925 14. FAUST EC, KE-FANG Y, KHAW O K, YUNG-AN C. Experimental therapy i n Clonorchis infections. Proceedings of the Society for Experimental Biology and Medicine 23: 607-608, 1926 15. FAUST EC, KHAW OK. Excystment phenomena in Clonorchis sinensis . Proceedings of the Society for Experimental Biology and Medicine 23: 245-248, 1925 16. FAUST EC, KHAW OK. Studies on Clonorchis sinensis (Cobbold) with a consideration of the molluscan hosts of Clonorchis sinensis (Cobbold) in Japan, China and southeastern Asia and other species of molluscs closely related to them. American Journal of Hygiene Monograph Series, Number 3, pp 284, 1927 17. FLAVELL DJ. Liver fluke infection as an aetiological factor in bile duct carcinoma of man. Transactions of the Royal Society of Tropical Medicine and Hygiene 75: 814-824, 1981 18. GALLIARD H. Recherches sur l'étiologie de la distomatose hépatique au Tonkin . Annales de l'École Supérieure de Médecine et de Pharmacie Indochine 2: 96-103, 1938 19. GUNN H. Clonorchis sinensis in Orientals arriving in the United States. Journal of the American Medical Association 67: 1835-1836, 1916 20. HEANLEY CN. The age incidence of 109 cases of Opisthorchis sinensis infection in Cantonese: its small pathologica l significance. Journal of Tropical Medicine and Hygiene 2: 38-39, 1908 21. HOEPPLI R. Histological changes in the liver of thirty-six Chinese infected wit h Clonorchis sinensis . Chinese Medical Journal 47: 1125-1141, 1933 22. HORSTMANN RD, FELDHEIM W, FELDMEIER H, DIETRICH M. High efficacy of praziquantel in the treatment of 22 patients with Clonorchis/Opisthorchis infections. Tropenmedizin und Parasitologie 32: 157-160, 1981 23. HOU PC. The pathology of Clonorchis sinensis infection of the liver. Journal o f Pathology and Bacteriology 70: 53-64, 1955 24. HOUDEMEYER E. Au sujet d'une coutume favorisant l'infestation des Indochinois par Clonorchis sinensis (Cobbold, 1875). Bulletins de la Société de Pathologie Exotique et de ses Filiales 27: 21-23, 1934 25. HOUGHTON HS. Notes on the life cycle of Clonorchis. China Medical Journal 27 : 168-171, 1913 26. HSU HF, CHOW CY. Studies on certain problems of Clonorchis sinensis . II.

Clonorchiasis

27.

28.

29. 30. 31. 32.

33. 34. 35.

36. 37.

38.

39.

40. 41.

42.

43.

44. 45. 46. 47. 48. 49.

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Investigation in the chief endemic centre of China, the Canton area. Chinese Medica l Journal 51: 341-356, 1937 HSU HF, LI SY. Studies on ce rtain problems of Clonorchis sinensis . VIII. Experimental proof of Bithynia longicornis as the first intermediate host of C. sinensis. Chinese Medical Journal, Supplement 3: 241-243. 1940 HSU HF, LI SY. Studies on certain problems of Clonorchis sinensis . IX. The migration route of its larval stages in the snail, Bithynia fuschsiana . Chinese Medical Journal , Supplement 3: 244-254, 1940 HUECK O, WEN HH. Zur Fuadinbehandlung bei Opisthorchis sinensis . Archiv für Schiffs- und Tropen-Hygiene 42: 25-27, 1938 IJIMA I. Notes on Distoma endemicum , Baelz. Journal of the College of Science , Imperial University, Tokyo 1: 47-59, 1886 ISHIZAKA K. Igaku Zasshi (40): 20-26, 1878. In Japanese JOHN L, WANG CN, TSENG FJ, FAN KC, TU CC, CHANG TF, SUN KJ, CHI N CM, TU SF. Hexachloroparaxylol in the treatment of clonorchiasis sinensis. Chines e Medical Journal 84: 8-16, 1963 KEAN BH, MOTT JE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 KHAW OK. The hatching pheno mena of Clonorchis ova. Proceedings of the Society for Experimental Biology and Medicine 22: 564-566, 1925 KOBAYASHI HARUJIRO. (A preliminary report on the source of the human live r distome, Clonorchis endemicus [Bälz][=Distoma spathulatum Leuckart]). Annotationes Zoologicae Japonenses 271-277, 1911. In Japanese, with English summary KOBAYASHI HARUJIRO. Saikingo Zasshi No. 202, pp 1-66, 1912. In Japanese KOBAYASHI HARUJIRO. A preliminary report on the source of the human live r distome, Clonorchis endemicum (Bälz)(Distomum spathulatum , Leuckart). Far Eastern Association of Tropical Medicine: Transactions of the Second Biennial Congress, Hong Kong, pp 108-112, 1912 KOBAYASHI HARUJIRO. On the life history and morphology of Clonorchis sinensis . Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilun g originale 75: 299-317, 1915 KOENIGSTEIN RP. Observations on the epidemiology of infections with Clonorchis sinensis. Transactions of the Royal Society of Tropical Medicine and Hygiene 42 : 503-506, 1949 KOMIYA Y. Clonorchis and clonorchiasis. Advances in Parasitology 4: 53-106, 1966 KUWABARA S, MUTO M. (Is immunization possible in liver distomiasis?) Chu o Igakkai Kw. Zasshi Nagoya pp 34-45, 1921. In Japanese. Abstracted in Japanese Journal of Medical Science 1: 145, 1922 LEIPER RT. Report on an exp edition to China to study the trematode infections of Man. Unpublished report to the Colonial Office, pp 4, 1915. Abstracted in Tropical Diseases Bulletin 6: 295-296, 1915 LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührende n Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sch e Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876 LOOSS A. On some parasites in the museum of the School of Tropical Medicine , Liverpool. Annals of Tropical Medicine and Parasitology 1: 123-152, 1907 McCONNELL JF. Remarks on the anatomy and pathological relations of a new species of liver-fluke. Lancet ii: 271-274, 1875 McCONNELL JF. "Distoma sinense" (McConnell). Lancet i: 406, 1878 McGREGOR W. A new form of paralytic disease associated with the presence of a new species of liver parasite. Glasgow Medical Journal 9: 3-15, 1877 MEBIUS J. Clonorchiosis hepatis, cirrhosis parasitaria en typische groei van het galgangepitheel. Geneeskundig Tijdschrift voor Nederlandsch-Indië 60: 224-294, 1920 MOORE D. Note on the longevity of Clonorchis sinensis . Public Health Reports 39 :

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18021803, 1924 50. MUKOYAMA T. (Experimental study on the transmigration route of the liver distome in the body of the final host). Aichi Igakkai Zasshi 29, No. 2, 1922. In Japanese . Abstracted in Japan Medical World 2: 243, 1922 51. MUTO M. Ueber den ersten Zwischenwirt von Clonorchis sinensis . Verhandlungen der japanischen pathologischen Gesellschaft, Tokyo 8: 151, 1918. Abstracted in Tropica l Diseases Bulletin 17: 49, 1921 52. MUTO M. (On the primary intermediate host of Clonorchis sinensis ) Chuo Igakkai Zasshi 25, No. 3: 49-52, 1918. In Japanese. Translated in 33 53. MUTO M. On the duration of life of Clonorchis sinensis infecting the animal body. Japan Medical World 2: 224-226, 1922 54. NARDONE PM. La distomiasis sinense. Contributo allo studio delle sindromi d a "Clonorchis sinensis" nell'esturio dello Yangtzekiang e nella zona di Shanghai (Cur a chirugica con fistola biliare terapeutica). Annali di Medicina Navale 53: 59-78, 1948 55. OLDT F. Is clonorchiasis a health menace in China? China Medical Journal 41: 185-204, 1927 56. OLIVIER PH, KANDOU R. De behandeling van Clonorchiasis sinensis me t Gentiaanviolet Grübler. Geneeskundig Tijdschrift voor Nederlandsch-Indië 67: 59-63 , 1927 57. OTTO JH. Zur Frage der röntgenolo gischen Erkenbarkeit krankhafter Veränderungen am Magen-Darmkanal bei Patienten mit Opisthorchis sinensis . Archiv für Schiffs- un d TropenHygiene 41: 296-302, 1937 58. OTTO JH, TSCHAN TJ. Ueber de Behandlung der menschlichen Infektion mi t Clonorchis sinensis (Kobbold) mit Goldeinspritzungen. Archiv für Schiffs- un d Tropen-Hygiene 39: 99-106, 1935 59. PLOTNIKOV NN, SINOVICH LI. (Experimental therapy of clonorchiasis wit h hexachloroparaxylol. Preliminary communication). Meditsinskaya Parasitologiya i Parazitarn e Bolezni, pp 301-302, 1964. In Russian, with English summary 60. RIM HJ, LYU KS, LEE JS, JOO KH. Clinical evaluation of the therapeutic efficacy of praziquantel (Embay 8440) against Clonorchis sinensis infection in man. Annals o f Tropical Medicine and Parasitology 75: 27-33, 1981 61. ROUX, TARDIEU. Un cas de distomatose hépatique ( Opisthorchis sinensis ) chez une Européene. Bulletin de la Société Médico-Chirurgicale de l'Indochine 3: 528-532, 1912 62. RYUJI S. (Diagnostic value of complement fixation in distomiasis). Okayama Igakkwai Zasshi No. 384, 1922. In Japanese. Abstracted in Tropical Diseases Bulletin 19: 651 , 1922 63. SAITO S. (The internal organs of Clonorchis sinensis ova and the morphology of th e miracidium). Tokyo Igakkai Zasshi 12: 579-587, 1898. In Japanese. Partly translated in 33 64. SAMBUC E. Distomatose pancréatique. Bulletin de la Société Médico-Chirurgicale de l'Indochine 4: 331-333, 1913 65. SAMBUC E, BAUJEAN R. Un cas de cachexie aqueuse chez l'homme (distomatos e hépatopancréatique) avec syndrome pseudo-béribérique. Bulletin de la Sociét é Médico-Chirurgicale de l'Indochine 4: 425-429, 1913 66. SHATTUCK GC. Results of treatment for clonorchiasis. American Journal of Tropical Medicine 3: 475-494, 1923 67. SHIMUZU K, KAWADA T. Prevention of distomi asis hepatis as carried out in Okayama prefecture. Journal of the Public Health Association of Japan 13: 1-4, 1937 68. SHIRAI M. Studies on the tr eatment of experimental liver distomiasis with "Neostibnal". Scientific Reports of the Government Institute of Infectious Diseases 5: 633-645, 1926 69. STRAUSS WG. Clinical manifestations of clonor chiasis - a controlled study of 105 cases. American Journal of Tropical Medicine and Hygiene 11: 625-630, 1962 70. WANG QN, LIU JB, LIU YH, CHEN RX, QIU ZD, QU ZG. Comparison o f praziquantel, amoscanate and hexachloroparaxylol in clonorchiasis sinensis. Chines e

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Medical Journal 93: 849-856, 1980 71. WATSON FC. Clonorchis sinensis infection of the gall bladder and biliary passages with report of a case. Proceedings of the Medical Association of the Isthmus Canal Zone 10: 130135, 1917 72. WATSON-WEMYSS HL. Carcinoma of the liver associated with infection b y Clonorchis sinensis . Edinburgh Medical Journal 22: 103-104, 1919 73. WAYSON NE. An investigation to determi ne whether clonorchiasis may be disseminated on the Pacific slope. American Journal of Tropical Medicine 3: 461-473, 1923 74. WAYSON NE. Spontaneous hatching of Clonorchis ova. A preliminary note on th e investigation to determine whether clonorchiasis may be disseminated on the Pacifi c Slope. Public Health Reports 39: 861-862, 1924 75. WYKOFF DE, LEPES TJ. Studies on Clonorchis sinensis . I. Observation on the route of migration in the definitive host. American Journal of Tropical Medicine and Hygiene 6: 1061-1065, 1957 76. YOKOGAWA M. Chemotherapy of Clonorchis sinensis . II. Clinical observations on the treatment of clonorchiasis patients with 1,4-Bis-Trichloromethylbenzol. Japanese Journal of Parasitology 14: 526-533, 1965 77. YOKOGAWA M, KOYAMA H, YOSHIMURA H, TSAI CS. (Chemotherapy o f Clonorchis sinensis infection. I. Chemotherapy with 1,4-Bis-Trichloromethylbenzo l [Hetol] for animals infected experimentally with Clonorchis sinensis .) Japanese Journal of Parasitology 14: 233242, 1965. In Japanese, with English summary 78. YOSHIMURA H. The life cycle of Clonorchis sinensis : a comment on the presentation of the seventh edition of Craig and Faust's Clinical Parasitology. Journal of Parasitology 51: 961966, 1965

Table 6.1. Landmarks in clonorchiasis _________________________________________________________________________ 1874 1887 1911

McConnell discovered adult worms in the bile ducts of a human Ijima found the parasite in cats Kobayashi discovered the second intermediate host by feeding cyprinidine fis h infected with certain cysts to cats then recovering adult worms 1912 Roux and Tardieu diagnosed cl onorchiasis in a living patient by finding eggs in the faeces 1915 Kobayashi suggested that larvae migrated from the gut directly into the biliar y system 1918 Muto discovered the first intermediate host by incubating naturally infected snails with fish then feeding the fish to dogs then finally recovering adult worms 1918 Muto infected a snail with a miracidium and found a single sporocyst 1920 Mebius emphasized the possible pa thological consequences of C. sinensis infection 1922 Mukoyama confirmed the larval migration route suggested by Kobayashi 1940 Hsu and Li showed that miracidia hatch only in the alimentary canal of susceptible snails and described their development in molluscs 1981 Various investigators report ed that praziquantel was the most effective drug for the treatment of clonorchiasis _________________________________________________________________________

Chapter 7

Paragonimus westermani and PARAGONIMIASIS

SYNOPSIS Common name: lung fluke Major synonyms: Distoma ringeri, D. pulmonale, D. westermani Distribution: eastern Asia (related species are found in West Africa) Life cycle: the ovoid flukes, 7-12 mm long by 4-6 mm wide and thick, live in cavities in the lungs and produce eggs which are coughed up in the sputum. The ova develop in water over two weeks then each miracidium escapes and invades snail intermediate hosts of the genera Semisulcospira and Brotia. The miracidium becomes a sporocyst which produces rediae then cercariae. The emergent cercariae invade the gills then the muscles of a number of freshwater crabs and crayfish where they encyst. On ingestion by a human, the enclosed metacercariae excyst in the duodenum, migrate through the intestinal wall to the peritoneal cavity then pass through the diaphragm and the pleural spaces to the lungs where they mature in cysts or "capsules" over two to three months Definitive hosts: humans, cats, dogs, mongoose etc Major clinical features: fever, cough, sputum, dyspnoea, abdominal discomfort and epilepsy in heavy infections Diagnosis: demonstration of eggs in sputum, pleural aspirates or faeces Treatment: bithiniol, praziquantel

DISCOVERY OF THE ADULT WORM In June 1879, a Portuguese resident of Tamsui, Formosa (Taiwan) die d suddenly from a ruptured aneurysm of the ascending aorta. Since he was a foreigner, the local physician, Dr BS Ringer, was able to perform a post mortem examination without incurring the wrath of the Chinese who wer e extremely prejudiced against mutilating the human body after death. A t autopsy, Ringer found, in addition to the aneurysm, a parasite in the lungs . Since the dead man had been a patient of Patrick Manson's in Amoy, Chin a during November and December of the previous y ear, Ringer wrote to Manson detailing his findings. With respect to the worm, he wrote: After making a section I found the parasite lying on the lung tissue - it might have escaped from a bronchus. Whilst alive a number of young (microscopic) escaped from an opening in the body. There were some small deposits of tubercle, no cavities, and, if I remember aright, slight congestion of the lungs. 104

On 24 April of the following year (1880), a 35 year old Chinese man, who was a secretary in a mandarin's office, consulted Manson about an eczematous 159

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eruption on his face and legs. While the patient was speaking, he was seized by a fit of coughing and expectorated small quantities of reddish sputum . Manson (who at that time was trying to find the daytime location of periodic microfilariae) placed some of this material on a microscope and was astounded to find that instead of the anticipated microfilariae, it: contained, besides ordinary blood and mucus corpuscles, large numbers of bodies evidently the ova of some parasite. These bodies were oval in form, one end of the oval being cut off by an operculum, granular on the surface, bloodstained, measuring on an average 1/300" x 1/500". Firm pressure on the covering glass caused them to rupture and their contents to escape, the shell being left empty and fractured at the opercular end....No distinctly organised embryo could be made out in the uninjured ovum, but when the contents were expressed, they resolved themselves into oil masses, and granular matter having very active molecular movements. 69

Concerned that there might be a parent worm in the mouth or throat, Manson examined the oral cavity caref ully but failed to find such a parasite. In order to exclude accidental introduction of ova in food, he obtained a fresh specimen of sputum two days later and confirmed the presence of eggs. He wrote in his diary at this time that "I cannot but think that the parent of the ova and th e haemoptysis are associated as cause and effect" 72. Several years later he recalled that "I concluded that a parasite must reside somewhere below th e vocal cords, probably in the lungs, and that I had stumbled on a new disease." 71 Further enquiry revealed that the patient had o nly been in Amoy for one year. He was a native of Foochow in China but fifteen years previously he had gone to Taiwan to live and had remained there for nearly ten years. Moreover, the attacks of haemoptysis had begun after he had been on that island for about a year. He had lived in a town called Tacktc ham, a place about two days' journey from Tamsui, and this reminde d Manson of the parasite discovered by Ringer. Accordingly, he wrote to Ringer who s ent him the solitary specimen preserved in "spirit of wine". Manson placed a little of the sediment in the spirit under a microscope and "found in it several ova of the same shape, colour, an d dimensions as those I had some time before found in the Chinaman' s sputum."69 The parent parasite was light brown in colour, of a firm, leathery texture, and measured nearly half an inch in length. Manson realised that it was a trematode, but being unsure of whether or not it was a new species, sent it to Spencer Cobbold in London together with a covering letter dated 4 May 1880 saying: I could not find in your 'Parasites' a worm to correspond, and as I have some idea that the worm is not an unfrequent cause of haemoptysis in Chinese, I turn to you for more information. I send the worm - evidently a fluke - and also a sample of the Chinaman's sputum.68

Cobbold communicated news of the discovery to the meeting of the Quekett Microscopical Club on 25 June 1880, and there announced his intention t o name the fluke Distoma ringeri after its discoverer. The first notice of thi s event appeared in an abstract in The Lancet of 3 July 1880 13 then Manson's

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letter to Cobbold was published in the Journal of the Quekett Microscopical Club the following month 68. In an Appendix to this paper, Cobbold added that he had now viewed the worm sent to him by Manson: I satisfied myself that the fluke was new to science and accordingly I propose to call it Distoma ringeri after the discoverer. Though mutilated, the oral sucker was well shown, as also were traces of an organ which I regarded as the remains of the ventral acetabulum. When flattened on a glass slide, the capsules of the vitellarium were well seen, and occupied fully four-fifths of the body, lying deep under the dermal surface. The worm reminds me very much of the Distoma compactum, which many years ago I detected in the lungs of an Indian ichneumon, but it is much larger and evidently a distinct species.36

Manson's detailed account of the ova and clinical aspects of the case appeared in the Medical Reports of the Imperial Maritime Customs (China) 69, was reproduced in the Medical Times and Gazette in 1881 69, and was retold in The Lancet in 1883 71. Meanwhile, the same eggs had been seen in 1878 in Tokyo, Japan, by Erwin Baelz, although he failed initially to recogniz e their true nature. Baelz had gone to Japan from Germany in 1878 as a lecturer at the Imperial University i n Tokyo. Soon after his arrival, he became in terested in a respiratory disease that had been mistaken previously for tuberculosis. In September 1880, Bael z reported that he had seen 19 patients with haemoptysis in whose sputum h e had found parasites. He described these organisms as being of two forms: (1) as intensive yellow-brown, oval bodies, 0.13 mm in length and 0.07 mm in width. They have an sharp, doubly refractile shell, 0.02 mm thick, which shimmers greenish or reddish....At the blunt end a kind of cover is often found; here the cyst of the "egg" opens. The contents consist of a viscous gelatin in which three to five (most often four) lumps are embedded....(2) motionless balls ....having no shell and measuring 0.01 to 0.04 mm in diameter.16

He believed that the larger bodies were psorosperm cysts and that the smaller balls were immature psorosperms. Since psorosperms were thought at tha t time to be a stage in the development of gregarines (i.e. protozoa), Baelz in his first publication stated that he: wish(ed) to name this disease Gregarinosis pulmonum and the parasite Gregarina pulmonalis, or perhaps also, because of its color, Gregarina fusca.16

Soon afterward, Baelz sent specimens containing these bodies to Leuckart in Germany who pronounced them to be eggs of a trematode. In the meantime, Baelz, while awaiting Leuckart's reply, had come to the same conclusio n himself, as is indicated in his letter to Manson quoted below. An abstract of Baelz's report appeared in The Lancet of 2 October 1880 13. Manson read this and recognized the likely connection between the eggs h e was studying and the parasite found by Bael z. He therefore wrote to Baelz who sent him some sputum containing the bodies, together with an accompanying letter dated 19 February 1881 (publ ished in Manson-Bahr and Alcock 74 where it is misdated as 1880, and in Manson-Bahr 73): Dear Dr. Manson, - First of all I have to apologize for not having written to you earlier. I always waited for a good case of the Haemoptöe parasitica, to send you a

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specimen. At last I have got a prominent one, and trust you will be able to compare the eggs in the sputa with those which you found in the lung of a patient affected with distoma. It is not at all improbable that you will find them identical. I had called them Gregarinae, because they are exactly what is described as such, but now when I send my first notice of them to Europe, I saw some cases what seem to me to prove that the oval bodies must be eggs of some worm, and if so, there could hardly be question of another than distoma. I wrote this to Leuckart, and he too is of the same opinion.... P.S. I ask your pardon for my bad English, I have not much practice in writing the language, and feel only too well that I always make mistakes. 18

When Manson examined the specimens sent to him by Baelz, he found that the bodies were identical in every respect with those coughed up by his ow n patient and with those expressed from Ringer's fluke 70. It was now clear that Baelz's Gregarina pulmonalis were none other than ova of the fluke named D. ringeri by Cobbold. Near the end of 1880, the Japanese investigator, Nakahama, who had been a medical student at Tokyo Imperial University and a pupil of Baelz, went to Okayama in Japan to study the disease. He surveyed patients who came to the clinic of the Okayama Prefectural Hospital between November 1880 an d October 1882, and found 52 cases of the infection. In November 1881 in the same hospital, Drs Kiyono, Suga and Yamagata performed their first autopsy on a patient with parasitical haemoptysis and found about 20 cysts, each containing one or two worms. Nakahama tried to study the morphology of these worms but they had shrunk so badly in alcohol that it was impossible t o discern details of their structu re. Nevertheless, he sent several worms to Baelz in Tokyo with the suggestion that they be named Distoma pulmonalis. In March 1883, Nakahama and Suga carried out a second autopsy and obtained several more worms. Nakahama published his findings in four parts between February and September 1883 94, then Baelz prepared a report (published in a German journal) in which he named the species D. pulmonale 17, even though he must have known that Cobbold had called the same parasite D. ringeri. Before all these events occurred, however, a royal tiger had died in th e Amsterdam Zoological Gardens in Holland in September 1877. At autopsy, worms thought to be a species of Distoma were found in the lungs. These helminths were sent by the director of the zoo, Dr CF Westerman, to the Dutch zoologist Coenraad Kerbert for further identificaton. Kerbert described th e worms, which were nearly one centimetre long, as being: found, always in pairs, inside rather thick, fibrous capsules, which, because of the somewhat blue color, were noticed immediately on the outer surface of the lungs. 49

Since flukes had already been found in the lungs of an otter by Natterer an d described by Diesing in 1850 (D. rude) and in an Indian mongoose by Cobbold in 1859 (D. compactum), Kerbert thought that this trematode migh t prove to be one of those species. Detailed examination revealed that this was not so, and Kerbert recorded the discovery in 1878, naming the worm afte r

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Westerman and wrote: "I feel justified, therefore, in introducing this unknown worm to zoologists as Distoma westermanni, n. sp"49. Three years later, another tiger died in the Zoological Gardens in Hamburg, Germany, and a similar parasite was found in its lungs. This material was also forwarded to Kerbert, enabling him to undertake an intensive morphological study50. The specimens studied by Kerbert were re-examined later by Leuckart and Nakahama (who had gone from Japan to study parasitology in Germany with Leuckart), and they compared them with the Japanese flukes. Nakahama, incidentally, later returned to Japan and was awarded the degree of doctor o f medicine by Tokyo Imperial University. Much was expected of him as he was the first Japanese to receive such an extensive parasitological training, but he soon abandoned this vocation and took up a position as chief of the medical section of the Nippon Life Insurance Company. In 1889, Leuckart wrote that in his and Nakahama's opinion, the European and Japanese forms of th e worms were identical 64. This view became accepted and Stiles and Hassa l voiced the general opinion when they stated that the human parasite "though originally supposed to represent a new species, is now generally admitted to be identified with Kerbert's form from the tiger. 107. Since Kerbert's description had priority, Cobbold's name of D. ringeri and Baelz's D. pulmonale lapsed, and the parasite became known as D. westermanni, although there were pleas to the contrary, such as that written by Paul in Japan: 'Distoma pulmonale' is the best name; it raises no question as to priority of discovery, and by its affinity with the names 'distoma haematobium' and 'distoma hepaticum' it aids the memory and pleases an orderly mind.101

There was considerable confusion over the correct spelling of the specifi c name, however, with the forms westermanni, westermanii and westermani all being used by different authors, and even by the same author; eventually the last description became generally accepted even though Kerbert had first described it as westermanni. A number of authors realized that the morphological features of this fluke were so distinctive that it should not be retained in the genus Distoma. In 1899. Max Braun erected the genus Paragonimus for the mammalian lung flukes, making P. westermani (Kerbert) the type species 21. The name Paragonimus was derived from the Greek words (PARA) meaning "by the side of" and µ (GONIMOS) meaning "gonad" or "genitalia". Later in the same year, and unaware of Braun's revision, Arthur Looss gave a detailed description, which was the most accurate and complete that wa s available for many years, of the parasite. He established the genus Polysarcus for the mammalian lung flukes 66, but because of its slightly later appearance, this name was relegated to synonymy.

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ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND THE INTERMEDIATE HOSTS Manson concluded his paper of 1880 by remarking that the questions of the existence and identity of the intermediate host or hosts of the parasite offered a very interesting field for further investigation 69. Almost 40 years were t o pass, however, before the life cycle of P. westermani was finally determined. As soon as he first saw the ova, Manson realized that their contents wer e undeveloped. For about 18 months after his discovery of the eggs, he scrut inized sputa of about 150 persons in a fruitless search for more ova; he hoped that these would enable him to observe t he development of the larva within the egg and characterize the conditions under which it hatched. He deduced that the infection was not endemic in Amoy, and eventually obtained some fres h infected sputum from Taiwan which permitted him to continue hi s experiments. He placed some phlegm in water jars in his laboratory, the n examined them daily for the first fortnight or so, but the ova refused to hatch. He then forgot about the specimens for six weeks or so until his wife com plained of an odour emanating from the laboratory. The smell was comin g from the decomposing sputum on which fungi of all descriptions wer e growing. When he examined this material, Manson found that miracidia had developed and escaped from the ova by way of the opercula 70. He reasoned that the intermediate host must be an inhabitant of fresh water, common t o Japan and Taiwan where parasitic haemoptysis appeared to be endemic, but rare on the Chinese mainland around Amoy. With great foresight, h e considered the possibility of a snail being the intermediate host. He wrote to R Hungerford, a conchologist in Hong Kong for further information . Hungerford replied on 21 October 1881 and with remarkable prescience put his finger on the correct species: My dear Manson, Your discoveries about the lung fluke are decisively interesting, and any help I can give you in this matter is very much at your service. I know of one fresh water species which I think answers all your requirements of 16 shells of which I am sending you from my collection in the mail. Let me know if you would like to have a few specimens in spirit and I will write to a friend in Nagasaki to send them down. The shell I speak of is Melania libertina (Gould)....It occurs in Japan at....places widely apart....I have found none of this species in China, however,....On the whole I think M. Libertina must be your friend, he is a hardy beast and will reach you from Tamsui alive....It will be something in favour of my hobby, if it helps clear up a doubtful point in the natural history of flukes. 38

The full significance of Manson's perspicacity is displayed when it is recalled that it was not until 1882 that Thomas and Leuckart demonstrated that Fasciola hepatica was transmitted by molluscs (see chapter 4). Unfortunately, the lack of potentially appropriate snails and the difficulty in obtaining a con tinuing supply of ova prevented Manson from pursuing the matter further. Manson's observations on the development and hatching of miracidia were confirmed by Nakahama in 1885, but no further significant advances wer e

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made until the Japanese physician, Koan Nakagawa, reported his discoveries in 1915.

DISCOVERY OF THE CRAB SECOND INTERMEDIATE HOSTS The discovery by Kobayashi that freshwater fishes were the second inter mediate host of Clonorchis sinensis (see chapter 6) encouraged Nakagawa , who had been appointed head of the public hospital in Shinchiku, Taiwa n where parasitic haemoptysis was endemic, to seek the intermediate host o f P. westermani. He knew that an intermediate host was necessary for he ha d shown earlier that miracidia were incapable of developing in the definitiv e host. In October 1913, he had both fed puppies with miracidia and immersed them in water containing miracidia but had failed to find flukes in the dog s 45-100 days later90. He therefore collected and examined all the molluscs , fishes, amphibians and insects that he could find. In September 1914, he captured a crab that was of type he had not seen before in a rivulet near Kalapai village. He identified this creatu re as Potamon obtusipes, although it was later shown to be P. rathbuni 53. In the liver of this crustacean, Nakagawa foun d numerous encysted larvae, 0.2 mm in diameter, which were unmistakabl y half-grown trematodes, but the specific identity of which was uncertain . Continued searching, however, revealed the worms that he had been seeking: as a result of further investigation I found in the gills full-grown ones with all the morphologic structures peculiar to the distome of the human lung. 89

The second form of encysted larvae measured 0.3-0.4 mm in diameter, had a short, thick, straight body and an oval sucker with a spine. Nakagawa at that time believed that both the large and the small cysts belonged to P. westermani, with the smaller variety being merely younger stages of the larger. Subsequently, he found both kinds of metacercariae in P. dehaani, and occasionally in another crab, Eriocheir japonicus. Nakagawa was convinced on morphological grounds that the larger cysts at least, were stages in the life cycle of P. westermani, but in order to prove the point, he had to raise adult worms from them. He therefore fed the liver, gills and other organs of a crab harbouring numbers of encysted larvae to two puppies that had been obtained fr om an area where paragonimiasis was unknown. One of the dogs died 60 days later; post-morte m examination showed the lungs to have a large number of cysts. Within each cyst, two or three P. westermani were present, although they were insufficiently mature to produce eggs. The second dog died 90 days after eating infected crab. At autopsy, the lungs of the dog were found to contain numerous cysts enclosing adult flukes ready t o discharge ova. He then repeated the experiment with three more puppie s brought from a nonendemic area; two were fed with a large quantity of th e internal organs of infected crabs while the third was left as a control. The first two dogs died about seven weeks later and were found to be infected wit h

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Paragonimus, while the control puppy remained uninfected. These result s were first published in Japanese in 1915 87 then appeared in English in the following year 89. In that paper, Nakagawa summarized his findings thus: In conclusion, I may say that of the three species of freshwater crabs, the encysted larvae of the human lung distomes are found in the first and second species, the occurrence in the third being problematical.89

This discovery was soon confirmed by Ando, Hisao Kobayashi, Matsui, S Yokogawa and Yoshida, all of whom reported their experiences in the same year (1915). Yoshida found that in Japan, the species of crabs that were th e second intermediate hosts of P. westermani were Potamon dehaani, Sesarma dehaani and E. japonicus; cysts were found in the gills, muscles and liver of the crustaceans, the exact distribution depe nding upon the species of crab 132,133. He fed cysts to three cats and a dog and eventually recovered adult P. westermani. In Korea, Harujiro Kobayas hi found that in addition to E. japonicus, the crayfish Astacus (Cambaroides) similis was also an intermediate host of P. westermani 54,55. In 1917, Sadamu Yokogawa argued that the two forms of cysts found in the crab by Nakagawa belonged to distinct species, with the larger one being the intermediate stage of the lung fluke 127. Yokogawa based this conclusion upon the observation that the smaller cysts were sometimes found in regions where paragonimiasis was not endemic. Furthermore, the smaller cysts could b e reared, at least partially, in mice and the resultant immature worms inhabited the bile duct and did not have a spine on the oral sucker. As will be discussed later, Nakagawa in 1917 accepted that Yokogawa's views were correct. The precise mode by which humans and animals became infected wit h P. westermani was a matter of some debate. While infection could clearly be acquired by eating undercooked crabs, a number of investigators realized that paragonimiasis sometimes occurred in regions where people did not take crabs as food134 or else they always cooked them thoroughly first 40 . This led to the assumption that infection may result from contamination of food and water by freeliving cysts discharged from infected crabs.

DISCOVERY OF THE SNAIL FIRST INTERMEDIATE HOSTS It is difficult, if not impossible, to pinpoint precisely who first described th e primary intermediate host of P. westermani and the time when this was done. As described earlier, Hungerford in 1881 suggested that M. libertina was a likely species, purely on the basis of circumstantial evidence. Subsequen t investigators added experiment to hypothesis, but the details of most of their experiments were unclear, imprecise or incomplete. The first person after Hungerford to close in on the molluscan intermediate hosts was Nakagawa. Indeed, before he discovered cysts in the crab, he had made an extensive study of freshwater molluscs obtained from ponds an d

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streams in the region. He found 17 different kinds of cercariae, but could not distinguish those of the lung fluke. He therefore put various snails in wate r containing P. westermani miracidia in order to see which kinds of molluscs the miracidia would infect: It resulted that they infected Melania libertina Gould and M. oblique-granosa Smith most abundantly. From this it may be assumed that these two species of fresh water molluscs are the first intermediate hosts of the lung distomes. 89

Nakagawa tried to keep the snails alive in an experimental pond but they all died within a few weeks and no fully-developed cercariae could be seen. He did find, however, that all the M. libertina living in the creeks of a highl y endemic area contained sporocysts in the liver and a particular cercaria which he then described. He wrote in 1916 that "it may not be unreasonable to conclude that these cercariae are tho se of the lung distome. However, we have not yet any experimental proof" 89. In 1917, Nakagawa added new data to his earlier observations and indicated that M. tuberculata was also a likely vector. He published a detailed des cription of the development of larvae in the snails, but it is unclear whethe r these snails were infected experimentally with miracidia derived from human P. westermani ova or whether they were naturally-infected snails. It is probable that he was dealing with the latter case since he justified his assertion that the resultant cercariae were P. westermani on a number of grounds, including the resemblance between the cercariae and the small type of cyst he ha d described in the livers of crabs. Further, he attempted to establish the link in the life cycle between molluscs and crabs by infecting crabs with cercaria e derived from snails. He had considerable difficulty in obtaining crabs free of flukes, but finally secured 50 P. obtusipes and 20 P. dehaani. He put these together with Melania snails in a stream on 4 September 1915 but was re warded with only scant success. Again, it is uncertain whether the snails were infected experimentally or naturally. It seems likely that they were the latter, in which case the identity of the parasites is doubtful. When Nakagaw a examined the crabs 36 days later, he found none of 20 P. obtusipes and only one of 20 P. dehaani infected. When the remaining 30 crabs were dissected after a further three weeks, he could find only three infected animals . Nakagawa was uncertain why it was so difficult to infect the crustacean s experimentally. Indeed, the few crabs found to have been infected may wel l have acquired their infection naturally in the wild. Nevertheless, Nakagaw a was convinced that he had demonstrated the life cycle of P. westermani, and in 1917 published his findings in the Journal of Experimental Medicine 90. As mentioned earlier, Yokogawa in 1917 showed that the two types of cysts found by Nakagawa in crabs represented different species of flukes. Thi s confuses further the validity of the observations just described. Nakagaw a recognized he veracity of Yokogawa's assertions and admitted that the forms taken by him to be developmental stages of P. westermani belonged to some unknown fluke. He thereupon published a new series of illustrations of th e

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various stages in the development of the larvae which form large cysts 91,92 to replace the earlier series which had depicted both forms of larvae. The smaller cysts were subsequently identified as belonging to a previously undescribe d fluke, Stephanolecithus parvus 92,93. Inconclusive attempts to passage P. westermani through M. libertina were also made by Kakami 40. In 1918, Kobayashi working in Korea, showed tha t under experimental conditions, P. westermani miracidia attacked M. gottschsei, M. nodiperda var. quinaria and M. extensa vigorously. He concluded cautiously that the genus Melania was probably concerned in the metamorphosis of Paragonimus 55. He then examined the effects of infecting M. paucicincta with P. westermani miracidia reared from human sputum. Th e miracidia penetrated the skin readily and gave rise to sporocysts localized near the surface. Within each sporocyst, a single redia was formed. The redia e migrated into the deeper parts of the snail's body and formed secondgeneration rediae which in turn migrated into the liver and produced cercariae 56. Similar experiments were performed and results obtained at almost the same time by K Miyairi78,79. In a new attempt to prove that snails were the intermediate host of P. westermani, A Ando (also known as R Ando) took cercariae isolated from (probably) naturally-infected Melania and introduced them through the mouth, gills, genital openings and wounds on the surface of crabs, but the cercariae failed to develop or else the crabs died. He therefore put P. dehaani into a pool with snails heavily infected with cercariae; the snails had been obtained from a n area that was highly endemic f or paragonimiasis. Many crabs became infected subsequently with P. westermani, and some of the parasites were induced to develop into adult Paragonimus when the infected crabs were fed to youn g dogs6 . Ando also showed that a second intermediate host was necessary fo r maturation, for when cercariae obtained from s nails were fed to or injected into experimental definitive hosts, they failed to develop 8. Although Ando later contended that he had proved definitely that Melania libertina was the intermediate host of P. westermani 14, S Yokogawa and Wakeshima in 1934 still believed that there was no conclusive proof that Melania species were involved, for experimental infections had never been carried through from the miracidial through the cercarial and cystic to the adult stages using defined worms obtained from infected individuals 130. It was not until 1934 that the complete life cycle of any Paragonimus (P. kellicotti) was carried through experimentally 3. Finally, in 1952, M Yokogawa succeeded in infecting experimentally P. dehaani, E. japonicus and P. clarkii with P. westermani by feeding the crabs with cercariae in the digestive glands of M. libertina121. This technique was necessary because Yokogawa had found that cercariae were rarely shed from the snails under natural conditions. H e concluded, therefore, that the second intermediate hosts were infected b y eating snails containing mature cercariae. The snail intermediate hosts of P. westermani all belong to the family

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Thiaridae which contains several hundred species of large, operculate snails that live in fresh or brackish water. Fo r many years, the members of this family that served as intermediate hosts for trematodes were assigned to the genu s Melania. In 1948, Abbott revised the nomenclature of these snails 1; since that time, Melania libertina, for example, has been known as Semisulcospira libertina.

STUDIES OF THE MIGRATION AND DEVELOPMENT OF LARVAE AND PATHOLOGICAL REACTIONS IN THE DEFINITIVE HOST For a number of years, the route o f migration of P. westermani larvae from the mouth to the lungs was in doubt. Otani (1887) favoured the haematogenous route100, while Yamagiwa (1890) believed that direct migration from th e peritoneal cavity across the diaphragm to the pleural space and lungs wa s more likely119. Once the final part of the life cycle was discovered by Naka gawa, however, the pathway of migration of larvae was determined independently and with incredible speed by f ive investigators, with Ando 4, Hisao Kobayashi60, Nakagawa88,89 and Sadamu Yokogawa 125,126 first reporting their results in 1915 and Yoshida 134 doing likewise in the following year. Each of thes e persons reported similar findings, so it is impossible to assign priority to any particular individual. The most accessible of these papers, however, are those of Nakagawa89 and Yoshida134 . In the experiments performed by these tw o investigators, dogs and cats were fed upon infected crab flesh then killed after varying periods. Once the larvae had escaped from the cysts, they penetrated right through the intestinal wall, usually that of the jejunum, and entered the peritoneal cavity, mostly within 48 hours. They then crossed the abdomina l cavity and perforated the diaphragm to reach the pleural spaces after several days. The larvae then travelled beneath the visceral pleura before burrowing into the lung parenchyma where cysts were formed and the worms matured. As Yokogawa remarked: metacercariae....don't instantly penetrate the parenchyma, but rather they penetrate the visceral pleura; from that point, they form the tiny vacuoles or tunnels. Even if they move into the parenchyma, the young larvae penetrate freely into the tissues of the lung and form petechiae in many places there. 126

In the lungs, the larvae developed into adult worms and often persisted fo r many years. Ando and Tsuyuki recorded the case of a patient who still ha d eggs in his sputum 20 years after leaving an endemic area 10. Sometimes the migrating flukes took aberrant paths such as into th e abdominal wall where they moved about in the muscles and connective tissue planes, or through the mediastinal connective tissues, particularly via th e perivascular sheaths, to the neck and head. Under these circumstances , however, they failed to complete their development. Thus, Nakagawa wrote: These parasites can bore through various tissues and may reach other organs than the lungs, where they form their regular cysts, but the lungs seem to be the most

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favourable place for their development and the laying of their eggs. In other organs, they can never reach the perfect growth.89

These views were echoed by S Yokogawa: metacercariae....are able to live and grow in connective tissues such as the mediastinum, the greater omentum, subcutaneous connective tissue, orbit, eyelids, the scrotum and brain. They don't have means of discharging eggs or ovulation. What is more a mechanical stimulation causes suppurative inflammation in the area, thus the larvae might be destroyed by lack of nutrition. In contrast to the above fact, those parasites which reside in the lungs easily produce ova when the nutrients are provided; thus they stay there longer and produce those symptoms which initially attracted my attention to them as parasites.126

Subsequent studies, however, showed that this was not always true. Fo r example, Kimuri found large numbers of eggs in the neighbourhood of cysts in the brain 52, and Choy and Ludlow noted ova in a mass in the anterio r abdominal wall 28. In order to determine whether resistance to reinfection could be induced in paragonimiasis, Ando fed cysts repeatedly to dogs that were already infected with adult flukes. He found that the number of flukes which matured declined progressively. Furthermore, when puppies born of infected bitches were challenged, flukes failed to develop in the lungs. Thus, Ando concluded that a n effective immunological response was mounted 9. Pathological reactions in the definitive host were studied in experimenta l animals and in humans that came to autopsy, with attention being focused on both the worms in the lungs and those in aberrant sites. S Yokogawa 126 and other early investigators found that migrating larvae caused little reaction . Sometimes, petechiae were noticed in the intestinal wall where larvae ha d presumably penetrated and a m ild inflammatory reaction in the serous cavities was evoked occasionally. Similarly, helminths migrating through the body not infrequently left small haemorrhages marking their tracks. Kau and Wu studied the histopathology of the lungs of cats infected experimentally and note d collapse, congestion, oedema and leucocytic infiltration which culminated in the formation of a fibrous cyst wall around worms 45. Ova surrounded by chronic granulomatous inflammation were seen in the walls of cysts, in th e bronchial mucosa and submucosa, and in the hilar lymph nodes. Simila r changes were described in infected human lungs 37,86,100. Cysts about 1 cm in diameter were found more commonly in the deeper parts of the lungs, with a matrix of small blood vessels in the capsule and with openings into th e airways, thus allowing egress of ova and any blood surrounding the worms. In ectopic locations, chronic inflam mation produced granulomatous tubercle-like lesions which sometimes suppurated.

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RECOGNITION OF THE CLINICAL FEATURES The major symptom of paragonimiasis, haemoptysis, was first described b y Baelz in 1880. He recognized that in contrast to that other prevalent cause of spitting blood, tuberculosis, the afflicted individuals were generally otherwise completely well: the disease manifests itself in that otherwise completely healthy individuals cough up blood-containing sputum for a long time, very often for many years either frequently or intermittently....The patients show absolutely no symptoms except for occasional throat irritation and a completely untroublesome cough. 16

This was also appreciated in the same year by Manson who described his first patient, Tso-tong in detail: When he was 22 years of age, he first spat blood. Everyday for 19 days he brought up from an ounce to half an ounce of blood; he emaciated slightly, but had very little cough. Haemoptysis returned about six months later, smaller in quantity, but, as in the former attack, the blood at first was pure, unmixed with mucus, and of a bright red colour; this second attack lasted for a few days only. Since then, he says he has spat blood for two or three days at a time, in small quantities, every second or third month. He has never had much cough, and he says that the blood is always mixed with mucus after the first mouthful....Though rather thin, he enjoys good health. I could discover no signs of lung disease on auscultation. 69

Manson's next two patients, who were servants of a friend of his on Taiwan, had similar symptoms, one having recurrent haemoptysis for 11 years and the other for four years 71. Manson realized that recurrent bleeding might induc e anaemia in certain persons and expo sed them to the possibility of a dangerous, sudden, profuse lung haemorrhage. Nevertheless, he remarked I am not in a position to assign to this parasite its exact share among the causes of grave disease, but I have no doubt that in time it will be found to operate prejudicially on the populations of the countries in which it is endemic. 71

Clinical studies over the years have generally confirmed these observation s with the additional realization that secondary infection may be a distressin g complication of pulmonary paragonimiasis 20. In a recent series, Lu and col leagues found that a productive cough, a t times streaked with blood, chest pain and night sweats were the most common symptoms, but that no characteristic signs were present on clinical examination 67. Clinical manifestations of ectopic paragonim iasis, however, were recognized gradually over the years in a small proportion of infected patients. Masse s were observed in the abdomi nal wall and complicating abscess formation was seen28 . Migration of parasites through the peritoneal cavity was thought t o sometimes cause abdominal pain and tenderness. Most importantly, Otani in 1887 found cysts as well as eggs of P. westermani in the frontal and occipital lobes of the brain during the post-mortem examination of a man who had suffered from recurrent epileptic attacks; cysts were also observed in the liver , intestinal wall, peritoneum, diaphragm, mesentery and cervical glands 100. The importance of paragonimiasis as a cause of Jacksonian epilepsy was the n emphasized by Yamagiwa 119,120, although according to Katsurada 44, Yamagiwa

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subsequently concluded that the eggs that he had seen were really those o f Schistosoma japonicum. Nevertheless, Kawamura and his colleagues late r claimed that Paragonimus infection may be a significant cause of centra l nervous system disease 46,47. In one village of 686 inhabitants, 11 cases of brain complications were found among the children, so me of whom died. An autopsy was performed on only one of these children, however; it disclose d Paragonimus eggs in caseous cysts in the brain. The outstanding clinical features were described as follows: It begins with sudden severe headaches with vomiting and dizziness. In many cases, there are epileptic attacks....These attacks are repeated several times and may last from one to two hours or as long as ten or fifteen days. Various symptoms at the time of the onset disappear gradually....mentality is weakened in some cases and in worst cases they become idiotic.47

In other patients, spastic paraplegia followed infection, most commonly when it involved the lower thoracic area with extradural deposits of worms 98, the first such patient being reported in 1917 by Moriyasu 85.

DEVELOPMENT OF DIAGNOSTIC METHODS Paragonimiasis is one of the helminthic infections in which the method o f diagnosis was established before the adult worm itself was defined. As des cribed earlier, Baelz found ova in the sputum of patients while he was looking, presumably, for tubercule bacilli 16 and Manson saw them in sputum whil e looking for microfilariae 69. Microscopical examination of the sputum ha s remained the diagnostic method of choice since that time, although eggs are sometimes seen only in the faeces, when sputum is swallowed 61. Spasmodic attempts have been mad e to develop immunoassays for the diagnosis of paragonimiasis, beginning with Ando in 1919 who showed tha t complement fixing antibodies were present in the sera of infected humans and dogs5. An intradermal test was introduced by Nunogami in 1930 95. Ando and Yamada in 1916 were the first to report on the possibility of using chest radiography in the diagnosis of paragonimiasis 11. In 1937, Wang and Hsieh showed that structural damage to the lung could be demonstrated b y chest radiography, although aetiological diagnosis was not possible 113. In contrast, ectopic paragonimiasis has b een much more difficult to diagnose and this has depended upon finding either ova or worms in biopsy or autopsy material.

THE SEARCH FOR EFFECTIVE TREATMENT When Manson found Paragonimus ova in the sputum of his patients, he naturally turned his attention towards trying to cure them and made many attempts of dislodge the parasites. With consi derable ingenuity, he introduced a number

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of potentially parasiticidal agents, including quassia, kousso, santonin , turpentine and sulphurous acid into the airways via a steam spray, but success did not attend his efforts71. Efficacy was claimed for pills containing a mixture of quinine, ergot and opium by Lara 63, but the apparent effectiveness of thi s therapy was probably merely associated with periodical waxing and waning of the disease. Stibnal was said to be of value when tried in 19 patients by Kondo 62, but tartar emetic was not deemed to be very effective 75. Claims were made by many observers for the value of emetine, although its effectiveness in man y cases could hardly be called dramatic. In 19 15, Ikeda reported that he was able to cure three patients with 12-33 injections of emetine hydrochloride 39. Three years later, Kikuiko and Imamura described favourable results following the subcutaneous or intravenous inj ection of emetine daily for up to one week, but noted that patients with longstanding disease were more prone to develo p untoward side-effects from the drug51. Some patients required prolonged therapy to effect a cure, Martin, for example, inst ancing one individual who needed 70 injections; he believed, however, that concurrent use of mercurochrom e shortened greatly the duration of emetine treatment 75. In 1939, S Yokogawa and Ro investigated the effect of combining emetine with the sulphonamide, prontosil, in experimentally infected dogs and thought that it brought about a rapid and radical cure 129. Eggs disappeared from th e sputum and examination of the lungs disclosed dead, degenerating worm s which then became atrophic and calcificied. In control dogs which had been given emetine alone, there was only a partial reduction in egg numbers an d little killing of adult worms in the lungs. A combination of emetine an d prontosil was therefore tried by Yokogawa and his colleagues in nine human patients with paragonimiasis. Of the nine patients so treated, seven could be followed up; four had no recurrence of symptoms, one died of an unrelate d disease, and two relapsed with severe haemoptysis 131. Encouraging results with chloroquine were reported in 1954 by Chung and colleagues who treated three patients with paragonimiasis 29. In 1961, however, bithiniol was introduced and this became the drug of choice for nearly tw o decades. Following in vitro experiments and animal trials, Yokogawa and his collaborators used bithionol to treat 13 patients, most of whom had bee n unsuccessfully treated previously with emetine and a sulphonamide. All o f them were cured after 5-15 doses given on alternate days; eleven had transient side-effects, the most frequent bei ng diarrhoea 124. Katamine and his colleagues gave bithionol in various schedules to 22 patients. When the largest dose was used, sputum and stool specimens became negative in all patients 3-15 days after beginning treatment, and there were no parasitological relapses after a period of up to four months. Haemoptysis ceased in four of the five patient s who had been troubled with that symptom, and the chest X-ray appearances improved in four persons 43. Two new drugs have been shown recently to be highly effective. In 1975 ,

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Rim and his colleagues showed that niclofolan was effective in cats and dogs infected with P. westermani 102. In the following year, menichlopholan ( = niclofolan) was shown to give a cure rate of between 73% and 90% in humans infected with P. uterobilateralis in Nigeria97. Ripert and colleagues then examined the efficacy of a single dose of niclofolan in Cameroon and obtained a cure rate of 100% 105. Finally, praziquantel (see chapter 3) has been shown to be highly effective. In 1981, Rim and co-workers in Korea reported that up to 100% effectiveness could be obtained, depending upon the dose of prazi quantel used103. In contrast to niclofolan, however, praziquantel had negligible side-effects. Thus, this agent seems destined to become the standard agent for the therapy of paragonimiasis.

UNDERSTANDING THE EPIDEMIOLOGY As the mode of transmission between first and second intermediate hosts was clarified and as the various reservoir hosts of the adult worms were identified, the epidemiology of paragonimiasis gradually began to be understood. Th e first advance was the discovery of infection in Potamon obtusipes (= P. rathbuni) and then in P. dehaani and Eriocheir japonicus by Nakagawa. This was followed by the demonstration by various investigators that in addition to Potamon and Eriocheir, other genera of crabs, including Potamiscus, Parathelphusa and Siamthelphusa, were important in transmission in some countries. Furthermore, the cr ayfish, Cambaroides and Procambarus, and the shrimp, Palaemon, were also found to be vectors of infection. Similarly, the realization that a snail, Melania (= Semisulcospira) libertina was the first intermediate host of P. westermani was followed by the discovery that species of Brotia were also susceptible to infection. It became appreciated tha t different species of both primary and secondary intermediate hosts ha d different habitats, some living in mountain streams, whereas others inhabited delta regions. Transmission of infection, however, depended upon the presence of definitive hosts excreting P. westermani ova into the environment. In addition t o humans and the tigers originally shown to be infected by Kerbert, a wide range of vertebrates, including dogs, cats, pigs, panthers, wolves and foxes, wa s shown to be infected in nature 58,59. Railliet in 1890 was apparently the firs t person to report the occurrence of P. westermani in dogs, the specimen being shown in the Japanese veterinary exhibit at the Paris exposition and bein g named by him "Metagonimus pulmonalis , or better M. ringeri, or better still, M. westermanni". In 1892, Janson reported that Tokishige found the lung fluke in dogs and pigs in Japan, while the parasite was found in cats by Inouye and Katsurada in 1893 (cited in 128). For humans to acquire infection, however, cysts have to be ingested in a viable state. The dietary habits and methods of preparing crustaceans var y

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from place to place. In China, the eating of crabs dates back at least 3,00 0 years118. The dish may be well- or slightly-cooked, or eaten uncooked , depending upon the preference of the consumer. Sometimes the crabs ar e merely immersed in millet or rice wine, so that these "drunken" crabs are still living when devoured. In some areas, the crab juice is a domestic remedy for such ailments as whooping cough a nd measles 77, while Koreans commonly eat fresh crabs as an antipyretic and an tidiarrhoeal remedy 57. Famine may increase the consumption of crabs and thus precipitate an outbreak of paragonimiasis, as happened in eastern Nigeria du ring the Nigerian Civil War of 1967-1970 96. Finally, infection may occur even without eating crabs as was indicated by the disease occurring in American soldiers who were presumed to have drun k contaminated water 106. Although paragonimiasis has been found most commonly in eastern Asia, infection was recognized gradually amongst th e indigenous inhabitants of other regions, including Central America 63, South America19 , Central Africa65 and Melanesia35. Even though some of these infections may have been acquired as a result of transmission via immigrant carriers from endemic regions, as may have happened, for example, with the Peruvian engineer who was a patient of Barton19, it is now realized that in some of these foci, infections are caused by species of Paragonimus other than P. westermani (see differentiation of species).

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Even without knowing anything of the life cycle of P. westermani, Manson was able, by the use of elementary epidemiological principles, to indicat e accurately the means by which human infection could be prevented: It is only necessary to boil or filter water, and never to eat uncooked vegetables or other uncooked food.71

The validity of these views was established when the life cycle wa s determined, with particular attention being paid to avoiding uncooked crabs and other potentially-infected crustaceans. If these measures were adopted , paragonimiasis could be eliminated in human populations. To this end, health education campaigns have been carried out in several heavily endemic areas, but it is difficult to change the entrenched habits of a population. Attempts to break the life cycle of Paragonimus by attacking one of the intermediate hosts are difficult. Extermination of crabs is next to impossible, even if desirable, owing to their hiding in deep holes and under stones in river beds57. Similarly, control of molluscs is often not practicable, although chemical agents and natural predators such as ducks and carp have been tried 7.

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DIFFERENTIATION OF SPECIES Speciation in the genus Paragonimus has long been a subject of confusion and controversy. As discussed earlier, Baelz classsified the human parasite no w known as P. westermani as two separate species, but this view was no t generally accepted. For a number of years, the lung flukes found in variou s animal species were also equated with P. westermani. This seemed not unreasonable because it appeared until 1894, that all of these animals could hav e been infected in areas in which human paragonimiasis was endemic. In 1894, Henry Ward described a lung fluke obtained from a cat in Michigan, USA. Although differences were m entioned between this worm and those described by Kerbert in tigers and by Leuckart and others in humans, th e parasite was nevertheless assigned tentatively to the species, P. westermani, especially as there was a possibility that the host had been brought as a pe t from the Orient114. Exotic infection seemed less likely, however, when Kellicott later that year discovered worms in the lungs of a dog in Columbus, Ohio; these parasites were sent to Ward and he identified them as being identica l with those reported earlier by him from the cat 116. No doubt remained tha t paragonimiasis was endemic in the USA when Stiles and Hassal in 1900 recorded the discovery made two years earlier by AJ Payne of many lung flukes in pigs in Cincinatti, Ohio, this parasite also being given the tentativ e designation, P. westermani 107. In 1908, however, Ward reached th e conclusion that the lung fluke found in cats, dogs and pigs in the United States was undoubtedly a distinct species, and to this he gave the name, P. kellicotti 115. In 1915, Ward and Hirsch compared Kerbert's original specimens from the tiger with animal material from the USA and human flukes fro m eastern Asia. On the basis of the structure and distribution of the cuticula r spines, they concluded that these flukes represented three separate specie s which they named P. westermani, P. kellicotti and P. ringeri, respectively 117. Kobayashi, on the other hand, believed that there was but one species, for when he examined flukes from a variety of both natural and experimental hosts in Korea, he found great variation in the cuticular spines 56. Ameel in 1934 reached the view that differentiation of species on the basis of cuticular spines was very doubtful, but found that there was a clearcut difference between P. kellicotti and P. westermani in the anatomy of the digestive tract 3. Despite the difficulties in establishing the systematic position of new isolations, a number of new species have been described in the last two decades. By 1975 , Yokogawa was able to list 31 species of Paragonimus but recognized that some of them were not or may not be valid 122. At least nine species ar e believed cause to disease in man, although some of them may be synonymous.

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OTHER SPECIES OF PARAGONIMUS P. AFRICANUS This fluke was found in the mongoose and dog and was first described by Voelker and Vogel in 1965 in West Africa 111. The snail and crab intermediate hosts are probably Potadoma freethii and Sudanautes species, respectively. Later in the same year, Vogel and Crewe identified P. africanus eggs in sputa from 30 patients 112. P. ECUADORIENSIS This species was found in 1979 by Voelker and Arzube in a coati in Ecuador109. The crab host is Hypoloberca aequatoralis but the first intermediate host is as yet unknown. The same authors identified eggs in th e sputum of two patients in Ecuador as P. ecuadoriensis. P. HETEROTREMUS This fluke was first reported in rats by Ch'en and Hsia in 1964 27. It was described later in the same year as P. tuanshanensis by Chung and colleagues30. Tricula gregoriana and Potamon species were shown to be the first and second intermediate hosts, respectively. It was first found i n humans in the subcutaneous tissues of the chest of a 13 year old boy i n Thailand by Miyazaki and Harinasuta in 1966 81, then in the lungs of 39 year old Laotian male 80. P. HUEITUNGENSIS Immature forms of this worm were first found in biopsy of migratory subcutaneous nodules from two children in China and colleagues in 1977 , then the adult worms were recovered from rats, cats and dogs infecte d experimentally32. The snail host is Tricula cristata and the crab hosts are species of Siropotamon and Isalopotamon. P. KELLICOTTI As discussed earlier, this worm was described as a separate species i n North America by Ward in 1908115. Pomatiopis lapidaria and Cambarus are the first and second intermediate hosts, respectively. Human infection has been reported only once 2.

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P. MEXICANUS This species was found in opossums in 1968 by Miyazaki and Ishii 83. P. peruvianis, reported by Miyazaki and colleagues from Peru in 1969 82, is now thought to be a synonym. Miyazaki and Ishii 83 also identified the eggs in the lungs of a 35 year old Mexican, and which had been described as P. westermani by Martinéz Báez and Jiménez Galán in 1961 76, as being those of P. mexicanus. Details of the life cycle were described by Brenes and collaborators in 1980 22. P. MIYAZAKII This fluke was first recovered from a cat which had been infected with a crab by Kamo and colleagues in Japan in 1961 42. Bythinella species41 and P. dehaani 108 were shown to be the first and second intermediat e hosts, respectively. Human infections have also been described 123. P. SKRJABINI This worm was recovered from Paguma larvata (Viverridae) by Ch'en in 195923, then described more fully by the same author two years later 24 . A parasite recovered from cats, and described as P. szechuanis by Chung and Tsao in 196233, is generally considered to be a synonym. Infection i n humans was described by Ch'en25 and by Chung and colleagues 34 in 1962. It commonly occurs in ectopic locations, especially in subcutaneous nodules. Assiminea lutae 26 and Tricula gregoriana 31 are the first and second intermediate hosts, respectively. P. UTEROBILATERALIS This trematode was recovered from a swamp mongoose in West Africa and described by Voelker and Vogel in 1965 111. The crab hosts are species of Sudanonautes. Human infection with this parasite was first describe d under this name by Onuigbo and Nwako in Nigeria in 1974 99 then by Voelker and Nwokola in 1977 110. Praziquantel was shown to be effective in treatment by Monson and colleagues in 1983 84.

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3. AMEEL D. Paragonimus, its life history and distribution in North America and its taxonomy (Trematoda: Troglotrematidae). American Journal of Hygiene 19: 279-317, 1934 4. ANDO A. (Investigation on Paragonimus westermani.) Chugai Iji Shinpo Nos. 847, 851, 856, 1915. In Japanese 5. ANDO A. Komplementablekung bei der Distomiasis pulmonum. Verhandlungen der japanischen pathologischen Gesellschaft, Tokyo 7: 128, 1917. Also: (Complement fixation test of paragonimiasis) Nihon Byori Gakkai 7: 633, 1917. In Japanese 6. ANDO A. (The first intermediate host of Paragonimus westermani.) Tokyo Iji Shinshi Nos. 2175-2178, pp 21, 1920. In Japanese. Abstracted in Tropical Diseases Bulletin 17: 51, 1921 7. ANDO A. (A supplementary notice on the prevention and elimination of pulmonary distomiasis.) Nippon Biseibutsakkwai Gakka Zasshi 15: 43-56, 1921. In Japanese. Abstracted in Japan Medical World 1: 19, 1921 8. ANDO A. (Morphologische und biologische Untersuchung ueber die Zerkaria vonParagonimus westermani.) Chugai Iji Shinpo 41: 286-297, 1921. In Japanese. Abstracted in Tropical Diseases Bulletin 21: 538, 1924 9. ANDO A. (Can immunisation be obtained by the infestation of Paragonimus westermanii?) Iji Shinbun No. 1070, 1921. In Japanese. Abstracted in Tropical Diseases Bulletin 20: 209-210, 1923 10. ANDO A, TSUYUKI A. (On the endemic of pulmonary distomiasis in Tokigun, Gifu prefecture.) Iji Shinbun No. 1136, pp 327-337, 1924. In Japanese 11. ANDO A YAMADA M. Chuo Igaku Zasshi No. 128, pp 1-11, 1916. In Japanese. Also published as ANTO R, YUMATA R (X-ray diagnosis of pulmonary lesions of Paragonimus westermani.) Taiwan Igakukai Zasshi No. 169, pp 934-935, 1916. In Japanese. Abstracted in Tropical Diseases Bulletin 10: 109, 1917 12 ANONYMOUS. Microfilariae. Lancet ii: 25, 1880 13. ANONYMOUS. Parasitical haemoptysis. Lancet ii: 548-549, 1880 14. ANONYMOUS. In, 406th Medical General Laboratory. Annual Historical Report 1951. Professional Section, Tokyo, pp 304, 1952. Cited in 128 15. ARCE J. La paragonimiasis en El Peru. Crónica Médica, Lima 32: 249-254, 1915 16. BAELZ EO. Ueber parasitäre hämoptoë (Gregarinosis pulmonum). Centralblatt für die medicinischen Wissenschaften 18: 721-722, 1880. Translated in 48. Abstracted in Lancet ii: 548-549, 1880 17. BAELZ EO. Ueber einige neue Parasiten des Menschen. Berliner klinische Wochenschrift 20: 234-238, 1883 18. BAELZ EO. Cited in 73 and 74 19. BARTON. Cited in 15 20. BERCOWITZ Z. Clinical studies on human lung fluke disease (endemic haemoptysis) caused by Paragonimus westermani infestation. American Journal of Tropical Medicine 17: 101-122, 1937 21. BRAUN MG. Über Clinostomum Leidy. Zoologischer Anzeiger 22: 489-493, 1899 22. BRENES R, ZELEDÓN R, ROJAS G. Biological cycle and taxonomic position of a Costa Rican Paragonimus and the present status of Paragonimus from the New World. Brenesia 18: 353-366, 1980 23. CH'EN HT. (New species of lung flukes and note on Paragonimus species in China as related to human infections.) 1958 Annual Report of the Chungshan Medical College, p 152, 1959. In Chinese 24. CH'EN HT. Taxonomic consideration of Paragonimus, including morphological notes on P. skrjabini. Acta Zoologica Sinica 12: 27-36, 1960 25. CH'EN HT. The etiologic agent of human paragonimiasis in China. Chinese Medical Journal 81: 345-353, 1962 26. CH'EN HT. Paragonimus, Pagumogonimus and a paragonimus-like trematode in man. Chinese Medical Journal 84: 781-791, 1965 27. CH'EN HT, HSIA TK. (A preliminary report on a new species of Paragonimus.) Zhongshan Daxue Wuebo 2: 236-238, 1964. In Chinese, with English summary 28. CHOY PD, LUDLOW AI. Ova ofParagonimus westermani encysted in the abdominal wall. China Medical Journal 40: 326-328, 1926 29. CHOY HL, CH'EN CH, HOU TC. Preliminary observations on efficacy of chloroquine in

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treatment of paragonimiasis. A report of 3 cases. Chinese Medical Journal 72: 1-14, 1954 30. CHUNG HL, HO LY, CHENG LT, TS'AO WC. The discovery in Yunnan Province of two new species of lung flukes Paragonimus tuanshanensis sp. nov. and Paragonimus menglaensis sp. nov. Part I. Studies on morphology and life history with discussion on possible pathogenicity to man. Chinese Medical Journal 83: 641-659, 1964 31. CHUNG HL, HO LY, TS'AO WC, HSING PH, TUNG YC, MU SH. The discoveryof a minute freshwater snail, Tricula sp. as the first intermediate host of Paragonimus szechuanensis. Chinese Medical Journal 82: 712-717, 1963 32. CHUNG HL, HSU CP, HO LY, KAO PC, LAN S, CHIU FH. Studies on a new pathogenic lung fluke - Paragonimus heit'ungensis sp. nov. Chinese Medical Journal 3: 379-394, 1977 33. CHUNG HL, TS'AO WC. Paragonimus westermani (Szechuan variety) and a new species of lung fluke - Paragonimus szechuanensis. Part I. Studies on morphological and life history of Paragonimus szechuanensis. Chinese Medical Journal 81: 354-378, 1962 34. CHUNG HL, TS'AO WC. Paragonimus westermani (Szechuan variety) and a new species of lung fluke - Paragonimus szechuanensis. Part II. Studies on clinical aspects of paragonimiasis szechuanensis - a new clinical entity. Chinese Medical Journal 81: 419434, 1962 35. CILENTO RW, BACKHOUSE TC. Paragonimiasis: its first recorded occurrence in the Territory of New Guinea. Medical Journal of Australia i: 79-81, 1927 36. COBBOLD TS. Note by the President. Journal of the Quekett Microscopical Club 6: 139140, 1880 37. DIACONITA GH, GOLDIS G. Investigations in pathomorphology and pathogenesis of paragonimiasis. Acta Tuberculosea Scandinavica 44: 51-75, 1964 38. HUNGERFORD R. Cited in 73 39. IKEDA M. (Report on treatment of lung fluke disease with emetine hydrochloride.) Namman Igukkwai Zasshi 3: 120-126, 1915. In Japanese 40. KAKAMI. (Paragonimus westermanii, investigation of the lung distoma in South Ham Kyung Province, Korea.) Chosen I Ho No. 12, pp 151-156, 1916. In Japanese. Abstracted in Tropical Diseases Bulletin 8: 504, 1916 41. KAMO H, HATSUSHIKA R, MAEJIMA J. Studies on Paragonimus miyazakii Kamo, Nishida, Hatsushika et Tomimura 1961. I. Snail intermediate host and intrasnail stages. Yonago Acta Medica 11: 26-34, 1967 42. KAMO H, NISHIDA H, HATSUSHIKA R, TOMIMURA T. On the occurrence of a new lung fluke, Paragonimus miyazakii n. sp. in Japan (Trematoda: Troglotrematidae). Yonago Acta Medica 5: 43-52, 1961 43. KATAMINE D, MURAKAMI F, MOTOMURA K, NIKISHUBO K, AJISAKA S, TAKATSO H. (Treatment of human paragonimiasis with bithionol). Endemic Diseases Bulletin, Nagasaki University 3: 130-138, 1961. In Japanese, with English summary 44. KATSURADA F. Schistosoma japonicum, a new human parasite which gives rise to an endemic disease in different parts of Japan. Journal of Tropical Medicine and Hygiene 8: 108-111, 1905 45. KAU LS, WU K. Preliminary report on histopathology of paragonimiasis in cats in China. Chinese Medical Journal Supplement 1: 101-105. 1936 46. KAWAMURA R, ISHIBARA C, YAMAGUCHI S. (Paragonimus westermanii infection in children, with invasion of the brain.) Tokyo Iji Shinshi No. 2064, pp 449-454, 1918. In Japanese. Abstracted in Tropical Diseases Bulletin 16: 130, 1920 47. KAWAMURA R, YAMAGUCHI M. On the pulmonary distomiasis which caused brain symptoms in children. Japan Medical World 1; No. 4: 1-7. 1921 48. KEAN BH, MOTT KE, RUSSELL AJ. Tropicalmedicine and parasitology. Classic investigations, two volumes, Cornell University Press, Ithaca, pp 677, 1978 49. KERBERT C. Zur Trematoden-Kenntnis. Zoologischer Anzeiger 1: 271-273, 1878. Partly translated in 48 50. KERBERT C. Beitrag zur Kenntnis der Trematoden. Archiv für mikroskopische Anatomie und Entwicklungsmechanik 19: 529-578, 1881 51. KIKUIKO M, IMAMURA H. (Paragonimus westermanni infection, treatment by emetine hydrochloride.) Chu Gai Iji Shimpo No. 908, 1918. In Japanese. Abstracted in Tropical Diseases Bulletin 15: 214-215, 1920

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52. KIMURI O. A case of cysts in the brain caused by Paragonimus westermani. Mittheilung aus der pathologischen Institut der kaiserlich-japanischen Universität zu Sendai, Japan 1: 375-384, 1921 53. KOBA K. Revision of the specific name of a crab as a second intermediate host ofParagonimus westermani in Formosa. Science Reports of the Tokyo Bunrika Daigaku 39: 201-207, 1936. Abstracted in Tropical Diseases Bulletin 34: 397, 1937 54. KOBAYASHI HARUJIRO. (A crayfish as one of the intermediate hosts ofParagonimus westermanii) Chosen Igakukai Zasshi No. 19, pp 65-69, 1917. In Japanese. Abstracted in Tropical Diseases Bulletin 12: 174, 1918 55. KOBAYASHI HARUJIRO. Studies on the lung fluke in Korea. I. On the life-history and morphology of the lung fluke. Mittheilungen aus der medizinischen Fachschule zu Keijo 2: 97-115, 1918 56. KOBAYASHI HARUJIRO. Studies on the lung fluke in Korea. II. Structure of the adult worm. Mittheilungen aus der medizinischen Fachschule zu Keijo 3: 16-36, 1919. Abstracted in Tropical Diseases Bulletin 14: 139-140, 1919 57. KOBAYASHI HARUJIRO. On the development of Paragonimus westermanni and its prevention. Japan Medical World 1: 14-17, 1921 58. KOBAYASHI HARUJIRO. On the animal parasites in Korea. Japan Medical World 5: 9-16, 1925 59. KOBAYASHI HARUJIRO. Lung-fluke disease in Chosen. Mittheilungen aus der medizinischen Akadamie zu Keijo 9, Nos. 3 & 4, pp 3, 1926 60. KOBAYASHI HISAO. (The migratory course of the lung fluke in the body of the final host.) Tokyo Iji Shinshi Nos. 1925 & 1930, 1915. In Japanese 61. KOMIYA Y, YOKOGAWA M. The recovery of Paragonimus eggs from stools of patients by AMS III centrifuging technic. Japanese Journal of Medical Science and Biology 6: 207-211, 1953 62. KONDO K. (Antimony treatment of paragonimiasis.) Tokyo Iji Shinshi Nos. 2383-2385, 1924. In Japanese. Abstracted in Tropical Diseases Bulletin 22: 474, 1925 63. LARA A. Hemoptysis endemica de los Paises tropicales. Revista de Medicina de Yucatan 9: 1-5, 1913 64. LEUCKART R. Die parasiten des Menschen und die von ihnen herrhührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sche Verlagshandlung, Leipzig, Abtheilung 2, volume 1, pp 897, 1886-1901 65. LIBERT C. A case of paragonimiasis. West African Medical Journal 5: 51-52, 1932 66. LOOSS A. Weitere Beiträge zur Kenntnis der Trematoden-Fauna Aegyptens zugleich Versuch einer naturlichen Gliederund des Genus Distomum Retzius. Zoologische Jahrbücher Abteilung für Systema 12: 521-784, 1899 67. LÜ CH et al. Clinical observations of195 cases of Paragonimus in children. Chinese Journal of Pediatrics 8: 143-146, 1957 68. MANSON P. Further observations on microfilariae, with descriptions of new species, communicated (with a prefatory note) by the President. Journal of the Quekett Microscopical Club 6: 130-140, 1880 69. MANSON P. Distoma ringeri. China Imperial Maritime Customs. Medical Reports for the half year ended 30th September 1880. 20th issue, pp 10-12, 1881. Reprinted in Medical Times and Gazette ii: 8-9, 1881 70. MANSON P. Distoma ringeri and parasitical haemoptysis. China Imperial Maritime Customs. Medical reports for the half yearended 30th September 1881. 22nd issue, pp 55-62, 1882. Reprinted in Medical Times and Gazette ii: 42-45, 1882 71. MANSON P. On endemic haemoptysis. Lancet i: 532-534, 1883 72. MANSON P. Cited in 73 73. MANSON-BAHR P. Patrick Manson as aparasitologist. A "critical review". In International Review of Tropical Medicine, D R Linicombe (Editor), Academic Press, New York, pp 77-129, 1961 74. MANSON-BAHR PH, ALCOCK A. The life and work of Sir Patrick Manson, Cassell, London, pp 273, 1927 75. MARTIN SH. Paragonimiasis and its treatment. China Medical Journal 41: 457-460, 1927 76. MARTINÉZ BAELZ M, JIMÉNEZ GALÁN A. Un cas de trematodiasis pulmonar reg-

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istrado en Mexico. Revista del Instituto de Salubridad y Enfermedades Tropicales 21: 101114, 1961 77. MINAMI S, SATO T. Hautgeschwülste durch Lungen distoma (Paragonimus westermani). Arbeiten aus der medicinischen Universität zu Okayama 2: 78-88, 1930 78. MIYAIRI K. (A contribution to the knowledge and development of the lung fluke). Sai Kin Gaku Zasshi No. 281, 1919. In Japanese 79. MIYAIRI K. Beitrag zur Kenntnis der Entwicklung für Paragonimus westermanii. Mittheilungen aus der medizinischen Fakultät der kaiserlichen Universität Kyushu Fukuoka 6: 313-319, 1922. Abstracted in Tropical Diseases Bulletin 21: 539, 1924 80. MIYAZAKI I, FONTAN R. Mature Paragonimus heterotremus found from a man in Laos. Japanese Journal of Parasitology 19: 109-113, 1970 81. MIYAZAKI I, HARINASUTA T. The first case of human paragonimiasis caused by Paragonimus heterotremus Chen et Hsia, 1964. Annals of Tropical Medicine and Parasitology 60: 509-514, 1966 82. MIYAZAKI K, IBANEZ N, MIRANDA H. On a new lung fluke found in Peru. Paragonimus peruvianus sp. n. (Trematoda: Troglotrematidae). Japanese Journal of Parasitology 18: 123-130, 1969 83. MIYAZAKI I, ISHII Y. Studies on the Mexican lung flukes with special reference to a description of Paragonimus mexicanus (Trematoda: Troglotrematidae). Japanese Journal of Parasitology 17: 445-453, 1968 84. MONSON MH, KOENIG JW, SACHS R. Successful treatment with praziquantel of six patients infected with the African lung fluke, Paragonimus uterobilateralis. American Journal of Tropical Medicine and Hygiene 32: 371-375, 1983 85. MORIYASU R. (A case of myelitis caused by parasitism of Paragonimus westermani in the vertebral canal.) In Japanese. Cited in 128 86. MUSGRAVE WE. Paragonimiasis in the Philippine Islands. Philippine Journal of Science B 2: 15-63, 1907 87. NAKAGAWA K. (A preliminary report on the discovery of the intermediate host of the human lung fluke.) Tokyo Iji Shinshi No. 1910, 1915. In Japanese 88. NAKAGAWA K. (On the migratory course of the lung fluke in the body of the final host). Tokyo Iji Shinshi No. 1923, 1915. In Japanese 89. NAKAGAWA K. The mode of infection in pulmonary distomiasis. Certain freshwater crabs as intermediate hosts of Paragonimus westermanii. Journal of Infectious Diseases 18: 131-142, 1916 90. NAKAGAWA K. Human pulmonary distomiasis caused by Paragonimus westermanni. Journal of Experimental Medicine 26: 297-323, 1917 91. NAKAGAWA K. (Description of the cysts and young developing worms ofParagonimus westermanii.) Taiwan Igakukai Zasshi No. 176, pp 366-368, 1917. In Japanese. Abstracted in Tropical Diseases Bulletin 12: 174, 1918 92. NAKAGAWA K. (A new species of lung fluke infesting the pond crabs, Potamon dehaani, of Kalapai as an intermediate host.) Juzankai Zasshi 23: 1-2, 1918. In Japanese 93. NAKAGAWA K. Further notes on the studyof the human lung distome Paragonimus westermani. Journal of Parasitology 6: 39-43, 1919 94. NAKAHAMA T. (Ueber den Bau des Distomum pulmonis.) Tokyo Iji Shinshi Nos. 254, 261, 282 and 283, 1883. In Japanese 95. NUNOGAMI M. (Skin reaction in paragonimiasis.) Kumamoto Igakkwai Zasshi 6: 513, 1930. In Japanese 96. NWOKOLO C. Outbreak of paragonimiasis in eastern Nigeria. Lancet i: 32-33, 1972 97. NWOKOLO C, VOLKMER KJ. Single dose therapy of paragonimiasis with menichlopholan. American Journal of Tropical Medicine and Hygiene 26: 688-692, 1977 98. OH SJ. Spinal paragonimiasis. Journal of Neurological Science 6: 125-140, 1968 99. ONUIGBO WI, NWAKO FA. Discovery of adult parasites of Paragonimus uterobilateralis in human tissue in Nigeria. Zeitschrift für Tropenmedizin und Parasitologie 25: 433436, 1974 100. OTANI S. (Cysten des Gehirns mit Eiern von Distomen sonst in der Leber, Darmwand, Peritonäen, Lymphdrüsen.) Tokyo Igakkwai Zasshi 1: 458-460, 1887. InJapanese, with German summary. Also, with the same title, Zeitschrift für medicinischen Gesellschaft,

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Tokyo 1: 8-9, 1887 101. PAUL ME. Distoma pulmonale. Lancet ii: 1789, 1896 102. RIM HY, KIM S, HA JH, CHANG DS. Experimental chemotherapeutic effects of niclofolan (Bayer 9015, Bilevon) on the animals infected withParagonimus westermani or P. iloktuensis. Korean Journal of Parasitology 14: 140-146, 1976 103. RIM HJ, LYU KS, LEE JS, JOO KH, SUH WH, TSUJI M. Clinical evaluation of praziquantel (Embay 8440; Biltricide [R]) in the treatment of Paragonimus westermani. Korean Journal of Parasitology 19: 27-37, 1981 104. RINGER BS. Cited in 69 105. RIPERT C, CARRIE J, AMBROISE-THOMAS P, BAECHERE R, KUM NP, SAMEEKOBO A. Étude épidemiologique et clinique de la paragonimose au Cameroun. Résultats du traitement par le niclofolan. Bulletin de la Société de Pathologie Exotique 74: 319-331, 1981 106. ROQUE FT, LUDWICK RW, BELL JC. Pulmonary paragonimiasis: a review with case reports from Korea and the Philippines. Annals of Internal Medicine 38: 1206-1221, 1953 107. STILES CW, HASSALL A. The lung fluke (Paragonimus westermanii) in swine and its relation to parasitic haemoptysis in Man. Annual Report of the Bureau of Animal Industry 16:560-611, 1900 108. TOMIMURA T, MORIBANI M, TERAUCHI J, TAKEYAMA K. (Observations on the incidence of encysted larvae of Paragonimus miyazakii in Potamon dehaani in Rokuroshi, Iwakuni City, Yamaguchi Prefecture.)Japanese Journal of Parasitology 13: 204-214, 1964. In Japanese, with English summary 109. VOELKER J, ARZUBE RM. Ein neuer Lungenegel aus der Küstenkordillere von Ecuador: Paragonimus ecuadoriensis sp. n. (Paragonimidae: Trematoda). Tropenmedizin und Parasitologie 30: 249-263, 1979 110. VOELKER J, NWOKOLO C. Human paragonimiasis in Eastern Nigeria caused byParagonimus uterobilateralis. Zeitschrift für Tropenmedizin und Parasitologie 24: 323-328, 1973 111. VOELKER J, VOGEL H. Zwei neue Paragonimus-Arten aus West-Afrika:Paragonimus africanus und Paragonimus uterobilateralis (Troglotrematidae: Trematoda). Zeitschrift für Tropenmedizin und Parasitologie 16: 125-148, 1965 112. VOGEL H, CREWE W Beobachtungenüber die Lungenegel-Infektion in Kamerun (Westafrika) Zeitschrift für Tropenmedizin und Parasitologie 16: 125-148, 1965 113. WANG SH, HSIEH CK. Roentgenologic study ofparagonimiasis of lungs. Chinese Medical Journal 52: 829-842, 1937 114. WARD HB. Ueber das Vorkommen von Distoma westermanii in den Vereinigten Staaten. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 15: 362-364, 1894 115. WARD HB. Data for the determination of human entozoa. II. Transactions of the American Microscopical Society 28: 177-202, 1908 116. WARD HB. Cited in 117 117. WARD HB, HIRSCH EF. The species of Paragonimus and their differentiation. Annals of Tropical Medicine and Parasitology 9: 109-152, 1915 118. WU K. The epidemiology of paragonimiasis in China. Far Eastern Association of Tropical Medicine. Comptes-Rendus Dixième Congrès, Hanoi 2: 689-713, 1938 119. YAMAGIWA K. Beitrag zur Aetiologie der Jacksonischen Epilepsi. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (R Virchow) 119: 447-460, 1890 120. YAMAGIWA K. Ueber die Lungen-distomen-Krankheit in Japan. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (R Virchow) 127: 446-456, 1892 121. YOKOGAWA M. Studies on the biological aspects of the larval stages ofParagonimus westermanii, especially the invasion of the second intermediate hosts. Japanese Journal of Medical Science and Biology 5: 221-237, 501-515, 1952 122. YOKOGAWA M. Paragonimus and paragonimiasis. Iranian Journal of Public Health 4: 42-51, 1975 123. YOKOGAWA M, ARAKI K, SAITO K, MOMOSE T, KIMURA K, SUZUKI S, CHIBA N, KUTSUMI H, MINAI M. Paragonimus miyazakii infections in man first found in Kanto District, Japan - especially, on the methods of immuno-serodiagnosis for paragonimiasis.

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Japanese Journal of Parasitology 23: 167-179, 1974 124. YOKOGAWA M, YOSHIMURA H, OKURA T, SANO M, TSUJI M, IWASAKI M, HIROSE H. Chemotherapy of paragonimiasis with bithionol. II. Clinical observations on the treatment with bithiniol. Japanese Journal of Parasitology 10: 317-327, 1961 125. YOKOGAWA S. (On the migratory course of the lung fluke in the body of the final host.) Tokyo Iji Shinshi Nos. 1920, 1922, 1934; Year 1915. In Japanese 126. YOKOGAWA S. (On the route of migration of Paragonimus westermani in the definitive host.) Taiwan Igakkai Zasshi No. 152, pp 685-700, 1915. In Japanese. Translated in 48 127. YOKOGAWA S. (Paragonimus ringeri, Study of stages from the crab and points of difference distinguishing it from similar cysts occurring there.) Taiwan Igakukai Zasshi No. 175, pp 298-307, 1917. In Japanese. Abstracted in Tropical Diseases Bulletin 12: 173-174, 1918 128. YOKOGAWA S, CORT WW, YOKOGAWA M. Paragonimus and paragonimiasis. Experimental Parasitology 10: 81-137, 139-205, 1960 129. YOKOGAWA S, RO M. Studies on the treatment of paragonimiasis. Part I. Experimental treatment and efficacy on dogs harbouring lung flukes (Paragonimus westermanii). Acta Japonica Medica Tropica 1: 1-18, 1939 130. YOKOGAWA S, WAKESHIMA T. (Cercariae in Semisulcospira libertina collected from the endemic area of paragonimiasis, Shinchuku Province, Formosa.) Taiwan Igakkwai Zasshi 33: 875-876, 1934. In Japanese 131. YOKOGAWA S, WAKISAKA K, SO K. Studies on the treatment of paragonimiasis. Part II. On the efficacy of prontosil in combination with emetine against lung flukes during treatment. Acta Japonica Medica Tropica 2: 23-54, 1940 132. YOSHIDA S. (On the intermediate host of the lung fluke in Tokushima Prefecture.) Tokyo Iji Shinshi No. 1936, 1915. In Japanese 133. YOSHIDA S. On the intermediate hosts of the lung distome, P. westermani Kerbert. Journal of Parasitology 2: 111-118, 1916 134. YOSHIDA S. Some notes on the encysted larva of the lung distome. Journal of Parasitology 2: 175-180, 1916

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Table 7.1. Landmarks in paragonimiasis __________________________________________________________________ 1877 1879 1880

1880 1881 1887 1913 1914 1915 1915 1916-22

1939 1961 1965 1974 1975 1981

Kerbert discovered adult worms in the lungs of a tiger and named the parasite Distoma westermanni Ringer discovered an adult worm in the lung of a human Baelz and Manson discovered independently eggs in the sputum of humans and recognized that haemoptysis was the main symptom with the patients being otherwise usually well Manson observed that eggs needed to incubate for several weeks before miracidia were released Manson postulated that a snail may be the first intermediate host and Hungerford suggested that Melania libertina was a likely candidate Otani found parasites in the brain Nakagawa showed that miracidia were not infective to dogs Nakagawa found encysted larvae which resembled adult Paragonimus in the gills of a crab which could be a second intermediate host Nakagawa reported that adult worms developed in dogs fed these cysts Ando, Kobayashi, Nakagawa and Yokogawa determined independently the pathway of migration of larvae in the definitive host Nakagawa, Yokogawa, Kobayashi, Miyairi and Ando all concluded independently that snails of the genus Melania (= Semisulcospira) were probably the first intermediate host Yokogawa proposed a combination of emetine and prontosil for treatment Bithiniol was shown to be an effective treatment P. africanus infections were identified in humans by Vogel and Crewe P. uterobilateralis infections were identified in humans by Onuigbo and Nwako Niclofolan was shown in experimental animals to be an effective treatment Rim and colleagues showed that praziquantel was a very effective drug

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Chapter 8

Schistosoma haematobium and SCHISTOSOMIASIS HAEMATOBIA

SYNOPSIS Common name: vesical blood fluke; causes vesical or urinary schistosomiasis or bilharziasis Major synonyms: Distoma haematobia, Bilharzia haematobia Distribution: Africa, Middle East, (Portugal, India) Life cycle: The adult worms are unisexual. The male worm, 12 mm in length by 1 mm in breadth, carries a slender female worm, 20x1 mm in size, in its gynaecophoric canal. The adult worms live in the portal venous system, especially in the vesical plexus, and produce eggs, some of which are transported through the bladder wall and are passed in the urine. On dilution in water, the ova soon hatch miracidia which invade snail intermediate hosts of the genus Bulinus (Ferrisea and Planorbarius in small foci in Portugal and India, respectively). Each miracidium becomes a sporocyst which in the course of 6-8 weeks produces second generation sporocysts, then cercariae. The cercariae emerge from the snail, swim about in water, then penetrate the skin of persons immersed in that water, lose their tails to become schistosomula, then migrate through the bloodstream via the lungs to the portal venous system where they mature over three months Definitive hosts: humans (monkeys, baboons, chimpanzees) Major clinical features: haematuria; obstructive uropathy and secondary bacterial infections in heavy infections Diagnosis: demonstration of eggs in the urine Treatment: hycanthone, metrifonate, niridazole, praziquantel

DISCOVERY OF THE ADULT WORMS Before Theodor Bilharz went to Cairo, Egypt in 1850, he sought the advice of his erstwhile teacher and mentor, Carl von Siebold, as to which branch o f natural science he should particularly direct his attention. Von Siebol d recommended that he concentrate on h uman helminths, as it seemed likely that the "strange country" would provide a fruitfu l field for such investigations. And so it did. Bilharz was astonished at the variety and numbers of worms , especially intestinal nematodes, that he encountered during the course o f performing some 200 post-mortem examinations. In early 1851, whil e carrying out an autopsy on a young man, he made a discovery that astounded him. He found a worm, which not only had he never seen before, but whic h 187

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was located in the blood vessels, a location hitherto unrecognized in humans. He appreciated that this blood-dwelling worm, or haematozoon as he called it, was a trematode, but at first was misled by his initial failure to realize that the specimens that he was examining were all male worms. Bilharz's confusion is not at all surprising since all species of flukes known at that time wer e hermaphroditic. In some excitement, he wrote a letter, dated 1 May 1851, to von Siebold in Breslau, Germany (now Wroclaw, Poland), recounting hi s discovery: Soon after my attention had been directed to the liver and its associated structures, I found in the blood of the portal vein a number of long, white helminths which, with the naked eye, I considered to be nematodes, but soon recognized as something new. A look into the microscope revealed a splendid Distomum with a flat body and a spiral tail at least ten times as long as the body....the tail....was a continuation of the flat body of the worm itself, rolled sideways towards the stomach surface in a half canal; the forked blind end of the intestinal canal extended into it very plainly....I found no mature sexual organs. 32

He concluded his description by asking the question: What then is this animal? In spite of its long tail, it probably cannot be called a cercaria, which is completely different, histologically and morphologically. 32

It was not long, however, before he was able to shed some light on tha t question himself. He discovered that these helminths were unisexual and that he had been looking at the male worms. In another letter to von Siebold dated 28 August 1851, he explained how he had made this observation: I have not yet reported to you the new stages of my portal vein worm. It did not, as I had expected, develop into a wonderful old wives' tale but into something more wonderful, a trematode with divided sex. The worm I described in my last letter was a male. When I searched the intestinal veins more carefully (and more expediently by holding the undamaged mesentery against the light), I soon found specimens of the worm which harboured a gray thread in the groove of their tail. You can imagine my surprise when I saw a trematode protruding from the frontal opening of the groove and moving back and forth; it was similar in shape as the first, only much finer and more delicate. Instead of the groove-shaped tail, it had a ribbonlike posterior end which was completely enclosed in the groove-shaped half canal of the male posterior, similar to a sword in a scabbard. The female was easily pulled out of the male's groove and was recognized most clearly by its internal structure.32

He then went on to describe the anatomy of both male and female worms. In a third letter to von Siebold in December 1851 he enclosed preserve d specimens of the parasites and provided illustrations and a definitiv e description, including coining of the term "gynaecophoric canal" to denote the rolled ventral surface of the male worm which surrounded the filiform female worm. Furthermore, he named the worm Distomum haematobium, the specific name presumably derived from a combination of the Greek words µ (HAIMA, HAEMA) [combini ng form µ - (HAIMAT-)] meaning "blood" and (BIOS) meaning "life, course or way of living", to indicate that these worms lived in the bloodstream. V on Siebold announced Bilharz's discoveries to the Congress of Naturalists in Gotham, then published Bilharz's letters ,

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together with his own annotations, in Zeitschrift für wissenschaftlich e Zoologie which both he and Kölliker edited 32. Bilharz's discovery was soo n confirmed by a number of pathologists including Griesinger, Reinhard an d Lautner, all of whom found worms in the portal veins and its tributaries in the mesentery and bladder.

CONTROVERSIES OVER NOMENCLATURE On 4 December 1857, T Spencer Cobbold found a similar bisexual fluke in the portal vein of a sooty monkey (Cercopithecus fuliginosus ) which had died in the Zoological Society's menagerie in Lon don. Cobbold at the time believed it was a new species and on 20 January 1859 presented his findings to th e Linnean Society, naming the worm Bilharzia magna. Thus, he erected a new genus, named in honour of Bilharz, to encompass these distinctive distomes, and gave it the specific epithet, magna, to denote its large size 54. He was eventually to agree with Leuckart that the fluke found in the monkey and that described by Bilharz were identical and that bo th worms should thus be termed Bilharzia haematobia. During the period between Cobbold's discovery of the worm and the formal publication of his finding, Diesing communicated to the Vienna Academy his Revision der Myzelminthen in which he placed the fluke in a new genus, Gynaecophorus, to indicate the characteristic gynaecophoric canal71. Both Cobbold's and Diesing's designations were ultimately to laps e because of the law of priority in nomencla ture, however. Even earlier, in 1858, Weinland had used the name Schistosoma to describe this parasite in a list of all the worms that had thus far been found in man 202. This latter term was derived from the Greek words (SCHISTOS) meaning "split" an d µ (SOMA) meaning "body". All of these authorities were agreed on one thing, - the extraordinary unisexual character of these flukes required thei r separation from the genus Distoma. Subsequently, Moquin-Tandon proposed the name Thecosema for the genus, since Saint-Hilaire had used the nam e Schistosoma previously to describe a particular form of monster 164. Moquin-Tandon's suggestion never met with any acceptance, but the names Schistosoma and Bilharzia both continued to be used for many years. In October 1863, a resident of the Cape of Good Hope, South Africa , consulted by mail John Harley, assistant physician to King's College and the London Fever Hospital, concerning the slight haematuria with which he had been afflicted for many years. He also noted that many people in certain parts of the Cape were affected similarly and sent a number of samples of his urine to Harley. In all of these specimens, Harley found eggs of a worm. One o f these eggs hatched to reveal a "minute, ciliated animalcula" 102. Furthermore, Harley secured urine specimens from the tw o sons, who had also suffered from haematuria, of a South African colleague, Dr Dunsterville; in both instances, he was able to demonstrate the characteristi c eggs. Harley recognized the close

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similarity between these eggs and those of S. haematobium described by Bilharz and Griesinger in Egypt (see next section), and presented his findings to a meeting of the Royal Medical and Chirurgical Society in London on 2 6 January 1864. Since the eggs that he had found differed in certain respect s from those described by Bilharz, however, Harley felt obliged to place them in a separate species which he named Distomum capense 102. In the subsequent discussion, Cobbold declared that there was no doubt that the eggs described by Harley were identical to those of Bilharzia haematobia, and therefore, that the name of Distomum capense should not stand 56. Harley's reported response to this is incomprehensible circumlocution: He had referred to it as a new species, because, after careful comparison with Griesinger's figures and description, and Leuckart's review of them in his recently published work, he could hardly refer the ciliated embryo he had described to Gynaecophorus haematobium. On the other hand, the resemblances were so close and so many that it was probable that they were identical; but from a bare comparison with the figures, he could not justly infer that they were actually so. 102

Again, in 1870, his assertions are not clear, but it is apparent that he was then troubled by the absence of a lateral spine in any of the ova that he had found: I have never had much doubt of the identity of the North and South African parasites; still I can only deal with facts, and my position with regard to the question is pretty much the same as it was seven years ago....both Bilharz and Griesinger describe and figure two forms of eggs, the one with a terminal and the other with a lateral spine. In all my own cases I can say positively that only one form of egg has existed, viz. that with a terminal spine. I have never seen any egg with even a tendency to the formation of a side spine.104

In fact, as discussed in chapter 9, he was correct and Bilharz and Griesinger were mistaken, for S. haematobium ova do not posssess a lateral spine, as was clearly shown by Leiper when he demonstrated the life cycle of S. haematobium many years later. Thus, B. capense became synonymous with S. haematobium. More vexed was the question of the name of the genus. Cobbold ardently defended his name Bilharzia against both Gynaecophorus and Schistosoma 57. With respect to Diesing's Gynaecophorus he wrote: but, when it was subsequently found that the title Bilharzia had been proposed by myself some six months before Diesing communicated his paper to the Vienna Academy, the choice of several systematists and others fell upon my title, which had the additional advantage of handing down the true discoverer's name to posterity.57

Laudable though the latter objective may have been, Cobbold does not seem to have been entirely accurate in his facts, for his nomenclature was no t presented publicly until after that of Diesing. Concerning Weinland' s Schistosoma he wrote: In a letter which I received from Dr. Weinland (dated September 6th, 1861) that able helminthologist willingly abandoned the claims of Schistosoma, remarking that 'the generic term Bilharzia has the preference'.57

In 1931, Senn put forward Bilharzia von Hemsbach 1856 as the valid name

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of the genus, that name being adopted earlier than either Schistosoma Weinland 1858, Gynaecophorus Diesing 1858 or Bilharzia Cobbold 1859 183. In the same year, Leiper also tried to beat off the term Schistosoma by again drawing attention to the use o f the word for nearly a century by teratologists to denote a fairly common type of monstrosity in domesticated animals 140. Nevertheless, the International Commission on Zoological Nomenclature by Opinion 77 in 1922 placed Schistosoma on the Official List of Generi c Names 113. Thus, the valid names for the organism and the disease ar e Schistosoma and schistosomiasis, respectively.

DISCOVERY OF THE EGG AND MIRACIDIUM In his second communication to vo n Siebold in August 1851, Bilharz reported that he had seen eggs in the oviduct and uterus of female worms, and note d their characteristic morphological features - the terminal spine writing, "th e eggs are oval and pointed at one end" 32. In the following year, he found these same eggs in the bladder mucosa and observed that they contained activ e embryos which escaped from the egg shells: "Many of these eggs containe d mature, actively motile embryos: next to them lay broken, empty egg shells" 32. He then went on to recount the manner in which these larvae escaped fro m their constraints: (the) embryos....moved briskly in all directions, now contracting spherically, now stretching out, and finally tearing the egg shell: in this process they stretch out to their full length and tear the shell with a strong sideways pull. 32

Bilharz then described the appearances of the free embryos (now known a s miracidia): The organism that emerged had a long, cylindrical cone-shaped form which was thicker anteriorly and more rounded posteriorly, with a proboscis-like protruberance anteriorly. It was completely covered with rather long cilia which enabled it to swim around in the water with a lively, rotating motion. 32

He then examined the behaviour of these organisms and found that they swam around in the water for an hour or so, developed blister-like bulges on thei r surfaces, assumed a mulberry shape, then finally lost their motility and dis integrated. Bilharz was uncertain as to the fate of the embryos. In 1851, he had noted calcified areas in the liver along with S. haematobium eggs: "strange bodies provided with spines, approximately similar to those eggs in size" 32. These were probably empty egg shells of S. mansoni (see chapter 9), but Bilharz did not recognize them as such. He found them again in the following year and put forward the hypothesis that they were capsules representing a further stage in the development, perhaps a kind of pupal covering to protect the embryos when newly emerged from the eggs. Since these bodies wer e found in patients with old, healed dysentery, he speculated that the healin g process had prevented the embryos from making their normal egress, and that they prematurely went through a phase of development that normally occurred

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outside the human body. Following Bilharz, a number of investigators including Harley 104, Cobbold57, Sonsino186, Brock37 and Looss141 studied the anatomy and behaviour of S. haematobium miracidia.

THEORIES ON THE MODE OF TRANSMISSION Soon after the discovery of schistosomes, Griesinger speculated on the ways in which infection might be acquired. Since he was about to leave Egypt, he was unable to investigate the question himself, but with considerabl e disingenuousness, thought that the problem should not present too muc h difficulty: Had I remained longer in Egypt, I would have set myself two large practical tasks. First, I would wish to discover the ways in which these entozoa penetrate the body. This is relatively easy considering the simple food of the people. 100

Little did Griesinger realise that more than 60 years of confusion, concoction and controversy would have to pass before light dawned on this problem. He pointed a finger of suspicion at three main potential culprits: impure Nil e water, contaminated bread or grain and/or dates, and the half-rotten fish that were beloved by the fellaheen. He believed that patient investigation ough t eventually to disclose eggs, larvae or mature worms in one or other of these vehicles. It is perhaps surprising that neither Bilharz nor Griesinger appear to have paid any serious attention to the possibility that infection might be transmitted by snails, or that von Siebold did not make this suggestion in hi s correspondence with Bilharz. This is more understandable in the case o f Griesinger, for although he made major contributions to parasitology , particularly schistosomiasis and hookworm disease, his major interests lay in the field of psychiatry, and it was for that reason that he was about to return to Germany. Bilharz, however, was a pupil of von Siebold's and knew of th e latter's work on the relationship between miracidia of the trematode , Monostomum mutabile, a parasite of geese, and certain cercaria-sacs found in snails, and he must surely have known of Steenstrup's theory of th e "Alternation of Generations" (see chapter 4). In their defence, however, it must be admitted that 30 years were to p ass before Thomas and Leuckart elucidated the life cycle of Fasciola hepatica, that many authorities in the early 1850's did not accept a connection between cercariae an d distomes, and that schistosomes were very unusual flukes in that they were unisexual. Spencer Cobbold in London, however, was on the right track. He was an experienced and widely read helminthologist, and in his textbook of 1864 on the human entozoa, he wrote that: it is more probable that the larvae in the form of cercariae, rediae and sporocysts, will be found in certain gasteropod molluscs, proper to the localities from whence the adult forms have been obtained.55

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Cobbold thought that human infection was probably acquired either b y swallowing the snails themselves, or by drinking unfiltered water into which the larvae had escaped. These views were echoed in the same year by Harley who wrote that: it may safely be assumed that between the ciliated embryo....and the adult sexual animal there are probably two distinct forms which serve to complete the chain of metamorphosis connecting these two extremes of development. What these forms are, and what are their transmigrations, are questions which require careful elucidation. The ciliated embryo is adapted for an aquatic existence. Swimming freely about, these minute organisms probably come in contact with certain molluscs and become developed within them into what have been called cercaria sacs.102

Harley later put this idea to the test by examining some fresh-water molluscs (Unio kaffre) sent to him by Dr Dunsterville from an endemic area in South Africa but failed to detect any schistosomes 103. Nevertheless, he also kept his options open for as well he canvassed the possibility that the parasite migh t develop directly from ova introduced into the human body. He then examined this possibility in 1870 by attempting to infect experimental animals directly. He fed large numbers of S. haematobium eggs to two rabbits and two dogs in their food. Three animals were killed, one each at two, three and six months after infection, but no trace of schistosomes could be found 104. Meanwhile, Cobbold in the same year, had indicated to a meeting of th e British Medical Association meeting in Liverpool, that he had undertake n some experiments in order to trace the development of the worm i n invertebrate intermediate hosts. The results of these studies were published in 1872, together with the outcome of his attempts to infect various species o f fish. He used ova obtained from patients infected in South Africa and: tried to induce the ciliated embryos to enter into the bodies of a great variety of animals, such as gammari, dipterous larvae, entomostraca, limnei, paludinae, different species of Planorbis, and other fresh-water molluscs, but neither in them nor in sticklebacks, roach, gudgeon, or carp, did they seem inclined to take up their residence.57

However, Cobbold quite rightly qualified his findings by indicating that h e may not have reproduced the conditions obtaining in endemic areas: These experiments, however, are by no means conclusive, since the conditions under which the experiments were made departed in several respects from those that are presumably essential to success in the ordinary course of Nature. 57

These two approaches, the direct infection experiment of Harley's and the search for a molluscan intermediate host by Harley and Cobbold, formed the basis for subsequent attempts to elucidate the life cycle of schistosomes . Unfortunately, the debate on this subject ofte n sank into the depths of acrimony and vituperativeness. Cobbold, in his usual dogmatic way, began this with an attack on Harley in 1872. Having criticized him for his erection of B. capense, Cobbold remarked that he doubted whether Harley had looked carefully into the writings of other investigators and then wrote: On what grounds....Dr John Harley could possibly expect to rear Bilharzia by

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feeding dogs and rabbits with ova, I am at a loss to understand; and his apparent suspicion that parasites 'may increase in the (human) body from the development of eggs' in a direct manner, is to me a mere haphazard conception, and one which virtually sets at nought the well established experiences of every original experimenter whose name is known in connexion with the advancement of helminthology in its ontogenic bearings. Throughout the whole of Dr Harley's remarks on this head - and I confess to have the greatest difficulty in comprehending the purport of many passages - the generally received opinion as to the necessity of an intermediate host amongst the Trematoda seems to me to have been altogether overlooked, and therefore to that extent utterly ignored. So far as Dr Harley is concerned in this particular relation, the teachings of Leuckart, Pagenstecher, Guido Wagner, Siebold, van Beneden and especially Filippi, are altogether a dead letter.57

This was an unjust criticism for Harley had in fact been much more scientific in his approach than the cocksure Cobbold. As already intimated, Harley, as early as 1864, had suggested on general grounds than an intermediate hos t might be necessary, and had actually looked for schistosomes in snails before Cobbold had. But he realized, as Cobbold himself had remarked in justifying separate generic status for Bilharzia, that schistosomes were so different from other flukes that it did not necessarily follow that were transmitted in the same way. It was not only reasonable, but necessary, that direct infection should be proven or disproven by experiment. Permeating both the "direct" and "snai l" theories was the widely held belief that water was intimately concerned in the transmission of infection. Ther e were, however, two views as to the way in which infection was acquired from water. As early as 1864, Cobbold declared that it was quite clear to him that people in Africa were infecte d when they drank unfiltered waters 56. Two years later, Dr Rubidge of Port Elizabeth, South Africa, put forward a novel ide a based upon perspicacious epidemiological and clinical observations when he wrote to Harley in London in response to the latter's request for information on endemic haematuria. Harley quoted Rubidge in his second communication on the subject to the Royal Medical and Chirurgical Society: Pretty extensive enquires lead me to believe that bathing in rivers has something to do with the production of the disease. I have never met with a case in boys who do not frequently bathe in the Zwarlkojss or Booker's River. On the other hand, those few boys in the families of my patients who are free from the disease, bathe in the sea only. My impression is that the parasite gains entrance into the skin while the individual is bathing in the river and I may mention that the lad W. Jones . . described a sort of urticarious eruption attended with great irritation, as a frequent result of bathing in Booker's River....Females are rarely affected, if at all. I have not myself observed a single wellmarked case in this sex. 179

Following on from this, Harley in 1870 put forward the hypothesis that ov a may be inserted into the skin while bathing, perhaps by being injected by the ovipositor of a minute, leech-like animal 104. In 1882, attention was focused again on water as the vehicle of infection when a dozen staff of the Eastern Telegraph Company at Suez were attacked

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with schistosomiasis after drinking water from the Sweet Water Canal while walking or shooting nearby12. In the same year, Allen also noted that in Natal, South Africa, the infection was most common in natives and in the mal e children of white settlers, then put forward the following observation: The reason is very evident; they are the largest consumers of unfiltered water. It is not so often in girls, they staying at home more can as a rule get filtered water; boys and natives, living much in the veldt and drinking copiously from the first stream they come across, soon imbibe it.4

In this view, Allen was supported by Lyle, al so of Natal 150, Sonsino in Egypt 188, and Castle in East Africa 40. While agreeing that infection was much mor e common in males, Guillemard (1883) was not so sure that drinking infected water was the correct explanation. He referred to Sonsino's patients in th e Zagazig where not a single female case occurred, yet only unfiltered water was available. He favoured the possibility that infection occurred while bathing in contaminated water: The mode of infection, so far from being evident, is extremely obscure; but the supposition that river-bathing, which is but seldom indulged in by women, is in some way connected with the acquirement of disease seems the most tenable. 101

Allen later (1888) came around to this notion, remarking that: Nearly all the youths bathing in the Umdimdusi and Drop Spruit are infected, while the girls, who do not bathe, remain free of the disease. 6

and suggested that an unknown larval stage might enter the body through the skin. In 1894, Brock supported this view strongly. After stating that "it i s among boys, who are fondest of swimming, that the symptoms earliest make their appearance." 38 and that females were rarely affected, he remarked that: other things being equal, the chances of infection occurring will be greater from the large quantity of water which must come in contact with the body in bathing, than from the comparatively small amount conveyed into the stomach by drinking; so that granting the larvae to have the power of penetrating the body by some means, we should expect to meet with a much larger proportion of cases among bathers than among those who only drink the infective water. 38

In contrast, Bronte Elgood (1908) examined the relationship between the prevalence of schistosomiasis and water contact in schoolgirls and in female hospital patients in Cairo. She found that i nfection was common in young girls, even in those who did not bathe in the Nile, but was rare in adult women. She concluded that infection was unlikely to be due to bathing, was possibly a consequence of faulty storage of water, or was a result of the consumption of raw vegetables or fruit that had been washed in dirty canals or rivers 73. Looss acidly replied that Dr Elgood's conclusions "appear deficient in lucidity , disconnected, contradictory" 145, for he considered it impossible that miracidia could live under the conditions suggested. In fact, Leiper was later to show that Cairo had two water supplies; in addition to piped filtered water for drinking, there was a separate supply of unfiltered water direct from the Nile fo r gardens, and suggested that it was via this route that the girls acquired thei r infection137. Elgood and Cherry later disputed the significance of Leiper' s

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observation, however, for they found vector snails in public ponds an d fountains and in private gardens in Cairo 74. A novel but logical suggestion for the acquisition of urinar y schistosomiasis was publicized by Norman Moore at a meeting of th e Pathological Society of London in 1882. He quoted a patient of his, a doctor who had practised in Africa, as telling him that the indigenous inhabitants of Central Africa believed that the parasite (or at least the cause of th e haematuria) entered the body via the urethra. Consequently, they tied up the penile orifice before they crossed a river 163. It has also been suggested tha t further evidence for such a belief is provided by the penile covers or condoms that are present on several ancient Egyptian statues and reliefs. In any event, the idea was sanctioned in a leading article in The Lancet (1900) in which infection via the oral and urethral routes was compared: It is by no means improbable that the parasite may enter the body by both of these methods, although haematuria would probably only follow invasion by the urinary route.16

This notion was espoused by Allen who wrote: There can be no doubt but that the prepuce plays a most important part in the entry of the parasite into the urethra. During the act of bathing the sac formed by the prepuce becomes filled with water, and if the distoma enters with it, it is obvious it would be guided almost immediately to the mouth of the urethra and sustained until it effected entry.7

He then went on to advocate universal, enforced circumcision as a contro l measure in every country where schistosomiasis was prevalent 8. Similarly, it was also suggested that infection might be ac quired per anum while bathing 180, but this idea was uniformly laughed out of court, Manson, for exampl e remarking that "Apes and the like do not practise ablutions - ergo thei r schistosomes could not be acquired in that way, and neither could those o f man"154. Following Harley's and Cobbold's negative but pioneering studies i n Britain, attention turned to experimental investigation of the transmission of infection in endemic areas. The first major contribution came from Sonsino in Egypt in 1884187, but he could not solve the problem. Nearly ten years later, three special missions visited North Africa between 1893 and 1894 in search of a solution: Sonsino, then a lecturer in parasitology at the University of Pisa went to Tunisia, Lortet and Vialleton were sent by the French government to Egypt, and Leuckart's assistant, Looss, went from the University of Leipzig to Alexandria, Egypt. Finally, Leiper led a team to Egypt in 1915. As mentioned earlier, these studies fell into two broad groups.

DIRECT INFECTION EXPERIMENTS Despite Harley's failure to infect rabbits and dogs with S. haematobium ova,

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this idea was not given up and was examined repeatedly by a number o f investigators. Mantey made some experiments in 1880 but his results wer e negative157, In 1882, Hatch in India failed to infect puppies by feeding the m with S. haematobium eggs in urine mixed with milk 108. In 1894, Lortet and Vialleton failed in all attempts to produce infection directly; they passed eggs into the stomach of guinea pig s through a tube, injected ova intravenously into rabbits, and fed Macacus monkeys with eggs in their food 149. Lortet even kept sheep with shaven, lightly excoriated legs plunged in water containing many S. haematobium miracidia for three months, but found no trace of adult worms at post-mortem examination 148. He had chosen sheep as the host as many sheep in Sicily were infected naturally with Bilharzia crassa, a parasite closely related to S. haematobium. Yet as Milton later justly remarked, thi s experiment would have been more meaningful if Lortet had used B. crassa miracidia instead 161. Also in 1894, Looss gave various species of monkeys (since Cobbold had shown that they were susceptible to infection) water containing miracidia to drink repeatedly for six to eight weeks; again the results were negative 142. Despite his failure to prove infection by this means, Looss championed th e notion that transmission did not require an intermediary host, albeit h e accepted eventually that infection occurred through the skin. The former tenet was held because he failed to find an infected intermediate host, as will b e detailed shortly. Looss explained the rea soning upon which the latter statement was based to the Egyptian Medical Congress in 1905. His argument wa s centred principally upon his demonstration that miracidia could not survive in stomach juice or hydrochloric ac id; perforce, they must travel through the skin as he had already shown was the case with hookworm larvae. He regretted , however, that he did not have any proof, despite repeated attempts to confirm his thesis: Unfortunately I still cannot furnish you with the indisputible proof by experiment. I have already made some trials for introducing larvae into the animals, but these experiments, fewer than the rest, and being conducted without system, did not give decisive results.143

Other investigators also kept trying. Wolff in German East Africa (1911) failed to infect a cat immersed for half an hour in water swarming wit h miracidia204. Bour in Mauritius (1912) was unable to infect two cynomolgous monkeys, either orally or percutaneously 36, while Joyeux in French Wes t Africa was unable to infect a Cercopithecus ruber monkey by bathing it in urine containing miracidia 117. In 1914, Conor carried out an extensive series of experiments in Tunis, administering miracidia orally, percutaneously an d subcutaneously to monkeys, sheep, rabbits, guinea pigs and rats, all wit h negative results61. Finally, Fülleborn, Leiper and some of Looss's ow n colleagues in unpublished studies 134 failed to achieve infection directly. Bu t Looss remained obstinate, explain ing all these failures with the claim that man was the only known host for S. haematobium 147.

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THE SEARCH FOR AN INTERMEDIATE HOST The first major attempt to investigate transmission in an endemic area wa s made by Prospero Sonsino, an Italian physician who had been appointed i n 1873 to the Khedividial laboratories in Cairo and had access to Kasr-El-Aini Hospital where he was able to examine patients and perform autopsies. Ten years after his arrival, he turned his attention to examining the life cycle of S. haematobium by following the approach already taken by Cobbold. Perhaps stimulated by the successful determination of the life cycle of Fasciola hepatica by Thomas and by Leuckart in 1882, Sonsino concentrated on snails as being the most likely intermediate hosts. His studies were divided into two parts. Firstly, he tried to infect experimentally snails kept in an aquarium . Species of Cleopatra, Melania, Physa and Vivipara were exposed to S. haematobium miracidia, but infection failed to develop. Secondly, local snails including species of Cleopatra, Corbicula, Limnea, Melania, Physa, Planorbis, Unio and Vivipara were examined while searching for evidence of natural infection with schistosomes, but again he met with no success. H e concluded: It is probable that Bilharzia, owing to several other peculiarities, differs from other genera of distomes and presents this peculiarity: that it possesses as intermediary host animals belonging to classes different from those which serve as carriers to other Distomidae. Moreover, this peculiarity invests to this end all its life-history, in part free in water, and in part parasitic in a single definitive host, and surely through alternating generations.187

Sonsino's work was regarded highly, with a special correspondent to th e British Medical Journal writing in December 1884: Dr Sonsino is continuing his researches....into the life history of parasitic trematode worms. In this way, it is to be hoped that he will discover the intermediate host of Bilharzia haematobia.13

Six months later, however, a further note appeared in the same journa l regretting Sonsino's departure for Italy. The correspondent then went o n optimistically: There is now a clear field for an investigator to find the intermediate host of Bilharzia haematobia. After Mr. Thomas's successful search in the case of sheep-rot, it should be much easier to set this question at rest. It would be worthwhile for the B.M.A. to select a man and set apart funds for research. The Khedividial laboratory....offers every facility; and there is good reason to hope that by working along the lines of Mr. Thomas, a successful result might be brought about in one or two years.14

Nothing happened. Eight years later in June 1893, Sonsino returned to North Africa to recommence his studies into this question. He went to Tunisia and found some patients who provided him w ith ova in sufficient numbers to allow him to rear miracidia in association with freshwater molluscs and arthropods. He believed that he had discovered that a small crustacean was th e intermediate host. Mysteriously, he d id not publish his results but sent a sealed

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letter dated 3 August 1893, i ndicating the nature of his discovery and when he had made it, to the secretary of the Societa To scana di Scienze Naturali in Pisa. Perhaps he was not sure of his facts, but was afraid that Lortet and Vialleton would beat him to the mark. In the event, he changed his mind and wrote to The Lancet, his paper appearing on 9 Se ptember 1893. Without providing any details of the experiments, he proclaimed: After many experiments I succeeded with a small crustacean (amphypoda) and obtained evidence that this same crustacean is an effective intermediary host of bilharzia, and so discovered the secret of the life history of the African parasite. 189

Sonsino then amplified his conclusions, indicating that S. haematobium resembled a holostome rather than a digenetic trematode and underwen t metamorphosis but neither alternation nor asexual generation in a smal l crustacean. He stated that the free-swimming miracidia penetrated th e crustacean at its head, then encysted. Human infection was acquired b y ingesting these infected crustaceans in contaminated drinking water. He then went on to say that his further researches had revealed that larvae of several kinds of aquatic insects were also efficient vectors. This report was received with acclamation in an accompanying Lancet editorial15, but in the following year further work indicated that these conclusions were completely untenable and forced Sonsino to withdraw them entirely 190. It must be admitted though, that this withdrawal was less public than it might have been - it was published in the Pisa Society's proceedings but not in The Lancet! Nevertheless, Sonsino's idea was adopted tentatively by Balfour in Khartoum, Sudan, i n 1904 when he wondered whether the minute crustaceans (probabl y Ostracoda) obtained from a school well and which took up miracidia might not be the long sought for intermediate host 24. Nothing came of this suggestion either. At around the same time as Sonsino (1894), Lortet and Vialleton reported that they were unable to infect a number of species of molluscs (includin g Corbicula, Lanistes, Melania, Physa, Unio and Vivipara), aquatic arthropods, or water plants with S. haematobium 149. Lortet then continued thi s experimental work in Lyon, France with local species of Lymnaea, but again without luck 148. Simultaneously, Looss in Egypt embarked upon the trail. Initially (1893), like Cobbold and Sonsino, he predicted that molluscs would be vectors, so he searched for natural infections amongst local molluscs: Naturally, the most likely course and that which one expected a priori was for the embryo after escaping from the egg-case to penetrate, in a manner similar to that observed in other species of distoma, into some intermediate host appertaining to the class of mollusca. In my experiments in this connexion, I repeated those of Cobbold and Sonsino, but with the like absolutely negative results. 142

Even when he dissected snails from the most notorious foci of human infection in the Nile delta, he failed to find any evidence of schistosomal infection. This led him to state categorically in 1894: It is more particularly these latter negative experiences that induce me now

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definitely to exclude mollusca as the intermediate hosts of our parasite. 142

In like manner, he failed to infect crustacea, insect larvae, small worms an d fish. This led him to the conclusion which he maintained stolidly, tenaciously and immovably for the next 20 years or so: The above described behaviour of the embryos towards other animals was in the main what led me finally to the definite conviction that probably no transference of the embryos by means of an intermediate host appertaining to the classes of the lower animals takes place. Hence the only possible solution that remained was that the embryo reached man directly, and develops into a sporocyst in the human host, the offspring of the cyst being subsequently distributed to its host. 142

He reiterated this view in 1905 143 and again in 1908144 , 1909145 and 1910146 . Even after Japanese investigators succeeded in infecting a variety of animals with S. japonicum by immersing them in flooded fields in endemic areas, but failed to do so when they were immersed in water full of miracidia, Loos s pontificated as late as 1914: It is remarkable that the Japanese authors do not appear to be able to come to any clear concept as to the nature of the invading form. Bilharzia japonica must differ essentially in its development from B. haematobia, for it seems a priori difficult to understand how an intermediate host that lives in water can participate in the spread of B. haematobia in the towns of Egypt.147

Nevertheless, there were dissenters, including Blanchard 35 and Manson 155 in their textbooks, although it mus t be admitted that their views were based upon theoretical considerations rather th an personal, practical experience. Such was the authority and vociferousness of Looss, however, that his dogmati c statements effectively inhibited the search for an intermediate host for 2 0 years. One commentator remarked: Hitherto, the scientific world had listened to the teaching of Looss, and any attempt at upsetting the classical research of the great authority was considered to be well-nigh sacrosanct.17

It was not until Looss was banished from Egypt by the British at the outbreak of World War I, that the way was left open for Leiper to make his epocha l discoveries.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND THE SNAIL INTERMEDIAT E HOSTS. At the outbreak of war in 1914, British authorities became concerned about the potential deleterious effects of schistosomiasis on British troops in Egypt. This concern was founded upon their e xperiences with schistosomal infections in British soldiers in South Africa during the Boer War, and had been given deeper expression by Lord Kitchener, the British administrator of Egypt, in his annual report in 1913 in which h e emphasized that "It is high time that serious steps should be taken to prevent the continuity of infection that has been going

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on so long in the country"129. British authorities were receptive, therefore, to Leiper's submission that he be allowed to study the problem of th e transmission of schistosomiasis in Egy pt. Robert Leiper had just returned from Eastern Asia where he and At kinson had been investigating the life cycle of S. japonicum and was familiar with the recent discoveries by Japanese workers. Consequently, Leiper and Drs RP Cockin and JG Thomson, who were to assist him, were given temporary commissions and sent to Egypt by the British War Office to "Investigate bilharzia disease in that country and advise as to th e preventive measures to be adopted in connection with the troops" 134. The mission arrived in Egypt on 8 February 1915 and was beset wit h difficulties almost from the start. Within a month of their arrival, Cockin fell sick and had to be invalided home. Leiper himself was afflicted with scarle t fever and was admitted to hospital. The influx of the wounded from th e Gallipoli campaign in May brought pressure for closure of the study. Finally, when experimentally infected animals were eventually obtained, Leipe r realized that it was imperative that he had expert pharmacological advice in the matter of testing anthelmintics; he returned to England on 15 July 191 5 leaving behind Thomson who had joined the general service of the Roya l Army Medical Corps. Neverthel ess, during this brief period and working with incredible speed, the team made discoveries of immense importance. Thei r findings were reported in three instalments in the Journal of the Royal Army Medical Corps, beginning in July 1915 134. Leiper continued his observations in England and again in Egypt on his subsequent return there in Novembe r 1915, and brought out two further pa rts of his report in 1916 135 and in 1918 137. By a stroke of irony, Leiper and his colleagues set up headquarters i n Looss's vacated laboratories in the Cairo School of Medicine. Leiper ha d reviewed the literature well and realized that of the 50 species of freshwater molluscs that had been described thus far in Egypt, only ten had bee n examined by the combined efforts of Sonsino, Lortet, Vialleton and Looss . Furthermore, his studies of S. japonicum cercariae while in Japan ha d convinced him that he could distinguish s chistosome cercariae, including those of S. haematobium from cercariae of the other distomes on morphologica l grounds, in particular, the absence of a muscular pharynx 137. Consequently, Leiper had his team set about the collec tion and identification of all the species of freshwater molluscs that they could find in the province of Qaliub, a highly endemic area a few miles north of Cairo, then dissected them in order to look for any larvae which showed morphological characteristics of schistosomes. In addition, snails were collected from ponds in the Botanical and Zoological Gardens at Giza. The second phase of the plan was to ascertain if schistosome miracidia exhibited chemotactic behaviour towards any species of mollusc . Thirdly, if cercariae could be found in snails, experimental animals were to be infected with them and the route of infection determined. Fourthly, if all o f these were successful, it was planned to assess the efficacy of variou s chemotherapeutic agents. Finally, th e bionomics of the molluscan intermediate

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host, if found, were to be studied. Attention finally focused on a village called El Marg, nine miles north of Cairo, which was the home of an Arab attendant in the Department o f Parasitology of the Cairo School of Medicine; 15 species of molluscs wer e recovered from this site. Altogether, almost 30 species of snails from various locations were examined. Four species, Bullinus (now known as Bulinus) species, Limnaea truncatula, Planorbis boissyi (now known as Biomphalaria alexandrina) and Pyrgophyla forskali were found to be chemotactic fo r miracidia hatched from schistosome ova. On dissection of wild snails, thre e forms of cercariae of the schistosome type were found in four species of snails from El Marg and the Gardens. Le iper wondered whether they represented the three species of Schistosoma that were supposed to occur in Egypt: S. haematobium of humans, S. bovis of cattle and Bilharziella polonica of ducks. The first form of cercaria, which was distinctive and which he thought wa s probably the avian form, was found in Planorbis mareoticus, P. boissyi and Melania tuberculata. The second type of cercaria was discovered in P. boissyi and M. tuberculata, while the third form was seen in P. boissyi and a species of Bullinus. Cercariae from these snails were used to infect a calf, a lamb , mice, rats, geese, ducks, chickens, crows and wagtails percutaneously. All the experiments on birds were negative but on 13 June 1915, a young rat which had been exposed on 4 May was found to be infected, as was on 24 June a mouse that had been infected on 2 May . Schistosome worms were found in the liver and mesenteric veins, but since they had not reached maturity , differentiation between S. haematobium and S. bovis was difficult. Encouraged with this success, Leiper infected with cercariae from P. boissyi or Bullinus, four mice, 26 white rats, 16 desert rats, two guinea pigs and four mangaby monkeys, and took them back with him to England . Examination of these animals when they arrived in England disclosed that all of them had enormous numbers of schistosomes with "characteristic eggs" in the portal system. Further, he was able to show that the incubation period of the infection was approximately 6-8 weeks. Leiper used the monkeys t o compare the percutaneous and oral routes of infection. Three monkeys were infected percutaneously and one was infected orally. All eventually died o f heavy schistosome infections, but Leiper thought it most likely that the las t animal was infected by cercariae penetrating the oral mucous membrane. While in Egypt, Leiper and his associates also studied the development of larvae in susceptible species of snails and found that miracidia gave rise t o sporocysts which in turn produced daughter sporocysts that migrated into the digestive gland. Cercariae developed within these sporocysts, and thes e eventually ruptured releasing the cercariae which were then discharged int o the water. Furthermore, they showed that each cercaria lost its bifid tail o n penetration of the skin of the final host. Thus, in 1915, Leiper was in no doubt that certain species of snails were the required intermediate hosts of the worm or worms that caused huma n

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schistosomiasis. Enough was known for a general understanding of th e epidemiology of the infections, and to devise effective control measures . However, it was still a matter of debate whether there were one or two species of schistosomes, and if the latter was the case, which snails were the vectors of which species. The studies which Leiper undertook in London and on his return trip to Egypt are detailed in chapter 9. Suffice it to say here, that th e upshot was that there were indeed two species, and that S. haematobium with the terminal-spined eggs was transmitted by snails known to Leiper a s Bullinus contortus, B. dybowski and B. innesi. Leiper and many of the other early investigators spelled the generic name of the snail intermediate host as Bullinus. Annandale 10 pointed out that the genus was described originally from a West African specimen by Adamson in 1757 who spelled it with a single "l" even though the word was derived from "bulla". Consequently, Oken in 1815 changed the name to Bullinus. The taxonomy of these snails was confused further when Ehrenberg in 183 0 erected the genus Isidora for certain Egyptian and Syrian forms. Many South African authors used this designation, although Annandale considered that it was synonymous with Bulinus 10, and other scholars treated it as a subgenus of Bulinus. Furthermore, Annandale in 1922 wrote that B. contortus, B. dybowski and B. innesi were all synonyms of each other and, moreover, that they were also synonymous with Physa truncata; since the latter specific designation had precedence, the correct name for the snail was Bulinus contortus 11. In 1927, Pilsbury and Bequaert declared that Isidora, amongst other names, was synonymous with Bulinus 173. It was not until 1931 whe n Baylis28 reiterated these points, howeve r, that the nomenclature of B. truncatus became accepted generally. Leiper's results were confirmed by Manson-Bahr and Fairley who studied schistosomiasis between 1916 and 1918 in Imperial troops of the Egyptia n Expeditionary Force. They recovered S. haematobium adults from monkeys infected experimentally with cercariae from Bulinus then infected Bulinus snails with S. haematobium miracidia and confirmed that Planorbis was resistant to these miracidia 156. Concurrently with Leiper's work in Egypt, and being stimulated by th e recent discoveries concerning the life cycle of S. japonicum in the Orient, FG Cawston turned his attention to determining the mode of transmission of the terminalspined S. haematobium in South Africa. In collaboration with Dr E Warren, Director of the Natal Government Museum, snails were taken from a swimming pool, which was believed to be the source of schistosomiasis in Pietermaritzburg, then mixed with urine containing S. haematobium eggs. After three to four weeks, cercariae with bifid tails, generally resembling those seen with S. japonicum, were found encysted within the liver of one of th e snails identified as Physopsis africana (now known as Bulinus [Physopsis] africanus), but not in Limnea (= Lymnaea) natalensis exposed similarly. Dr Watkins-Pitchford, Director of the South African Institute of Medica l

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Research, first communicated these results in July 1915 198, even though Warren looked upon these observation s as merely tentative and deprecated the drawing of definite conclusions, particularly as the snails could have bee n infected naturally and as there was no proof that they were the cercariae of S. haematobium. Publication of Leiper's discoveries prompted a flurry of activity by Cawston. He exposed a mouse and a guinea pig to washings obtained from infected snails, but the mouse escaped and schistosomes could not be found in the guinea pig at autopsy six months later. Nevertheless, Cawston the n indulged in what was to become a favourite hobby of his, publishing these indeterminate findings in three different journals 41. In the following year (1916), he recorded finding "bilharzia forms of cercariae" in 17.4% of 533 specimens of P. africana42. Cawston had made a quite unwarranted assumption an d Leiper condemned this when reviewing the paper for the Tropical Diseases Bulletin: The use of the term 'Bilharzia forms' for cercariae with bifid tails is exceedingly misleading. The presence of a bifid tail is no indication that a cercaria belongs to any special systematic group. In Egypt, 9 out of 27 recorded species of cercaria have 'bifid tails'.136

A multitude of papers flowed from Cawston's pen over the next several years, much to the exasperation of Leiper who wrote "There is no evidence that the various forms so loosely and repeatedly termed 'Bilharzia cercariae' in thi s author's numerous papers are actually such" 138 and "The subject matter ha s already been repeatedly reviewed in this Bulletin, and the present pape r contains nothing new" 139. In fact, one of these so-called cercaria of S. haematobium finally turned out (when sent to Leiper for identification) to be that of S. bovis43. In 1920, however, Annie Porter showed by infecting experimental animals that P. africana was naturally-infected with both S. haematobium (commonly) and S. mansoni (occasionally), and that Lymnaea natalensis rarely harboured cercariae of S. haematobium174. Porter was later to remark that cercariae of at least 22 different species has been found in P. africana 175. Cawston finally had a modicum of luck when he succeeded eventually in infectin g laboratory-reared P. africana with S. haematobium miracidia and obtained cercariae six weeks later 44. Several years later, Blacklock an d Thompson in Sierra Leone also infected Physopsis with miracidia from S. haematobium ova, obtained cercariae from these snails, infected monkeys and guinea pigs, then recovered S. haematobium adult worms 33. In 1921, 17 autochthonous cases of schistosomiasis were found i n Portugal. França investigated the attraction of various species of local snails for miracidia of S. haematobium and opined that Planorbis corneus var metidjensis (now known as Planorbarius metidjensis ) was likely to be the intermediate host 88; in this, he was later proven to be correct 29. A focus of infection with S. haematobium was found in a village nea r

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Bombay, India in 1952 by Gadgil and Shah 92, then it was shown by Gadgil in 1963 that the local vector was the limpet, Ferrisea tenuis 91.

CORRELATION OF INFECTION WITH PATHOLOGY In the patient in whom he found flukes, Bilharz apparently recognized no partcular pathology, for he made no comment on this subject in his first letter about this infection to von Siebold. In March of the following year (1852) , however, he and Griesinger fou nd evidence of bladder involvement when they performed an autopsy on a boy who had died from meningitis. When the y opened the bladder, they found: lentil- to pea-size, soft, spongy excrescences....They were ecchymotic and often encrusted with urinary salts. In the older lesions, we observed dark gray, leatherlike areas of mucosa covered with salt crusts; in the earlier lesions we saw areas surrounded by varicose capillaries coated with mucus and blood. 32

When some of the larger lesions were cut into, it became apparent that some of them were dilated blood vessels containing adult schistosomes. Earl y lesions on the other hand, harboured large numbers of S. haematobium eggs, either singly or in clumps. The same eggs had been noted previously in th e bladder by one of their colleagues, Dr Lautner, but he had not been able t o explain their nature. One week later, Bilharz had a second case in which there were not only bladder tumours, but also extensive dysenteric changes in th e intestine. In this patient, the bladder excrescences contained no worms bu t eggs in spherical heaps were embedded in the mucosa. In May of that year (1852), Bilharz again wrote to von Siebold stating his view that S. haematobium was the cause of extensive damage to the urinary tract: I no longer have any doubt that the worms cause the changes in the bladder, ureter and the seminal vesicle and so on. I, therefore, believe that the worm is related to a large extent to the frequency of bladder ailments, calculi and also certain renal diseases.30

Bilharz also noted that this worm may be related to disease of the large bowel and indicated that eggs had been found in dysenteric intestines, but the n qualified this remark by adding that cadavers of such patients were rare . Although he considered it likely that the pathological processes in the bladder and the gut were identical, and was convinced that the presence of worms in the bladder was a prerequisite for urinary disease, he was less certain abou t their role in dysentery, for he had two patients with this latter condition i n whom eggs could not be found. This led him to ask: Is my ineptness to be blamed or is the worm attracted by the initiation of primary disease of the intestine or is the worm the direct and immediate cause of the disease - but not solely responsible. I have not been able to reach a decision concerning these important questions.30

It is quite possible that Bilharz was sometimes dealing with cases of amoebic

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or bacillary dysentery, for neither of these conditions nor their causative agents were recognized at that time. What is less clear is how many of the eggs in the intestines that he saw were those of S. haematobium and how many were S. mansoni, for he did not differentiate between the two, labelling them all a s eggs of S. haematobium. It seems most likely that those patients with intestinal schistosomiasis as well as vesical schistosomiasis were infected concurrently with both S. haematobium and S. mansoni. In 1854, Bilharz's colleague, Griesinger, published a classic report on his findings in the 117 cases of schistosomi asis that he had encountered during the course of 363 autopsies. He descri bed the various changes that could be found in the bladder. In the mildest cases, there were simply: foci of hyperaemia....containing many fine extravasations of blood. The mucosa was somewhat swollen....and often....covered either with viscous mucus or with a soft grayishyellow, hemorrhagic exudate. In these secretions, the eggs of the Distoma were found, en masse.100

He noted that the urine in the bladder of these patients was generally light and clear. In more advanced cases, he described "polypoid patches of the mucosa which were....discolored....(and) often....showed a brittle crust on th e surface"100. Bilharz believed that these changes could be attributed to inflammation an d extravasation of blood consequent upon invasion of the small blood vessels by schistosomes and deposition of their eggs. He also recognized a third type of lesion: In some instances solitary clusters of pea-to-bean size, yellowish or ecchymotic papillomata or vegetations one to three lines high were found on the mucosa. They were wart-like or fusiform.100

There were countless transitional forms or intermediate stages between these tumours and the diffuse lesions, so he concluded that the former simply represented more advanced degrees of same process. Griesinger also noted that all these changes were often seen in the ureteric mucosa and sometimes even in the renal pelvis. He realized that th e consequences of the ureteric lesions were much more serious: Deposits on the mucosa and frequent thickening of the submucosa caused stricture of the ureter; in addition, there may be spindle-shaped or sac-like dilation of the lumen, muscular hypertrophy, and/or urinary retention with its complications. In cases where these changes had been present a longer time, fatty degeneration, pyelitis, hydronephrosis and complete atrophy of the kidney parenchyma were found.100

In the same manner as Bilharz, Griesinger connected vesical schistosomiasis with the urinary lithiasis endemic in Egypt "In addition, large urinary stones often formed in the kidneys, ureters and bladder with serious consequences" 100. Griesinger understood that these disturbances in the function of the urinar y tract sometimes led to a generalized chroni c disease, culminating in death from debilitation, pneumonia, dysentery and anaemia. Like Bilharz, he realized that urinary schistosomiasis was sometimes associated with intestinal disease ,

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having found that 50 of his 117 cases with urinary schistosomiasis had acute or chronic dysentery. Similarly, 20 of the pe rsons had died of "bilious typhoid", so he remarked cautiously that there was not necessarily a direct link between schistosomiasis and dysentery or typhoid fever. He suggested that an y relationship between schistosomiasis and both hepatic abscess and live r atrophy was worthy of investigation. Finally, his discovery of schistosome ova in the blood of the left side of the heart caused him to remark that "th e transportation of the worms or at least their eggs into the general circulation and to essential organs must be kept in mind" 100. In 1856, Bilharz published a lengthy paper on the relationship between S. haematobium and pathological changes in the urinary system 31. He classified the pathological changes in the urinary system into four groups: catarrha l inflammation of the bladder and ureters, induration and calcification of th e mucosa, polypoid growth of the mucosa, and mucosal ulceration. All of these changes Bilharz attributed to the presence of eggs in the mucosa. H e postulated that male worms carrying a pregnant female in the gynaecophoric canal migrated against the flow of blood to the small vessels of the vesica l venous plexus and that the female worms then deposited ova in a gelatinous substance. He suggested that the adult worms and eggs blocked blood flo w causing rupture of the vessels and extravas ation of eggs, either into the mucosa itself, or directly into the lumen of the urinary tract. If trapped in the tissues, the eggs acted as foreign bodies and stimulated an inflammatory reactio n which resulted in the lesions seen. These descriptions of the gross morbid anatomical changes in urinar y schistosomiasis have hardly been improved upon since. Following thes e pioneering studies, the histopathological changes of chronic inflammation and fibrosis around eggs were described by a number of investigators e.g . Zancarol205. The pathogenesis of these lesions is similar to that which occurs in S. mansoni infection and is described in the next chapter. Urinary schistosomiasis is sometimes complicated by the development of neoplasia. This was first suggested by Harrison in Liverpool in 1889; h e reported that four out of five specimens of bladder schistosomiasis sent to him from Alexandria by Mackie were complicated by the presence of squamou s carcinoma106. He acknowledged that further investigations were needed t o determine whether the worms were merely an irritant in persons predisposed to cancer or whether there was a direct aetiological relationship between the worm infection and cancer. A similar case was reported by Albarran an d Bernard in 1897 3. In 1911 Ferguson set the association on a firmer foundation when he described a series of 40 cases of malignant neoplasia, usuall y carcinoma, in the bladder of patients with schistosomiasis. He wrote: "I have no hesitation in affirming that cancer of the urinary bladder is the irritatio n cancer of Egypt." 83 To underscore his point, Ferguson went on to contrast this with intestinal schistosomiasis, remarking that he had not been able to trac e any relationship between schistosomiasis and cancer of the anus, rectum o r

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sigmoid colon. The behaviour of S. haematobium adult worms in blood vessels wa s studied in anaesthetized monkeys by Fairley 78,80. He observed that the adul t worms moved with a peristalsis-like action of the body and with the aid of the ventral sucker. When the time for egg-laying was at hand, the female worms left their male partners and retrogressed against the portal bloodstream to the small venules. By a process of elongation , each worm then worked the anterior truncated part of its body into a vessel of smaller diameter than its own, then ejected an ovum, with the spine pointing backwards into the current of blood. The adult worm then withdrew slightly and the overdistended venul e contracted down upon the egg, and so the process was repeated. Fairle y believed that the spine engaged the vessel wall, then rent a tear in it under the forces of the bloodstream, and was thus extruded into the perivenous tissue. This view was disputed later by Brumpt who could see no role for the spine 39. With respect to the location of the adult worms, Fairley showed tha t although they could be found in the portal and inferior mesenteric veins, the largest numbers were present in the vesical and uterine venous plexuses. I n this situation they may live for many years; one well-known English zoologist and physician was infected whilst on a naturalist expedition between th e Limpopo and Zambesi rivers in 1878, and continued to pass eggs for at least another 28 years 51. The pathological changes in the liver and lungs in S. haematobium infections broadly resemble those caused by S. mansoni ; the recognition of these effects is described in chapter 9.

RECOGNITION OF THE CLINICAL FEATURES It must have been clear to Bil harz and Griesinger when they first found ecchymoses and blood clots in the blad der of a boy with vesical schistosomiasis that passage of blood in the urine would be a promi nent feature of schistosomal infection. This, in fact, was the sign which gave Bilharz the clue to the diagnosis of schistosomiasis when later that year, he first found eggs in the urine of a living patient. In his review of urinary schistosomiasis in Egypt, Griesinge r listed haematuria, pyelitis, enlargement of the kidney, septicaemia and acute exacerbation of various obscur e and undiagnosed bladder and kidney ailments as the ways in which patients with the infection could present clinically 100. Bilharz later re-emphasized these points, making particular mention of a feeling of pressure and tenderness in the lower abdomen, increasing o n occasion to vehement burning or colicky pain, frequency of micturition , passage of mucus in the urine, and haematuria, the last being usually only a slight admixture of blood, but long-lasting and recurring frequently. Lik e Griesinger, he also thought that infection predisposed to urolithiasis, especially to stones in the ureter 31.

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These symptoms were similarly well-described by Harley in London i n 1864 in connection with his patient with the "endemic haematuria of the Cape of Good Hope". His patient complained that after micturition, a little blood , never exceeding a teaspoonful , or some dark "veins" (presumably blood clots) appeared with the last half ounce of urine. In this person, the urine itself was never bloody, but sometimes the "veins" would block the urethra and caus e obstruction for a few minutes. Moreover, he had occasional twinges of pain in the loins102. Harley later came to realise though that many robust person s (colonists) in South Africa were infected with the parasite without an y apparent detriment to their health 105. Once the clinical manifestations of S. haematobium infection were defined, it became possible to recognize earlier descriptions of schistosomiasis. Many Egyptologists have concluded tha t the - - disease mentioned in ancient texts such as the Kahun papyrus (c.1900 B.C.) and in the Papyrus Ebers (c.1500 2,109 B.C.)168 referred to haematuria, undoubtedly of schistosomal origin , although the Egyptians were probably no t familiar with the worms themselves. Indeed, haematuria was so common that it was mentioned some fifty times in papyri known by 1951 185. Moreover, description of the use of a basket to cover the penis as a protective measure against this affliction has been found in the Papyrus Ebers172. Formal proof that the ancient Egyptians played host to S. haematobium was provided when Ruffer found large numbers of calcified ova in the kidneys of two mummies dating from between the XVIII and X X Dynasties (1250-1000 BC) 181. It has even been postulated that urinar y schistosomiasis was the basis of Joshua's curse and the cause of th e abandonment of ancient Jericho 111. Similarly, it became clear that the epidemic which afflicted Napoleon' s troops in Egypt at the turn of the century before Bilharz discovered the worm and which was described graphically by Renoult was none other tha n schistosomiasis haematobia: A most stubborn haematuria....manifested itself among the soldiers of the French Army ....the continual and very abundant sweats diminished the quantity of urine, the latter becoming thick and bloody. Often even, the last drops are pure blood. The sickness gives sharp pains in the regions of the bladder, the last contractions of the bladder are accompanied by the most lively and piercing pains. 176

These symptoms and signs were again well-recognized in British troops i n South Africa during the Boer War and in Imperial soldiers in Egypt durin g World War I. For example, 75 troopers of the Australian light horse wer e infected by bathing whilst stationed at Serapeum and at Tel-el-Kebir in 1916. The clinical manifestations were divided into two phases. The early toxaemic stage occurred four to ten weeks after infection in more than half of th e soldiers and was characterized by fevers, rigors, sweats, headache, myalgia, urticaria and emaciation lasting from t wo to five weeks. A later stage appeared three months after infection; in 60% of the patients, the earliest symptom was a burning urethral pain on micturition, then terminal haematuria supervened

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after another one to four weeks 77. The kinetics of infection and the consequences of urinary schistosomiasis were particularly well-illustrated by a self-inflicted infection with S. haematobium. On 31 May 1944, Claude Barlow (who had earlier infecte d himself with Fasciolopsis buski), infected himself by applying eight cercariae from eight different specimens of B. truncatus to the skin of his forearm. On the following day, he placed eight more cercariae from the same snails around his umbilicus. Two weeks later, many cercariae from another six snails were again applied near the navel; 147 sma ll red papules were seen on the next day, thus confirming his previous observation that dermatitis may occur i n schistosomiasis haematobia 26. After a further week, more cercariae wer e similarly placed and 61 papules were seen 24 hours later. Barlow estimated that he was infected with a minimum of 224 cercariae. Eleven weeks after the major exposure on 14 June, he developed a mild fever, spermatozoa wer e found in his urine, and schistosome eggs were seen in the seminal fluid and in a plug of mucus in his stool. Ova ap peared in the urine on the 106th day. After 20 weeks, a nodule which discharged eggs appeared on the scrotum; further nodules developed and one was excised, revealing a pair of adul t schistosomes. Eggs continued to be excreted in the urine and faeces, wit h 20,000-30,000 being passed daily in the urine alone. An evening pyrexi a persisted and Barlow felt ill and prostrate. Micturition was frequent an d painful and blood, pus and shreds of m ucosa were seen in the urine. Blood and mucus appeared regularly in the stools. Barlow's blood eosinophil level was increased, ranging between 6% and 16%. Ten months after infection, he was treated with fouadin, this caused a fever, nausea, wheeze and cough. Th e numbers of eggs excreted were reduced greatly, although the drug did no t eradicate the infection completely 27. The amount of blood lost in the urine in patients with schistosomiasi s haematobia has been investigated on several occasions. Gerritsen and hi s colleagues showed in 1953 that between 1.3 and 6.1 ml of blood was lost per day in African males 94. A rather greater blood loss was estimated by Farid and his colleagues who used red blood cells radiol abelled with 59Fe: they calculated that between 2.6 and 126 ml of blood were lost each day in infecte d Egyptians82. While mild or moderate symptoms were the rule, it was realized that very intense infections may cause severe disease. Thus, Maddern described th e possible devastating consequences: He has constant micturition, really an incontinence and dribbling, with pain in the penis and deep down in the perineum near the rectum. He very often carries his scrotum in his hand, feeling that the support affords him some alleviation of his pain. A very small quantity of water is voided at a time, which is very offensive, dark brown in colour . . and turbid....On examining the abdomen, a hard mass may be felt in the suprapubic region, which is not at all tender, is very irregular and stony, and may extend as far as the umbilicus and to any extent laterally. One or both kidneys will be found enlarged and tender, and the much dilated and thickened

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ureters may be felt through the usually thin abdominal wall. On rectal examination, the bladder will be felt firm and contracted, and bimanually the great thickening of and around the bladder will be well appreciated. On introducing a sound, it can often only be passed just beyond the neck of the bladder into a very much contracted cavity.153

In addition, Maddern noted that urethral fistulae and a destructive, distorting false elephantiasis of the scrotum and perineum might supervene 153. With respect to prognosis, Bilharz recognized that the disease may last for many years, thus indicating that either the worms lived for a long time, or that reinfection was common. On the whole, he thought that the latter was more likely. Nevertheless, he did not reject the possibility that spontaneous cur e might occur, for he often encountered pigmented, leathery areas of bladde r mucosa which contained innumerable calcified ova but no living adult worms or fresh eggs31. Both Bilharz and Griesinger thought that death was ofte n caused by intercurrent illness, and this view was supported by practitioners in South Africa who claimed that they had never seen anyone die fro m schistosomiasis 4,150. Cobbold was among the first to realize that the severity of clinical manifestations bore some relation to the worm burden. He contrasted 'slight' and 'excessive' invasions thus: In cases of the former kind not more than a dozen or so of the parasite's eggs will be passed at each act of micturition, whereas in the latter it is not uncommon for the patient to pass fifty, or for that matter, a hundred dozen bilharzia eggs at a time. In severe cases the daily average of evacuated ova greatly exceeds this estimate. 59

Nevertheless, Cobbold went on to suggest that: the severity of the symptoms and consequent dangers are, as a rule, more dependent upon associated disorders than upon the actual number of parasites present.59

Infections in British troops in the South African war revealed that the disease was more prolonged than had hitherto been believed. Symptoms persisted for between five and thirteen years, often intermittently, but it was concluded that mortality arising from infection did not exceed 1% in the 466 soldier s studied107.

DEVELOPMENT OF DIAGNOSTIC METHODS In 1852, Bilharz made a provisional diagnosis of vesical schistosomiasis i n one living patient and proved the diagnosis in another. In the former case, he felt a rough surface in the bladder which he was able to palpate between his finger in the rectum and a catheter i n the bladder; unfortunately, he was unable to examine the urine of this patient. In another patient, however, he told von Siebold in a letter dated 2 August 1852 "I found fresh eggs in the urine of a young man who had moderate haematuria of unknown aetiology" 30. Griesinger later referred to this epochal observation: The eggs of the Distoma were found by Dr Bilharz while microscopically

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examining the urine of a boy who developed haematuria during convalescence from typhoid fever. The diagnosis can be established with this finding alone 100.

Many investigators believed that eggs could be found most frequently in the terminal urine, although this has been dispu ted by others. In more recent times, a rapid concentration technique using filters has been developed for rapi d quantification of eggs in the urine 171. An alternative but more complex method of making the diagnosis whe n facilities became available was by endoscopic biopsy of lesions in the bladder. This technique does, however, have the advantage of delineating the natur e and severity of damage to the blad der. Minet in 1915 appears to have been the first person to examine the bladder cystoscopically. He investigated tw o soldiers, one of whom had a light infe ction, while the other suffered from more severe disease. In the latter patient, he noted three types of lesions; smal l yellow granulations likened to grains of millet, infiltrated swellings of th e mucosa, and fungating vegetations of the mucosa 162. Structural damage to the urinary system can on ly be outlined radiologically. In 1917, Diamantis and Lotsy showed calcification of the left ureter an d bladder due to deposition of eggs in a plain x-ray of the abdomen 70. Intravenous pyelography provides a much more sensitive and complet e definition of the urinary tract and has been used in the last few decades 85,166. An increased number of eosinophils in the peripheral blood was found in a single patient by Coles 60 in 1902 then the presence of eosinophilia wa s confirmed in a series of patients by Douglas and Hardy 72. Many attempts have been made to diagnose schistosomiasis by immunological methods. In 1919, Fairley reported the development of a complement fixation test fo r antischistosomal antibodies 79 then he and Williams described an intradermal test for the infection 81.

THE SEARCH FOR EFFECTIVE TREATMENT The early investigators recognised the need for effective anthelmintics to cure schistosomiasis. Griesinger suggested that calomel and oil of turpentine might be effective, and that perhaps certain foods such as onions and garlic migh t exert a beneficial effect 100. Bilharz indicated that local pains usuall y disappeared rapidly after the use of opium, but he was less sanguine abou t prospects for eradication of the worms, for he thought it would be difficult for drugs to reach them in their domicile in the veins. He tried on a couple o f occasions to poison worms in diseased specimens with calomel, but wit h inconclusive results 31. In 1870, Harley reported the effects of his treatment for endemi c haematuria. He found that general therapy with potassium iodide and henbane was of little use, but that local injections of emulsions of oil of male fern o r potassium iodide in a strong infusion of wormwood or quassia into the bladder

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via a catheter were beneficial 104. A few years later (1882), Cobbold classified treatment into thre e categories. In the "heroic plan", medications such as a saturated alcoholi c solution of santonin were injected into the bladder. He remarked wryly tha t since patients did not return after this agonizing treatment, the proponent o f this therapy concluded that the treatment was successful 4. The "do-nothing plan" was based upon the assumption that the patient would outgrow th e disease. The so-called "rational plan" (presumably Cobbold's) consisted o f general support by way of a nutritious diet and the administration of iron and quinine 58. Cobbold's comments drew a vociferous reply from the injured J F Allen, the exemplar of the "heroic" system: Those who may have to treat cases of this kind must not be deterred from using injections into the bladder by Dr. Cobbold's describing the treatment as heroic; he is, I fear, so timid and ultra-conscientious that he would consider it heroic to use enemata in the treatment of ascaris vermicularis in the rectum. Injections into the bladder are more painful, more difficult, and followed by cystitis, but they are efficacious in the one case as in the other. It is to these injections Dr Cobbold objects so much, but as experience and common sense both point to their use, it is to be hoped that even he may be induced to adopt them. 5

In the interim, Cobbold's views had been supported by FH Guillemard wh o wrote from Japan expressly to dissuade the adoption of Allen's regimen. H e lamented the lack of any concrete evidence given by Allen for the efficacy of local treatment, then emphasized the toxicity of such therapy: Dr Allen allows that acute cystitis is a common result, and in a case with which I am unfortunately only too well acquainted, cystitis, acute nephritis with secondary pericarditis, and probable life-long ill-health have been the unlucky consequences.101

Cobbold's "rational" treatment also met with criticism. Harley remarked that he could see no reason why the parasite should not flourish all the more when the host was healthy, so he hardly thoug ht that improving the general condition of the patient was likely to result in cure 105. Sonsino then reviewed thes e arguments and concluded: "as yet, we have no means of curing the infection of Bilharzia better than it is done by nature" 188. In 1888, Fouquet in Cairo claimed that extract of male fern was beneficial in fifteen of his patients 87. In 1906, Stock suggested, on the basis of a couple of coincidental observations, that antityphoid serum may be of use 191. Salvarsan enjoyed a vogue after being introduced in 1911 by Dr Nicola s Joannidès, a physician in Cairo, then given wide publicity by Erlich, th e famous chemist115. Many observers were not convinced of its efficacy , however. For example, Day and Richards (1912) in Cairo assessed th e effectiveness of the drug in patients with urinary and/or intestina l schistosomiasis and found it wanting 66. Similarly, Schrecker had fou r longstanding and four recent cases, and in only two of them did the numbers of ova in the urine diminish even transiently 182. Thymobenzone was advocated in 1916177, but proved to be of little use. T hus, none of these drugs was of great value, and an eminent surgeon in Cairo wrote in April 1917: "Until now there

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is no curative treatment for schistosomiasis, and I think it is far from possible to find one in the near future" 18. He was wrong. In the following year, JB Christopherson reported that the antimonial compound, tartar emetic (antimonium tartaratum, potassiu m antimony tartrate) was of great value in the therapy of both urinary an d intestinal schistosomiasis 47,48. Christopherson, who was principal medica l officer at the Civil Hospital in Khartoum, Sudan, had treated a patient wit h kala azar (visceral leishmaniasis) with antimony. He noted that during thi s course of treatment, those symptoms that were due to schistosomiasis (wit h which the patient was concurrently infected), were alleviated. Christopherson followed up this serendipitous observation in other patients, and found tha t after intravenous injection of tartar emetic, the schistosome ova becam e shrivelled, dark-coloured and failed to hatch miracidia in water. After a fe w weeks, the eggs disappeared completely from the urine or faeces. He described his technique as follows: A 10 ccm. record syringe, with a fine needle was used. The injection was given into one of the conspicuous veins at the bend of the elbow. The patient lay down for an hour on a bed after the injection, or longer if symptoms intervened. The solution used was tartar emetic, 1/2gr to 20m aq. distill., and diluted with 2 vols of aq. distill. at the time of use. The injection was repeated and the dose increased by 1/2gr every other day until 2gr was reached and this was continued until 30gr had been injected.47

Christopherson also noted that it was essential to watch for signs of acute to chronic poisoning. Altogether, approximately 30 grains (O.46mg) given over 15-30 days were necessary to achieve a "killing dose". Further experienc e showed him that the drug was not only able to kill the adult worms, but also the embryos in the ova in the tissues 50. So convinced of the efficacy of th e treatment was Christopherson, that he wrote that it may be possible to rid the scourge of schistosomiasis from Egypt, so that the people would become a "clear-complexioned, rosy-faced race" 49. Christopherson's regimen was taken up enthusiastically by a number o f physicians, including Cawston (1919), Fairley (1919), Low and Newha m (1919), Innes (1919) and Taylor (1919) who also reported encouraging results in small series of patients. By 1921, Day was able to report an analysis o f toxicity and effectiveness of the drug in 1,000 persons treated as outpatients in a tent-annexe at the Kasr-el-Aini Hospital in Cairo: 88% of these patients had urinary schistosomiasis. He found that 13gr was the smallest curativ e amount, but that 24gr or more were usually needed. Day also noted that after the first weeks of intensive treatment, results appeared excellent, but that two to three months later, ova reappeared. Since it was thought unlikely tha t reinfection had occurred, these data were interpreted as indicating that th e primary effect of the drug was the destruction of ciliated embryos within their shell, the parent worm requiring a larger dose to achieve a lethal effect 65. The effectiveness of the drug was confirmed by Lasbrey and Coleman in Cairo in the same year, also with a series of 1,000 cases. Of those who finished th e

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course (20gr), 70% were pronounced cured and they remarked that: the successful treatment of complications dependent upon bilharziasis, such as urinary fistulae and rectal papillomata, is enormously facilitated by the elimination of the causative factor.133

The effectiveness of the drug was demonstrated amply by Shaw in 1921 who studied the cystoscopic appearances in 23 patients with schistosomiasis who were undergoing treatment. In half of these persons, there had been activ e nodules present before therapy, and these disappeared after administration of tartar emetic. Similarly, infiltrations and signs of subacute cystitis subsided , and even the fibrotic areas appeared to improve and become pink 184. Not surprisingly, when an effective drug was promulgated, others tried to cash in on the credit. In the week following Christopherson's paper, a lette r was published by JE McDonagh in which he recalled that he had use d antimony in 1911 and had eliminated ova from the urine in 23 cases; h e claimed that he had used the drug empirically because of its effectiveness in some other disease caused by animal parasites 151. He reiterated this claim two years later, quoting from the 1915 edition of his book Biology and treatment of venereal diseases : I should like to mention that I have had great success in treating cases of bilharziasis with intravenous injections of antimony. 152

This drew forth the riposte that although it was the earliest record of the use of antimony in bilharziasis, it could not have been more effectivel y pigeon-holed. Similarly, but more in the nature of an anecdote, Wiley wrote that a case of urinary schistosomiasis had been treated in a like manner at the Australian Dermatological Hospital in Cairo in 1916 203. Following the introduction of tartar emetic, a number of other trivalen t organic antimonials were developed, pentavalent antimonials being found to be ineffective in schistosomiasis. Sodium antimonyl tartrate (SAT) wa s claimed by some to be better tolerated than the potassium salt, but this view was not accepted universally. The advent of st ibophen (fouadin, neoantimosan) in 1929 was hailed as a considerable advance because it could be given b y intramuscular injection and as it was at first thought to have higher cure rates and less toxicity that tartar emetic 124,125. Lithium antimony thiomalat e (anthiomaline) was introduced in 1935 and could also be given b y intramuscular injection. Sodium antimonyl gluconate (triostam) given b y intravenous injection had variable effectiveness 75. Sodium antimonyl dimercaptosuccinate (TWSB, stibocaptate, astiban) was introduced b y Friedheim and colleagues in 1954 for schistosomiasis mansoni 90, and was then used in schistosomiasis haematobia in 1956 89. Unfortunately, these compounds, though less toxic, were less effective than tartar emetic. A major problem with the antimonials was the severe, sometimes fata l toxicity associated with their use. In 1936, Khalil estimated that antimon y killed about 2,000 persons in Egypt each year122. This appalled Diamantis who considered such therapy monstrous, seeing that the infection would not have killed the patients in that time, and that had they kept to certain rules, the y

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might have looked for a natural cure 69. In 1946, Alves and Blair introduced "intensive therapy" with antimonials. They treated 100 patients with S. haematobium and S. mansoni infections with full doses of sodium antimonyl tartrate frequently within a period of only two days. The therapeutic results were excellent and the apparent absence o f toxicity was remarkable 9. These problems with toxicity led to a continuing search for safer and more effective schistosomicides. The first major competitor for the antimonials was emetine. In fact, at almost the same time as tartar emetic was introduced, the virtues of emetine in the treatment of schistosomiasis were sung, particularly by continental European workers. In 1917, Diamantis reported that emetine was of value in a series of patients with schistosomiasis 68. In the following year, Mayer treated a case of urinary and intestinal schistosomiases b y subcutaneous injection of emetine and found that blood disappeared from the urine and stools, and the patient showed great improvement 158. In 1919, Erian reported that he had used large doses of e metine in 50 patients with both forms of schistosomiasis and claimed to have no failures 76. In 1921, Tsykalas, after declaiming the use of antimony as barbarous, promulgated the use of emetine. He indicated that 90% of 2,000 patients showed a complete and lasting cure, provided that the emetine was given in a total dose of 1.0-1.2 grams injected intravenously in aliquots over 10-12 days 193. As with antimony, controversy then ensued as to who first introduce d emetine therapy. The article by Tsykalas stimulated a letter from Mayer who claimed priority in the use of the disease, saying that he recommended it and gave it subcutaneously in 1915. Nevertheless, Mayer considered the drug to be inferior to antimony 159. Tsykalas responded to this by stating that he himself had given it intravenously in 1914, but that Tsamis of Alexandria had in fact used it as early as 1913 194. In order to facilitate administration of the drug, oral preparations wer e developed. In 1926, Gordon showed that emetine periodide was effectiv e when given orally 99. Nevertheless, emetine in its various forms did not achieve the long lasting popularity of the antimonials as it was generally considered to be both less effective and too toxic for outpatient use. In the middle of the 1930's, there was a spasm of interest in th e anti-schistosomal properties of acriflavine 84, but this proved to be short-lived 126. At the end of the Second World War, it became known that Dr H Mauss in Germany had synthesized a new series of compounds known as miracils . One of these preparations, miracil D (nilodin, lucanthone) was shown b y Kikuth and Gönnert to be active against S. mansoni in mice and in monkeys when given orally19, but because of the political circumstances, they were not able to publish details of their experiments until subsequently 127,128. Clinical trials were then carried out in Southern Rhodesia (Zimbabwe) and in Egypt, and it was found that S. haematobium was more susceptible to the drug than

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was S. mansoni 34. In 1967, another miracil derivative, hycanthone, was reported to be active against schistosomes in experimental monkeys 169. Later that year, Katz an d Pellegrino showed that it was effective in patients with schistosomiasi s mansoni118, then in 1969 it was reported to be active against human S. haematobium infections as well 53. Meanwhile, in 1964, Lambert had reported that a new drug, niridazol e (ambilhar) was active in mice infected with S. mansoni 131. In the following year, its efficacy in urinary schistosomiasis was reported following a clinical trial in Portuguese Guinea (Guinea-Bissau). The drug was given orally an d was well-tolerated 132. Subsequent studies showed that the agent was als o effective against S. mansoni but less so than against S. haematobium 116. Thus, by the early 1970's there were three major therapeutic agents used in urinary and intestinal schistosomia sis - antimony, hycanthone and niridazole - each with its supporters and opponents. The consensus of opinion was that tartar emetic was the most effective drug in bringing about a parasitological cure, but it needed to be given intravenously, the course was long, and th e toxicity was sometimes severe. Niridazole had the advantage of ora l administration and was effective, but was prone to provoke neuropsychiatric complications, particularly if there was hepatic insufficiency. Hycanthon e could be given by a single injection, but eradicated the infection in onl y 50-65% of patients, and was sometimes toxic to the liver 21. There was, however, a fourth drug which was useful in urinar y schistosomiasis. In 1962, Cerf and colleagues indicated that th e organophosphate compound, dipterex (trichlorophone, metrifonate) wa s effective in patients with schistosomiasis haematobia 45. This observation was confirmed by a number of investigators 86,192, but the drug was shown to b e inactive against S. mansoni 110. In the late 1970's, a pharmaceutical company collaborated with the World Health Organization to assess, in a uniform manner, the effectiveness an d toxicity of new agent, praziquantel (biltricide, droncit) against all three of the major schistosome species infecting humans 64. This drug had been identified in 1972 from a group of heterocyclic pyrazino-isoquinoline derivatives an d was found to have unusually b road anthelmintic activity. In 1977, a number of investigators reported that it was active against S. haematobium, S. mansoni and S. japonicum in experimental animals 97,114,170,201. This drug had the added advantages that it could be given orally and in a single dose. Subsequen t clinical studies showed that it was highly active against both S. haematobium in Zambia63 and against S. mansoni in Brazil119 . Moreover, it had very littl e toxicity. Praziquantel promises to become the drug of choice in the treatment of all forms of schistosomiasis. Occurring concurrently with these medical developments were changes in the surgical management of urinary schistosomiasis. Improvements in surgery and anaesthesia facilitated surgical intervention where necessary. In 1897 ,

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Curtis described partial resection of bladder for a vesical ulcer caused b y schistosomal infection 62. In 1903, Milton reviewed the surgical management of schistosomiasis haematobia and recommended that cystitis be treated b y bladder washouts with mild antiseptics such as quinine, lithotomy for th e removal of calculi, drainage of the bladder by perineal puncture for acut e retention of urine or in very late stages of the disease, plus removal o f schistosomal tissue if possible, and excision of fistulae 160. In 1918, Desnos investigated the effects of cystoscopic high frequency diathermy o f papillomatous and epitheliomatous gro wths of the bladder wall, and found that the procedure not only cauterized the lesions but also appeared to kill egg s infiltrating the bladder wall 67. The introduction of effective chemotherapy , however, has reduced greatly the need for surgical intervention.

UNDERSTANDING THE EPIDEMIOLOGY S. haematobium sometimes occurs in subhuman primates, as was first shown when Cobbold found the parasite in a monkey in London 54. It has been suggested that human schistosomiasis may have evolved at the same time as there was a shift in human populations from hunter-gatherer economies t o societies based upon domestic agriculture, since this parasitism requires a stable relationship between parasite a nd host. It is thought that schistosomiasis may have first evolved around the great lakes of East Africa, then sprea d together with the vector snails along the Nile and out into the Middle East via the trade routes 167. Some of the initial ideas on the epidemiology of schistosomiasis have been discussed earlier in relation to the various theories on the transmission o f infection. In particular, the geographical distribution of urinary schistosomiasis was recognized, the increased prevalence in males and the young was realized, and the association with water was commented upon. Nevertheless, failure to understand the life cycle led to a number of incorrect assumptions about the epidemiology of infection. This especially flowed from the view espoused by Looss that direct infection with miracidia without the mediation of a vecto r takes place. The consequences of this idea were the beliefs that transien t collections of water were dangerous if contaminated whereas large bodie s were not liable to be infective (because of dilution), infection could occur in both towns and in rural areas if puddles were contaminated, water woul d become safe automatically after 30 hours if the local population was removed (because miracidia have only a limited life span), autoinfection could occur for example in household baths, and infection could spread to any part of th e globe144. These concepts underwent a radical revision when Leiper showed in 1915 that infection only occurred via a mollus can intermediate host 134. In view of the time required for cercariae to develop, it became obvious that transient water

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collections were quite safe whereas permanent collections were potentiall y dangerous if the vector was present, infection in towns was possible if there was a supply of unfiltered water from contaminated water sources, prevention of urinary or faecal contamination of water would have no effect for som e months, autoinfection was impossi ble, and infection could only spread to parts of the globe where susceptible snails were present. Much effort was then expended on determining the prevalence an d intensity of infection in various endemic areas, the age and sex distribution of the infection, and the prevalence and density of vector snails. The frequency of infection ranged from near zero to 100% in different localities, but th e increased prevalence and intensity in males and in children was generall y confirmed. Urinary schistosomiasis was not a static process, however, fo r infection increased in some areas and fell in other. These fluctuation s depended upon changes in water resou rces93. Many examples of these changes have been recorded; several will be cited here. Before building the Sennar dam across the Blue Nile to irrigate the Gezira Province of Sudan in 1925, schistosomiasis haematobia was almos t non-existent in that part of Africa. Within two years, however, Bulinus species were present in all the waterways of the system and infection, introduced by Egyptian labourers, was spreading 112. In Egypt, the introduction of perennial as opposed to basin irrigation, i.e. irrigation only at the flood of the Nile , increased the infection rate between four- and forty-fold in a number o f villages in the three years from 1934 to 1937 123. In more recent years, a number of great man-made lakes in Africa including Lake Volta in Ghana , Lake Nasser in Egypt and Sudan, and Lake Kariba in Zambia, have bee n constructed to enhance economic development by improving water supplies and generating electricity. Unfortunately, scant regard was paid to the potential health hazards, and the occurrence of schistosomiasis has increase d enormously, in some places reaching epidemic proportions 23. Not only have changes occurred around the lakes themselves but along the Nile the pattern of schistosomiasis has altered downstream; in one village surveyed in 193 5 and again in 1979, schistosomiasis haematobia, which was once commo n (74% of the population infected), had almost disappeared (2.2%), but th e prevalence of schistosomiasis mansoni had shown an almost reciprocal effect, rising from 3.2% to 73%. These effects were ascribed to changes in th e densities of the respective vector snails consequent upon the changes in th e water-flow pattern of the Nile following construction of the Aswan High Dam and creation of Lake Nasser 1. In the final analysis, though, the habits of the human population are o f crucial importance, for there is no significant animal reservoir of infection . Urination in water sources by infected persons and contact with that water , whether for economic, social, domestic or recreational reasons, are essential for maintenance of the life cycle of the parasite and play a major part i n determining the prevalence and intensity of infection in a given population 196.

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THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The association of schistosomiasis with water was so strong that an editorial writer in the British Medical Journal of 1882 was able to suggest correctl y effective control measures, despite an inadequate understanding of the lif e cycle of the parasite. The editorial followed a minor epidemic o f schistosomiasis among the staff of the Eastern Telegraph Company at Suez, and remembering the affliction of French tr oops by endemic haematuria during the expedition of 1799 to Egypt, the writer was concerned that a similar fate might befall British troops then situated in that country: If drinking directly from the canals, or bathing much in muddy water be avoided, and water well-boiled or well-filtered....be alone used for drinking purposes, the disease may be prevented. The Mediterranean troops have, it seems, been left unprovided with any filters, and it is certainly greatly to be hoped that the authorities will immediately adopt measures to save our troops from so formidable and painful a disease as haematuria.12

This was good advice, but hardly applicable to the indigenous populatio n living along the banks of the Nile and in similar endemic areas, for many o f whom daily contact with water was necessary for survival. Methods for th e control of infection among the general population hinged upon whether or not infection was direct or occurred via an intermediate host. Irrespective of the mode of transmission, Looss was correct when he said: Infected persons should never evacuate urine or faeces into water, for this is the only way in which the latter becomes populated with dangerous germs. 146

This was easier said than done, however, and eradication depended upon education and complete sanitary control throughout the country, with the sustained cooperation of every individual being essential. This was and is an almos t impossible task. The demonstration of transmission through snails, however, provided a link in the chain which could be attacked without the cooperation of infected individuals. Further, it was now clear that large bodies of wate r rather than transient pools should be avoided. When Leiper worked out the life cycle of schistosomiasis in 1915, h e turned his attention to a consideration of both personal prophylaxis (wit h particular reference to troops) and control of the infection in general. Wit h respect to the former, he studied various physical and chemical measure s designed to kill cercariae and concluded t hat unfiltered water was safe if stored for 48 hours, water heated to 50 oC or treated with sodium bisulphate was safe, that filtration through sand was untrustworthy, and that personal contact with any kind of unfiltered water was risky 134,135. Concerning control of infection in the country as a whole, he noted that practically all the water in Egypt came from the Nile, and that if this fact were properly exploited, it could lead to the eradication of the disease in the course of a few years. He suggested tha t appropriate measures included periodical drying of waterways in agricultural areas to kill snails by drying, and storage of water before supplying it t o towns134. This approach was only partially successful, however, for Barlo w

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showed in field experiments that when the waterways were dried, the Bulinus snails took up a position with the shell-opening facing down and secreted a protective coat of slime, with the result that 50% of the snails survived 25. Nevertheless, snail eggs were killed by these physical measures. An alternative approach was to kil l the snails with chemical molluscicides. In 1920, Chandler showed in labora tory experiments that snails were killed by immersion in a 1 in 1,000,000 solution of copper sulphate 46, then Khalil in 1927 demonstrated in a field experiment that all the Bulinus in an oasis were killed by this measure and that none were alive six months later 121. In 1932, Humphreys reported that carbolic acid in a strength of 1 in 20,000 killed all the snails in the irrigation system in the Gezira region of the Sudan 112, but copper sulphate remained the mainstay of intervention. In 1941, Mozle y indicated that malachite green (mineralized basic copper sulphate) was just as effective and much less expensive 165. These molluscicides were in tur n followed in 1957 by sodium pentachlorophenate 130 then in 1959 by niclosamide (Bayer 73, Bayluscide) 96,98. Nevertheless, it was concluded i n 1962 that this approach had been unfruitful, largely because of the grea t expense involved, the difficulty in providing adequate teams to distribute the molluscicides, aestivation (similar to hibernation) of the snails, and toxicity of the molluscicides for aquatic fauna 20. More recently, a mood of optimism has returned, with Webbe writing in 1981: There is ample evidence that area-wide mollusciciding is now successfully controlling snails in major control programmes - for example, in Egypt and China - and that control of transmission based on the essential focality of transmission in many areas (St. Lucia, Ghana, Yemen and Saudi Arabia) is also being successfully prosecuted by killing snails and surveillance.200

A third technique of control is by the mass treatment of infected persons. This was hailed with enthusiasm following the introduction of specifi c treatment with tartar emetic in 1918. Christopherson himself wrote: It is in mass treatment in schools and villages where the hope to eradicating the disease lies....My own view is that there is more hope of successfully dealing with the schistosomiasis problem by the symptomatic treatment of individual cases wherever they are met than by attempting to eliminate the disease by destruction of snails which can only be a practicable proposition in limited areas. 52

In Egypt, a large number of treatment centres w ere set up in an effort to control the infection but less than 5% of the total number of infected persons wer e treated each year. In 1933, Rose reviewed the effectiveness of this programme and wrote: complete unanimity exists among all Egyptian specialists. No influence on the mere occurrence of the disease has been obtained by the present methods. But on the contrary, no doubt exists that....the grave cases of urinary fistulae, the pyo- and hydronephroses, the numerous urinary calculi, all these serious complications of Egyptian schistosomiasis have greatly diminished in number. 178

Control based upon mass chemotherapy lay in the doldrums for man y years. Recently the outlook has changed because of two factors. Firstly, more effective and less toxic drugs have appeared. Secondly, it has been realize d

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that among infected individuals in a population, a small number of person s harbour a large number of worms, and it is these people who are at most risk of developing disease and who make the greatest contribution to th e contamination of the environment with miracidia. This has led to th e introduction of "targeted mass treatment" in which only the heavily infecte d persons are treated. This has been eva luated in schistomiasis mansoni 197; it has the twofold aim of curing diseased persons and of reducing transmission , although the efficacy of the latter is yet to be proven. Another approach was to attempt to improve sanitation. A major project was undertaken by the Rockefeller Foundation and the Egyptian government between 1928 and 1937 in which bore-hole latrines were introduced to rural houses, but this measure alone had little effect. All these measure are more likely to be succes sful if used concurrently with health educational control programmes. Indeed, the best results are obtained when there is integration of chemotherapy, snail control and propagand a campaigns. Nevertheless, even th e most optimistic must doubt that these techniques are likely to control, let alone eradicate, schistosomiasis in the nea r future. Although the prospects of control by immunization have been touted 22, the problem of schistosomiasis seems unlikely to go away unti l socio-economic conditions improve to such an extent that provision of saf e water supplies and constant usage of reliable waste disposal systems become the norm in endemic areas.

REFERENCES 1. ABDEL-WAHAB MF, STRICKLAND GT, EL-SAHLY A, EL-KADY N, ZAKARIA S, AHMED L. Changing patterns of schistosomiasis in Egypt 1939-1975. Lancet ii: 242-244, 1979 2. ADAMSON PB. Schistosomiasis in antiquity. Medical History 20: 176-188, 1976 3. ALBARRAN J, BERNARD L. Sur un cas de tumeur épithéliale due à la Bilharzia haematobia, contribution à l'étude de la pathologie du cancer. Archives de Médecine Expérimentale et d'Anatomie Pathologique 9: 1096-1123, 1897 4. ALLEN JF. Remarks on Bilharzia. Lancet ii: 51-53, 1882 5. ALLEN JF. Bilharzia haematobia. Lancet i: 660-661, 1883 6. ALLEN JF. Parasitic haematuria, or bloody urine. Practitioner 40: 310-320, 1888 7. ALLEN JF. Bilharzia haematobia and circumcision. Lancet i: 1317-1320, 1909 8. ALLEN JF. Bilharziosis and how to prevent it. Lancet ii: 375-376, 1910 9. ALVES W, BLAIR DM. Schistosomiasis: intensive treatment with antimony. Lancet i: 9-12, 1946 10. ANNANDALE N. Freshwater snails from Mesopotamia. Records of the Indian Museum 15: No. 20. Abstracted in Tropical Diseases Bulletin 13: 200-201, 1919 11. ANNANDALE N. Notes on the genera Bullinus and Physa in the Mediterranean Basin (Mollusca Pulmonata). Indian Journal of Medical Research 10: 482-491, 1922 12. ANONYMOUS. Endemic haematuria in Egypt. British Medical Journal ii: 275, 1882 13. ANONYMOUS. Special correspondence, Cairo. British Medical Journal ii: 1264, 1884 14. ANONYMOUS. British Medical Journal i: 916, 1885 15. ANONYMOUS. A newly differentiated parasite. Lancet ii: 640-641, 1893 16. ANONYMOUS. Endemic haematuria. Lancet i: 249-250, 1900

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17. ANONYMOUS. The intermediate host in Bilharzia. Journal of Tropical Medicine and Hygiene 18: 232-234, 1915 18. ANONYMOUS. Cited in 95 19. ANONYMOUS. Combined Intelligence Objectives Subcommittee File No. 25, vol. 54, 1945. British Intelligence Objectives Subcommittee Final Report, vol. 116, 1946 20. ANONYMOUS. A century of schistosomiasis. Lancet i: 1223-1224, 1962 21. ANONYMOUS. Chemotherapy in schistosomiasis. British Medical Journal i: 128-129, 1972 22. ANONYMOUS. Immunological control of schistosomiasis. British Medical Journal ii: 366-367, 1972 23. ANONYMOUS. Menace of Man-made lakes. British Medical Journal i: 62-63, 1973 24. BALFOUR A. Endemic haematuria (Bilharzia). Wellcome Research Laboratory Report 1: 51-52, 1904 25. BARLOW CH. The effect of the "winterrotation" of water upon snails involved in the spread of schistosomiasis in Egypt, 1930-1931 and 1931-1932. American Journal of Hygiene 17: 724-742, 1933 26. BARLOW CH. Is there dermatitis in Egyptianschistosomiasis? American Journal of Hygiene 24: 587-599, 1936 27. BARLOW CH, MELENEY HE. A voluntary infection with Schistosoma haematobium. American Journal of Tropical Medicine 29: 79-87, 1949 28. BAYLIS HA. The names of some molluscan hosts of the schistosomes parasitic in man. Annals of Tropical Medicine and Parasitology 25: 369-372, 1931 29. BETTENCOURT A, BORGES I. Le Planorbis metidjensis, hôte intermédiaire du Schistosoma haematobium au Portugal. Confirmation expérimentale. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 87: 1039-1040, 1922 30. BILHARZ T. Fernere mittheilungen über Distomum haematobium. Zeitschrift für wissenschaftliche Zoologie 4: 454-456, 1853. Partly translated in 120 31. BILHARZ T. Distomum haematobium und sein Verhältniss zu gewissen pathologischen Veränderungen der menschlichen Harnorgane. Wiener medizinische Wochenschrift 6: 49-65, 1856. Abstracted in 195 32. BILHARZ T, von SIEBOLD CT. Ein Beitragzur Helminthographia humana, aus brieflichen Mittheilungen des Dr. Bilharz in Cairo, nebst Bermerkungen von Prof. C. Th. von Siebold in Breslau. Zeitschrift für wissenschaftliche Zoologie 4: 53-76, 1852-1853 (distributed2 September 1852). Partly translated in 120 33. BLACKLOCK DB, THOMPSON MG. Human schistosomiasis due toS. haematobium in Sierra Leone. Annals of Tropical Medicine and Parasitology 18: 211-234, 1924 34. BLAIR DM, HAWKING F, ROSS WF. The effect of Miracil D on human schistosomiasis. Lancet ii: 911-912, 1947 35. BLANCHARD R. Traité de zoologie médicale. J-B Baillière et fils, Paris, 2 volumes, pp 1689, 1885-1890 36. BOUR FE. On numerous cases of oedema of the legs and albuminuria occurring in a reformatory, with a contribution to the study of bilharziosis. Journal of Tropical Medicine and Hygiene 15: 148150, 1912 37. BROCK GS. Anatomy and physiology of the Bilharzia ovum. Lancet ii: 622-625, 1893 38. BROCK GS. On the Bilharzia haematobia. Journal of Pathology and Bacteriology 2: 52-74, 1894 39. BRUMPT E. La ponte des schistosomes. Annales de Parasitologie Humaine et Comparée 8: 263297, 1930 40. CASTLE RF. Haematuria in East Central Africa. Lancet i: 931-932. 1891 41. CAWSTON FG. Schistosomiasis in Natal. Journal of Tropical Medicine and Hygiene 18: 257-258, 1915; Bilharziosis in Natal. British Medical Journal ii: 746,1915; Bilharziosis. Lancet ii: 1427, 1915 42. CAWSTON FG. Report on the examination of 1,000 molluscs in Natal. Medical Journal of South Africa 11: 197, 1916 43. CAWSTON FG. Schistosomes of man andbeast in Natal. South African Medical Record 18: 264, 1920 44. CAWSTON FG. Experimental infestation of freshwater snails. Transactions of the Royal

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Society of South Africa 9: 301-303, 1921 45. CERF J, LEBRUN A, DIERICH XJ. A new approach to helminthiasis control: the use of an organophosphate compound. American Journal of Tropical Medicine and Hygiene 11: 514-517, 1962 46. CHANDLER A C. Control of fluke diseases by destruction of the intermediate host. Journal of Agricultural Research 20: 193-208, 1920 47. CHRISTOPHERSON J B. The successful use of antimony in bilharziosis administered as intravenous injections of antimonium tartaratum (tartar emetic). Lancet ii: 325-327, 1918 48. CHRISTOPHERSON JB. Intravenous injections of antimonium tartaratum in bilharziosis. British Medical Journal ii: 652-653, 1918 49. CHRISTOPHERSON JB. Antimony in bilharziosis. Lancet i: 79, 1919 50. CHRISTOPHERSON JB. Bilharzia disease: the sterilization of the ova during the course of cure by antimony (tartrate). Journal of Tropical Medicine and Hygiene 23: 165-167, 1920 51. CHRISTOPHERSON JB. Longevity of parasitic worms: the term of living existence of Schistosoma haematobium in the human body. Lancet i: 742-743, 1924 52. CHRISTOPHERSON JB. In, Forward to, Schistosomiasis vel bilharziasis, by C G Sharp, J Bale, London, 1925 53. CLARKE V de V, BLAIR DM, WEBER MC. Field trial of hycanthone (Etrenol Winthrop) in the treatment of urinary and intestinal bilharziasis. Central African Medical Journal 15: 1-6, 1969 54. COBBOLD TS. On some new forms of entozoa. Transactions of the Linnean Society of London 22: 363-366, 1859 55. COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference, more particularly, to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 56. COBBOLD TS. Discussion of 102. Lancet l: 157, 1864 57. COBBOLD TS. On the development of Bilharzia haematobia together with remarks on the ova of another urinary parasite (the so-called Trichina cystica of Dr. Salisbury) occurring in a case of haematuria from Natal. British Medical Journal ii: 89-92, 1872 58. COBBOLD TS. Discussion of 150. British Medical Journal 11: 1000, 1882 and Lancet ii: 848, 1882 59. COBBOLD TS. Endemic haematuria in Egypt. Lancet ii: 272, 1882 60. COLES AC. The blood in cases affected with filariasis and Bilharzia haematobia. British Medical Journal i: 1137-1138, 1902 61. CONOR A. Essais de transmission de la Bilharziose. Archives de l'Institut Pasteur, Tunis 9: 39-42, 1914, and Bulletins de la Société de Pathologie Exotique et de ses Filiales 7: 202-206, 1914 62. CURTIS BF. Partial resection of the bladder for ulcer caused by the Distoma haematobium. British Medical Journal ii: 964-965, 1897 63. DAVIS A, BILES JE, ULRICH AM. Initial experiences with praziquantel in the treatment of human infections due to Schistosoma haematobium. Bulletin of the World Health Organization 57: 773-779, 1979 64. DAVIS A, WEGNER DH. Multicentre trials of praziquantel in human schistosomiasis: design and techniques. Bulletin of the World Health Organization 57: 767-771, 1979 65. DAY HB. The out-patient treatment of bilharziasis, with an analysis of 1,000 cases. Lancet i: 525529, 1921 66. DAY HB, RICHARDS O. The treatment of bilharziasis by salvarsan. Lancet i: 1126-1127, 1912 67. DESNOS E. Bilharziose vésicale traitée par les cautérisations diathermiques (haute fréquence). Bulletin de l'Académie de Médecine 82: 37-40, 1918 68. DIAMANTIS. Sur un nouveau traitement de l'hématurie bilharzienne en Égypte. Journal d'Urologie Médicale et Chirurgicale 7: 17-25, 1917 69. DIAMANTIS A. Considérations sur la chimiothérapie antibilharzienne en Égypte à propos du "Fouadin Tolerance Test" du Prof. Khalil Bey. Journal of the Egyptian Medical Association 21: 45-56, 1938 70. DIAMANTIS, LOTSY Bilharziose urétéro-vésicale precoce. Diagnostiquée par la radiographie. Journal d'Urologie Médicale et Chirurgicale 7: 59-63, 1917

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71. DIESING KM. Revision der Myzhelminthen. Abtheilung: Trematoden. Sitzungsberichte der kaiserlichen Akademie der Wissenschaften in Wien. Mathematisch-naturwissenschaftliche Classe 32: 307-390. 1858 72. DOUGLAS SR, HARDY FW. Some remarks on 50 cases of Bilharzia disease with special reference to the characters of the white corpuscles found in the blood and urine. Lancet ii: 1009-1012, 1903 73. ELGOOD BS. Bilharziasis among women and girls in Egypt. British Medical Journal ii: 1355-1357, 1908 74. ELGOOD BS, CHERRY T. Bilharziasis: its incidence and eradication. Lancet ii: 636-637, 1919 75. ERFAN M, TALAAT S. Trivalent sodium antimony gluconate in the treatment of schistosomiasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 44: 123-126, 1950 76. ERIAN A. The treatment of bilharziosis by massive doses of emetine. Practitioner 103: 391-393, 1919 77. FAIRLEY NH. Observations on the clinical appearances of bilharziasis in Australian troops and the significance of the symptoms noted. Quarterly Journal of Medicine 12: 391-403, 1919 78. FAIRLEY NH. Bilharziasis: some recent advances in our knowledge. Lancet i: 1016-1021, 1919 79. FAIRLEY NH. The discovery of a specific complement fixation test for bilharziasis and its practical application to clinical medicine. Journal of the Royal Army Medical Corps 32: 449-460, 1919 80. FAIRLEY NH. A comparative study of experimental bilharziasis in monkeys contrasted with the hitherto described lesions in Man. Journal of Pathology and Bacteriology 23: 289-314, 1920 81. FAIRLEY NH, WILLIAMS FE. A preliminary report on an intradermal reaction in schistosomiasis. Medical Journal of Australia ii: 811-818, 1927 82. FARID Z, BASSILY S, SHULERT AR, ZEIND AS, McCONNELL E, ABDEL WAHAB MF. Urinary blood loss in Schistosoma haematobium infection in Egyptian farmers. Transactions of the Royal Society of Tropical Medicine and Hygiene 62: 496-500, 1968 83. FERGUSON AR. Associated bilharziasis and primary malignant disease of the urinary bladder, with observations on a series of forty cases. Journal of Pathology and Bacteriology 16: 76-94, 1911 84. FISHER AC. The treatment of schistosomiasis with acriflavine. Lancet i: 897, 1934 85. FORSYTH DM, BRADLEY DJ. Irreversible damage by Schistosoma haematobium in schoolchildren. Lancet ii: 169-171, 1964 86. FORSYTH DM, RASHID C. Treatment of urinary schistosomiasis. Practiceand theory. Lancet i: 130-133, 1967 87. FOUQUET. Note sur le traitement des accidents produits chez l'homme par la présence dans l'organisme de la Bilharzia. La France Médicale i: 667-680, 693-696, 1888 88. FRANÇA C. Bilharziose em Portugal. Medicina Contemporanea 39: 273-275, 1921 89. FRIEDHEIM EA. Le traitement de la bilharziose urinaire à S. haematobium par le dimercaptosuccinate d'antimoine (TWSb). Bulletin de la Société de Pathologie Exotique 49: 1247-1252, 1956 90. FRIEDHEIM EA, da SILVA JR, MARTINS AV. Treatment of schistosomiasis mansoni with antimony-a,a'-dimercapto-potassium succinate (TWSb). American Journal of Tropical Medicine and Hygiene 3: 714-727, 1954 91. GADGIL RK. Human schistosomiasis in India. Indian Journal of Medical Research 51: 244-251, 1963 92. GADGIL RK, SHAH SN. Human schistosomiasis in India. Discovery of an endemic focus in Bombay State. Indian Journal of Medical Science 6: 760-763, 1952 93. GAUD J, JAUBERTIE R. Rôle des facteurs humains dans la répartition géographique des bilharzioses en Afrique. Annales de Parasitologie Humaine et Comparee 26: 420-439, 1951 94. GERRITSEN J, WALKER AR, de MEILLON B, YEO RM. Longterm investigation of blood loss and egg load in urinary schistosomiasis in adult African Bantu. Transactions of

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the Royal Society of Tropical Medicine and Hygiene 47: 134-140, 1953 95. GIRGES R. Schistosomiasis (bilharziasis), John Bale, Sons and Danielsson, London, pp 527, 1934 96. GÖNNERT R. Results of laboratory and field trials with the molluscicide Bayer 73. Bulletin of the World Health Organization 25: 483-501, 1961 97. GÖNNERT R, ANDREWS P. Praziquantel, a new broadspectrum antischistosomal agent. Zeitschrift für Parasitenkunde 52: 129-150, 1977 98. GÖNNERT R, SCHRAUFSTÄTTER E. A new molluscicide: Molluscicide Bayer 73.In, Proceedings of the Sixth International Congress of Tropical Medicine and Malaria, Lisbon, 1958. Abstracts of the papers, Lisbon, Instituto de Medicina Tropical, vol. 2, p. 197, 1959 99. GORDON RM. Emetine periodide in the treatment of S. haematobium infections amongst West African children. Annals of Tropical Medicine and Parasitology 20: 229-237, 1926 100. GRIESINGER W. Klinische und anatomische Beobachtungen. Über die Krankheiten von Egypten. Archiv für Physiologie Heilkunde 13: 528-575, 1854. Partly translated in 120 101. GUILLEMARD FH. Bilharzia haematobia. Lancet i: 151, 1883 102. HARLEY J. On the endemic haematuria of the Cape of Good Hope. Medico-Chirurgical Transactions 47: 55-72, 1864. Abstracted in Lancet i: 156-157, 1864 103. HARLEY J. A second communication on the endemic haematuria of the Cape of Good Hope. Medico-Chirurgical Transactions 52: 379-387, 1869 104. HARLEY J. Third communication on the endemic haematuria of the southeastern coast of Africa, with remarks on the topical medication of the bladder. Medico-Chirurgical Transactions 54: 47-62, 1871. Abstracted in British Medical Journal ii: 641-642, 1870 105. HARLEY J. Discussion of, Cases of haematuria due to Bilharzia by TS Cobbold, presented to the Royal Medical and Chirurgical Society. British Medical Journal i: 1097, 1885; Lancet i: 985, 1885 106. HARRISON R. Specimens of Bilharzia affecting the urinary organs. Lancet ii: 163, 1889 107. HARRISON WS. The prognosis in bilharziasis. Journal of the Royal Army Medical Corps 21: 385-388, 1913 108. HATCH WK. Endemic haematuria. British Medical Journal ii: 737, 1882 109. HOEPPLI R. Morphological changes in human schistosomiasis and certain analogies ni ancient Egyptian sculpture. Acta Tropica, Supplement 30: 1-11, 1973 110. HUGGINS D. Ineficácia do K-7505 (Ronnel) no tratamento da esquistossomíase mansônica. Revista de la Sociedad Brasileira de Médica Tropica 2: 221-224, 1968 111. HULSE EV. Joshua's curse and the abandonment of ancient Jericho: schistosomiasis as a possible medical explanation. Medical History 15: 376-386, 1971 112. HUMPHREYS RM. Vesical schistosomiasis in the Gezira irrigated area of the Sudan. Transactions of the Royal Society of Tropical Medicine and Hygiene 26: 241-252, 1932 113. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. Thirty five generic names in Protozoa, Coelenterata, Trematoda, Cestoda, Cirrepoda, Tunicata and Pisces placed in the official list of generic names (Opinion 77), Smithsonian Miscellaneous Collections, Smithsonian Institution, Washington, D C, Publication 2657, 73: 71-73, 1922 114. JAMES C, WEBBE G, NELSON GS. The susceptibility to praziquantel of S. haematobium in the baboon (Papio anubis) and of S. japonicum in the vervet monkey (Cercopithecus aethiops). Zeitschrift für Parasitenkunde 52: 179-194, 1977 115. JOANNIDES NZ. Die Wirkung des Salvarsans auf dieBilharzia. Deutsche medizinische Wochenschrift 37: 1551, 1911 116. JORDAN P. Trial of Ambilhar, a nitrothiazole derivative, in S. mansoni infections in Tanzania. British Medical Journal i: 276-278, 1966 117. JOYEUX C. Note sur quelques cas de bilharziose observés à Kouroussa (Guinea Française). Bulletins de la Société de Pathologie Exotique et de ses Filiales 5: 504-505, 1912 118. KATZ N, PELLEGRINO J. Ensaio laboratorial e clínico com hycanthone nôvo agente esquistossomicida. Revista de la Sociedad Brasileira de Médica Tropica 1: 219-230, 1967 119. KATZ N, ROCHA RS, CHAVES A. Preliminary trials with praziquantel in human infections due to Schistosoma mansoni. Bulletin of the World Health Organization 57: 781-785, 1979 120. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic

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investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 121. KHALIL M. The eradication of bilharziasis: a successful attempt in an endemic area. Lancet ii: 1235, 1927 122. KHALIL M. Individual variation in the excretion of drugs as an important factor in their therapeutic results. A practical method for detecting the schistosomiasis cases with so-called idiosyncrasy to antimony to avoid fatalities and complications. Journal of the Egyptian Medical Association 19: 285-306, 1936 123. KHALIL M, AZIM MA. Further observations on the introduction of infection with Schistosoma haematobium through irrigation schemes in Aswan Province. Journal of the Egyptian Medical Association 21: 95-101, 1938 124. KHALIL M, BETACHE MH. Treatment of bilharziasis with a new compound "Fouadin". Report on 2041 cases. Lancet i: 234-235, 1930 125. KHALIL M, NAZMI M, PETER FM, EL DIN MS, EL BETASH MH. Die Behandlung der Schistosomiasis mit intramuskulären "Fuadin"-Injektion. Deutsche medizinische Wochenschrift 55: 1125-1126, 1929 126. KHALIL M, SALAH, M. Treatment of schistosomiasis with acridine compounds. Lancet ii: 862863, 1934 127. KIKUTH W, GÖNNERT R. Experimental studies on the therapy of schistosomiasis. Annals of Tropical Medicine and Parasitology 42: 256-267, 1948 128. KIKUTH W. GÖNNERT R. Experimentelle Untersuchungen und Erfahrungen mit dem neuen Schistosomiasismittel Miracil. Zeitschrift für Tropenmedizin und Parasitologie 1: 234-258, 1949 129. KITCHENER, LORD. Cited in 134 130. KLOCK JW, GERHARDT CE, ILDEFONSO V, SERRANO JM. Characteristics of sodium pentachlorophenate used against Australorbis glabratus in Puerto Rico. Bulletin of the World Health Organization 16: 1189-1201, 1957 131. LAMBERT CR. Chemotherapy of experimental Schistosoma mansoni infections with a nitrothiazole derivative, CIBA 32,644-Ba. Annals of Tropical Medicine and Parasitology 58: 292-303, 1964 132. LAMBERT CR, FERREIRA FS. Résultats du premier essai de traitement de la bilharziose vésicale par le CIBA 32,644-Ba. Bulletin of the World Health Organization 32: 73-82, 1965 133. LASBREY FO. COLEMAN RB. Notes on one thousand cases of bilharziasis treated by antimony tartrate. British Medical Journal i: 299-301, 1921 134. LEIPER RT. Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 25: 1-55, 147-192, 253-267, 1915 135. LEIPER RT. Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 27: 171-190, 1916 136. LEIPER RT. Tropical Diseases Bulletin 8: 610, 1916 137. LEIPER RT. Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 30: 235-260, 1918 138. LEIPER RT. Tropical Diseases Bulletin 12: 168, 1918 139. LEIPER RT. Tropical Diseases Bulletin 14: 143, 1919 140. LEIPER RT. Schistosome worms and schistosome monsters. British Medical Journal i: 817, 1931 141. LOOSS A. Beobachtungen über die Eier und Embryonen derBilharzia. In, Parasiten des Menschen, R Leuckart (Editor), CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 521-528, 1893 142. LOOSS A. Bemerkungen zur Lebensgeschichte der Bilharzia haematobia. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 26: 286-292, 340-346, 1894. Partly translated in 134 143. LOOSS A. Histoire naturelle de la Bilharzia. Premier Congrès Égyptien de Médecine, Comptes Rendus ii, Chirurgie, pp 3-18, 1905. Partly translated in 95 144. LOOSS A. What is Schistosomum mansoni Sambon 1907? Annals of Tropical Medicine and Parasitology 2: 153-191, 1908 145. LOOSS A. Bilharziosis of women and girls in Egypt in the light of the "skin-infection

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theory". British Medical Journal i: 773-777, 1909 146. LOOSS A. The life-history of the Bilharzia worm. Cairo Scientific Journal 4: 134, 1910 147. LOOSS A. Würmer und die ihnen hervorgerufenen Erkrankungen. In, Handbuch der Tropenkrankheiten, second edition, C Mense (Editor), J A Barth, Leipzig, volume 2, pp 331-374, 1914. Partly translated in 134 148. LORTET A. Expériences nouvelles sur le développement et le mode de pénétration du Bilharzia haematobia. Premier Congrès Égyptien de Médecine, Comptes Rendus ii, Chirurgie, pp 129-131, 1905 149. LORTET, VIALLETON. Étude sur le Bilharzia haematobia et la bilharziose. Annales de l'Université de Lyon 9: 1-118, 1894 150. LYLE V. On the endemic haematuria of the southeast coast of Africa, with an introduction by John Harley. Medico-Chirurgical Transactions 66: 113-132, 1883. Abstracted in British Medical Journal ii: 1000, 1882; Lancet ii: 848, 1882 151. McDONAGH JE. Antimony in bilharziosis. Lancet ii: 371, 1918 152. McDONAGH JE. The treatment of bilharziasis with antimony. Journal of Tropical Medicine and Hygiene 23: 165, 1920 153. MADDERN FC. The incidence of bilharziosis in Egypt and its clinical manifestations. British Medical Journal ii: 965-969, 1910 154. MANSON P. Discussion of 73. British Medical Journal ii: 1357, 1908 155. MANSON P. Tropical diseases. A manual of the disease of warm climates, fifth edition, Cassell and Co., London, pp 922, 1914 156. MANSON-BAHR P, FAIRLEY N H. Observations on bilharziasis amongst the Egyptian Expeditionary Force. Parasitology 12: 33-71, 1920 157. MANTEY. Distomum haematobium. Die durch dasselbe hervorgerufenen Krankheiten und deren Behandlung. Dissertation, Jena, pp 30, 1880 158. MAYER M. Behandlung der Bilharziakrankheit mit Emetin. Münchener medizinische Wochenschrift 65: 612, 1918 159. MAYER M. Zur Behandlung der Bilharzia-Krankheit mit Emetin. Wiener klinische Wochenschrift 35: 59, 1922 160. MILTON F. Bilharziosis surgically considered. Lancet i: 866-869, 1903 161. MILTON F. Speculations on the life-history of Schistosomum haematobium. Journal of Tropical Medicine and Hygiene 15: 225-227, 1912 162. MINET H. Deux cas de bilharziose vésicale provenant de l'Afrique septentrionate française. Annales des Maladies Vénériennes 10: 385-396, 1915 163. MOORE N. Discussion of 205. British Medical Journal i: 13, 1882 and Lancet i: 16, 1882 164. MOQUIN-TANDON A. Elements of medical zoology, translated by R T Hulme, Baillière, London, pp 423, 1861 165. MOZLEY A. Malachite in the control of bilharzia. British Medical Journal i: 511, 1941 166. NABAWY M, GABR M, RAGAB MM. Visceral bilharziasis in childhood: a clinico-radiological study. Journal of Tropical Medicine and Hygiene 64: 314-318, 1961 167. NELSON GS, TEESDALE C, HIGHTON RB. The role of animals as reservoirs of bilharziasis in Africa. In, Bilharziasis, Ciba Foundation Symposium, GE Wolstenholme and M O'Connor (editors), Little Brown, Boston, pp 127-148, 1962 168. PAPYROS EBERS. Das hermetische Buch über die Arzneimittel der alten Aegypter ni hieratischer Schrift Herausgegeben, mit Inhaltsangabe und Einleitung versehen von Georg Ebers. Mit hieroglyphisch-lateinischem Glossar von Ludwig Stern, Leipzig, two volumes, 1875. The Papyrus Ebers, translated from the German version by C P Bryan, Geoffrey Bles, London, pp 167, 1930 169. PELLEGRINO J, KATZ N, SCHERRER JF. Oogram studies with hycanthone, a new antischistosomal agent. Journal of Parasitology 53: 55-59, 1967 170. PELLEGRINO J, LIMA-COSTA FF, CARLOS MA, MELLO RT. Experimental chemotherapy of schistosomiasis mansoni. XIII. Activity of praziquantel, an isoquinoline-pyrazino derivative, in mice, hamsters and Cebus monkeys. Zeitschrift fur Parasitenkunde 52: 151-168, 1977 171. PETERS PA, MAHMOUD AA, WARREN KS, OUMA JH, SIONGOK TK. Field studies of a rapid accurate means of quantifying Schistosoma haematobium eggs in urine samples.

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Bulletin of the World Health Organization 54: 159-162, 1976 172. PFISTER F. Über die - - Krankheit der Papyri Ebers und Brugsch. Archiv für Geschichte der Medizin 6: 12-20, 1912 173. PILSBRY HA, BEQUAERT J. The aquatic molluscs of the Belgian Congo. With a geographical and ecological account of Congo malacology. Bulletin of the American Museum of Natural History 53: 69-602, 1927 174. PORTER A. The experimental determination of the vertebrate hosts of some South African cercariae from the molluscs Physopsis africana and Limnaea natalensis. Medical Journal of South Africa 15: 128-133, 1920 175. PORTER A. Some flukes bred from cercariae recurring in Schistosoma-transmitting molluscs in South Africa. Proceedings of the Royal Society of Medicine 18: 56-57, 1925 176. RENOULT AJ. Sur l'hématurie que les Européens éprouvent en Égypte. Journal Général de Médecine de Chirurgie et de Pharmacie 17: 366-370, 1803. Partly translated in Medical Times, New York 90i: 447-452, 1962 177. ROBERTSON W. Thymobenzene in bilharziosis. Lancet i: 698, 1916 178. ROSE G. Schistosomiasis in Egypt and its bearing on the schistosomiasis problem in China. Chinese Medical Association Special Report Series No. 2, pp 86, no date. Abstracted ni Tropical Diseases Bulletin 34: 864-866, 1937 179. RUBIDGE. Cited in 103. 180. RUFFER MA. Discussion of 73. British Medical Journal ii: 1356, 1908 181. RUFFER MA. Note on the presenceof "Bilharzia haematobia" in Egyptian mummies of the twentieth dynasty (1250-1000 B.C.). British Medical Journal i: 16, 1910 182. SCHRECKER. Ueber Salvarsanbehandlung bei Bilharziosis. Archiv für Schiffs- und TropenHygiene 19: 149-150, 1915 183. SENN E. Theodor Bilharz. Ein deutsches Forserchleben in Ägypten 1825-1862. Schriften des Deutschen Ausland-Instituts Stüttgart. Reihe D: Biographien und Denkwurdigkeiten. Ausland und Heimat Verlags-Aktiengelleschaft, Stüttgart, Band 5, pp 76, 1931. Abstracted in Tropical Diseases Bulletin 29: 167-168, 1932 184. SHAW CG. Cystoscopic appearances in bilharziosis. Medical Journal of Australia i: 85-86, 1921 185. SIGERIST HE. A history of medicine. Volume 1. Primitive and archaic medicine. Oxford University Press, New York, pp 564, 1951 186. SONSINO P. Ricerche intorno alla Bilharzia haematobia in relazione colle ematuria dell'Egitto e nota intono ad un nematoidea. &c. Rendiconti della Reale Accademia di Napoli 6: 71-83, 305321, 1874. Partly translated in 95 187. SONSINO P. Ricerche sullo sviluppo della Bilharzia haematobia. Giornale della Reale Accademia di Medicina di Torino 32: 380-395, 1884. Partly translated in 95 188. SONSINO P. The treatment of Bilharzia disease. British Medical Journal ii: 1197-1198, 1885 189. SONSINO P. Discovery of the life history of Bilharzia haematobia (Cobbold). Lancet ii: 621-622, 1893 190. SONSINO P. Aggiunta alla precedente nota sulla sviluppo della Bilharzia haematobia. Processi Verbali della Società Toscana di Scienze Naturali in Pisa, January 21, pp 10-14, 1894 191. STOCK PG. Endemic haematuria. Lancet ii: 857-858, 1906 192. TALAAT SM, AMIN N, EL MASRY B. The treatment of bilharziasis and other intestinal parasites with dipterex. A preliminary report on 100 cases. Journal of the Egyptian Medical Association 46: 827-832, 1963 193. TSYKALAS. Neue Wege in der Behandlung der Bilharziakrankheit in Aegypten. Wiener klinische Wochenschrift 34: 579-580, 1921 194. TSYKALAS. Erwiderungen auf obige Bemerkingen des Prof. Martin Mayer. Wiener klinische Wochenschrift 35: 60, 1922 195. WARREN KS. Schistosomiasis. The evolution of a medical literature: selected abstracts and citations, 1852-1972, MIT Press, Cambridge, Massachussetts, pp 1307, 1973 196. WARREN KS. Regulation of the prevalence and intensity of schistosomiasis in man: immunology or ecology? Journal of Infectious Diseases 127: 595-609, 1973

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197. WARREN KS, MAHMOUD AA. Targeted mass treatment: a new approach to the control of schistosomiasis. Transactions of the Association of AmericanPhysicians 89: 195-204, 1976 198. WATKINS-PITCHFORD W. Note on schistosomiasis. Medical Journal of South Africa 10: 226, 1915 199. WATSON JM, ABDEL AZIM M, HALAWANI A. Investigations on the antibilharzial actions of Miracil D (Nilodin). Transactions of the Royal Society of Tropical Medicine and Hygiene 42: 37-54, 1948 200. WEBBE G. Schistosomiasis: some advances. British Medical Journal ii: 1104-1106, 1981 201. WEBBE, G, JAMES A. A comparison of the susceptibility to praziquantel of S. haematobium, S. japonicum, S. mansoni, S. intercalatum and S. mattheei in hamsters. Zeitschrift für Parasitenkunde 52: 169-178, 1977 202. WEINLAND DF. Human cestoides. An essay on the tapeworms of man giving a full account of their nature, organization, and embryonic development; the pathological symptoms they produce, and the remedies which have proved successful in modern practice. To which is added an appendix, containing a catalogue of all species of helminthes hitherto found in man, Metcalfe and Co., Cambridge, Massachussetts, pp 93, 1858 203. WILEY CJ. The treatment of bilharziosis by intravenous injections of tartar emetic. British Medical Journal ii: 716-717, 1918 204. WOLFF. Ueber Bilharzia in Deutsch-Ostafrika. Archiv für Schiffs- und Tropen-Hygiene 13: 167, 1909 205. ZANCAROL G. A specimen of Bilharzia haematobia, with ova in the tissues of the bladder and large intestine. Transactions of the Pathological Society of London 33: 410-412, 1882. Abstracted in British Medical Journal i: 13, 1882; Lancet i: 16, 1882

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Table 8.1. Landmarks in schistosomiasis haematobia ___________________________________________________________________ 1851 1852 1852

Bilharz discovered adult worms Bilharz and Griesinger identified urinary lesions Bilharz diagnosed urinary schistosomiasis in a living patient by finding eggs in the urine 1866 Rubidge suggested on clinical and epidemiological grounds that infection was acquired by bathing in certain rivers 1889 Harrison suggested a relationship between vesical schistosomiasis and bladder cancer 1915 Leiper discovered that certain species of snails were chemotactic for S. haematobium miracidia, observed development of the parasite through the sporocyst to the cercarial stage in these molluscs, and produced patent infections in rodents and monkeys with cercariae derived from naturally infected snails that were collected in an area heavily endemic for schistosomiasis 1916 Leiper confirmed the differentiation of S. haematobium and S. mansoni 1917 Diamantis reported the value of emetine in treatment 1918 Christopherson reported the efficacy of tartar emetic 1944 Barlow produced a patent infection in himself after placing cercariae on his skin 1940's Kikuth and Gönnert showed that miracil D had schistosomicidal activity in experimentally infected animals 1947 Blair, Hawking and Ross reported that miracil D was effective in humans 1962 Cerf, Kebrun and Dierich reported that metrifonate was effective 1964 Lambert and Ferreira reported that niridazole was active 1969 Clarke, Blair and Weber showed that hycanthone was effective 1977 Various investigators reported that praziquantel was effective against schistosomes in experimental animals 1979 Davis, Biles and Ulrich reported that praziquantel was effective in humans __________________________________________________________________

Chapter 9

Schistosoma mansoni and SCHISTOSOMIASI S MANSONI

SYNOPSIS Common name: intestinal blood fluke; causes intestinal schistosomiasis or bilharziasis Major synonyms: Distoma haematobia, Schistosoma haematobia Distribution: Africa, South America, Caribbean islands Life cycle: Similar to S. haematobium except that the vectors belong to the genus Biomphalaria and eggs are excreted in the intestines Definitive hosts: humans (baboons, monkeys) Major clinical features: rash followed by urticaria, dysentery and hepatosplenomegaly in early, heavy infections; hepatosplenomegaly, ascites and oesophageal varices in chronic, heavy infections Diagnosis: demonstration of eggs in faeces, rectal mucosa or liver biopsy Treatment: hycanthone, niridazole, oxamniquine, praziquantel

ATTEMPTS TO DIFFERENTIATE SCHISTOSOMA MANSONI FROM S. HAEMATOBIUM In 1851, soon after he had discovered the adult forms of S. haematobium and had seen their ova with the charact eristic terminal spines, Theodor Bilharz found near S. haematobium eggs in calcified areas of a liver "strange bodies provided with spines, approximately similar to those eggs in size" 13. Although the illustration he provided is har dly recognizable as that of an S. mansoni egg shell, his accompanying description leaves little doubt that the bodies he was seeing were remnants of S. mansoni ova, for he wrote: They seemed to me to be long, yellow-brown bodies rounded on both ends. On one side, near the more rounded end was a conical appendage, directed obliquely toward the pointed end. No content was recognizable in these strange bodies. 13

In March of the following year, he found the same structures in a portion o f dysenteric large intestine removed from t he body of a boy who also had vesical schistosomiasis and had died from meningi tis. They were scattered through the mucosa and submucosa as well as being embedded in bloody mucus on th e surface of the mucosa. Bilharz's description of these bodies again indicates that these were S. mansoni eggs: "These bodies, compressed from all sides, ar e biconvex with a sharp edge from which the conical appendage protrudes" 13.

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These structures were empty apart from a few granules massed against th e inner edge. A few days later, however, Bilharz's colleague, Wilhel m Griesinger found the same bodies in a piece of large bowel, but on thi s occasion, they contained living o rganisms which crawled out and swam about, resembling S. mansoni miracidia. This naturally led Bilharz to put th e question: "Therefore, how should we regard these bodies. Are they a second type of egg or a kind of pupal covering assumed by the organism after leaving the egg?"13 As discussed in chapter 8, Bilharz came down in favour of the latte r proposition. There were two reasons for this. Firstly, he found S. haematobium eggs and these bodies intermingled in the tissues. Secondly, and mor e importantly, Bilharz believed that he had seen the same structure within a n adult female S. haematobium: Last summer I found one of these bodies in one of the first female specimens of Distomum haematobium that I studied. It was in the front part of the oviduct, the posterior of which contained the usual egg. I made a drawing of that specimen at that time.13

Since he had seen this phenomenon only once, he surmised that the specimen in the oviduct had metamorphosed abnormally early. This erroneou s observation was to set the scene for confus ion and controversy for the next half century as to whether there were one or two species of schistosomes tha t infected humans in Egypt. Bilharz, in forthright terms, left no doubt as to his views: That these shells belong to the developmental stages of Distomum haematobium and not to another organism seems indubitable to me. I not only found them intermixed with eggs of Distomum haematobium in the calcified areas within the liver, in the submucosa, and in the mucosa of the large intestine in acute dysentery, but also, although only once, in the oviduct of a female worm which also contained ordinary eggs.13

Proof that the bodies which occ upied Bilharz's mind were indeed egg shells of S. mansoni was, in retrospect, provided in 1853. In a letter to von Siebol d dated 4 January of that year, Bilharz included a drawing of a "capsule" which is clearly the shell of a lateral-spined S. mansoni ovum12. Griesinger accepted Bilharz's contention completely, for in the legend accompanying an illustration in his paper of a typical S. mansoni egg, he wrote: saclike bodies provided with a lateral spike (eggs? pupal coverings?); in any case, belonging to the developmental cycle of the Distoma haematobium, since such a body was once found in the fallopian tube of the organism. 43

As mentioned in the previous chapter, Harley in 1864 was so struck by the complete absence of lateral-spined ova in the urine of patients with endemic haematuria in South Africa that he was induced to name the parasite in tha t region Distoma capense 44. Sonsino then suggested that schistosomiasis was caused by two different species of worms, each producing characteristic ova which differed in the position of their spine, but later abandoned this thesis in favour of the postulate that one f orm of egg developed into a male worm while

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the other became a female schistosome. It gradually became clear to invest igators in Egypt that different types of egg were associated with different dise ases. Thus, in 1882, Dr Zancarol, a surgeon at the Greek Hospital in Alexandria, demonstrated to the Royal Medical and Chirurgical Society in London microscopical sections of vegetations from the large bowel of an Arab who had suffered from dysentery and noted that "as is usual when occurring in this situation, (the ova) were each provided with a large lateral spine" 124. He also exhibited sections from the bladder of another patient and remarked that "each ovum was provided with a spine, but here its situation was terminal and not lateral" 124. Even so, both conditions wer e attributed to infection with S. haematobium. Zancarol's views were supported in the same year by James Mackie , surgeon to the British consulate and Dea conesses' Hospital in Alexandria, who wrote: in my own experience the ova found in the rectum have in nearly all cases the spike placed laterally differing from those generally found in the urine, which have the spike at the extremity.78

Spencer Cobbold was not convinced, however, fo r when he presented 13 cases to the Royal Medical and Chirurgical Society in 1885, he attributed no pathological or clinical significan ce to the remarkable variations in the appearance of schistosome eggs 19. For many years, it was believed that schistosomiasis was restricted to Africa and adjacent regions. In 1902, however, Patrick Manson in England reported that a 38 year old British patient of his had contracted the infection in the West Indies where he had lived for 15 ye ars. The patient complained of vague aches and pains, and since he looked anaemic, Manson examined his stool s expecting to find hookworm eggs, but instead found schistosome ova. Furthermore, he remarked that "In this ca se, as so often happens in bilharzia ova from the alimentary canal, the spine is placed laterally" 81. Microscopical examination of the urine disclosed no ova. Thus, whereas schistosomiasis in Egypt was hopelessly intermingled with urinary and intestinal pathology and eggs with terminal or lateral spines, there were now cases on record exemplifying the two poles of the spectrum patients with urinary schistosomiasis and terminal-spined eggs as describe d by Harley, and patients with intestinal eggs with lateral spines as shown b y Manson. In fact, Manson in this paper made no great play about the egg s having a lateral spine; rather, he was concerned to suggest that a mollusc or arthropod common to both African and American regions might be the long sought for intermediate host. In the following year, however, he put forward the suggestion that: possibly there are two species of Bilharzia, one with its lateral-spined ova, depositing its eggs in the rectum only, the other haunting bladder or rectum indifferently. 82

Impetus to the idea that there may be more than one species of schistosome infecting humans was given by the discovery of S. japonicum by Katsurada in

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Japan in 1904 (see chapter 10). Manson's view was then championed by Louis Sambon, a lecturer at the London School of Tropical Medicine. Putting al l these thoughts together, he proposed at a meeting of the Zoological Society of London on 19 March 1907 that the worm producing lateral-spined eggs b e named Schistosomum mansoni 102. He so named the parasite in recognition of Manson's earlier suggestion that there may be two species of Africa n schistosomes: "In appreciation of this, one of his many genial intuitions, th e new Trematode is dedicated to him"103. Sambon justified his creation of a new species on the grounds of difference s in the morphology of the eggs, variations in the clinical manifestations, and dissimilar geographical distributions o f infection: the ova of the new species have a large, curved, lateral spine which distinguishes them from those of the old classic species with a short, straight spine at their posterior extremity....S. mansoni ova are eliminated solely by way of the intestine....The patients harbouring this parasite suffer from a haemorrhagic enteritis, but they never present haematuria....S. mansoni has a wide distribution throughout Africa....It is found also in the West Indies....and very likely in other places within the Tropics. 103

Sambon reiterated these points later in the year in a further communication , remarking on this occasion that although adult schistosomes of humans an d cattle were very similar in general appearance, with the exception of the male S. japonicum, he had no doubt that a minute comparative anatomical study of these worms would bring out info rmation about many structural differences 104. To further support his argument, Sambon drew attention to the report in July of that year by Holcomb of a large number of cases of schistosomiasis wit h lateral-spined eggs in the Caribbean, including no less than 167 cases i n Puerto Rico, yet endemic haematuria was completely unknown 47. Sambon's new species met with a vitriolic blast from Looss in a 39 pag e paper entitled "What is Schistosomum mansoni Sambon 1907?". He introduced his paper by remarking that: if Dr. Sambon's view were correct, all of us who have devoted attention to the subject, would have indeed been wandering in the dark since the time of Bilharz himself, fiftyseven years ago.73

And indeed, some of them, with Looss amongst them, were. Looss was th e arch protagonist of two controversial theories - the direct infection hypothesis and the single species stance - both of which he was destined to lose. Afte r bemoaning the fact that no notice had been taken of the (vague an d unspecified) cautionary "hints" that he had "dropped" while in London tw o years earlier (but precisely to wh om he could not remember), Looss castigated Sambon's credentials saying: Among scientific workers, it is a good custom that anyone who believes he has made a new discovery also takes the trouble to prove it; it is not customary among scientists to assert something then call for the help of others to establish it. 73

He then launched into an attack on Sambon's propositions. Looss's arguments were centred on the following b ases. Firstly, he insisted that the differentiation of species could only be made on the morphology of the adult worms, not on

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the appearance of the eggs. The foun dation stone of Looss's faith was Bilharz's statement that he saw both types of eggs in one worm. He then adde d sarcastically: This observation is now fifty seven years old and might have been known to Dr. Sambon if he had studied of those authors who he accuses of having failed to recognise an obvious fact.73

Looss then remarked that if his memory did not fail him, he had seen several similar female worms during the course of the years, and regretted that h e could not produce them. Nevertheless, to let it be absolutely clear where h e stood, he reiterated: The occurrence of terminal-spined and lateral-spined eggs in one and the same individual worm is one of the fundamental facts on which my views rest; I wonder how Dr. Sambon will explain it by his theory.73

Looss thought that the position of the spine depended upon the position of the egg during the process of its formation in the ootype. Extrapolating from his observations on a number of trematodes, Looss deduced that lateral-spine d eggs were abnormal and were probably produced by unfertilized femal e worms. He explained the presence of a miracidium in some of these eggs as being the result of a process of parthenogenesi s. Secondly, Looss dismissed the differing clinical and pathological pictures associated with the two forms o f eggs on the basis of variations in the habits of the human host and th e conditions of the country. He produced an amazing and intricate hypothesi s based upon the supposition that mirac idia were infective directly, and that they developed into sporocysts in the liver. He postulated that when the infecting dose of miracidia was high, there would be plenty of male worms present to carry the females off to the vesical venous plexus where they produce d terminal-spined eggs and caused urinary schistosomiasis. In contrast, h e suggested that when the infecting dose was low, solitary females sometime s developed, that these spinsters produced lateral-spined eggs, and that thes e lonely worms sometimes migrated as far as the large intestine. Moreover , Looss believed that there was not a sharp line of demarcation between these two responses. Finally, Looss contended feebly that the differences i n geographical distribution of the two forms of parasite and disease cited b y Sambon were based "upon a peculiarly one-sided interpretation of th e literature" 73. Looss concluded his lengthy paper: there is no possible doubt....that this species....must produce the same two shapes of eggs as does the Sch. haematobium....If, therefore, Dr. Sambon wishes to maintain that there is an independent "Sch. mansoni"....the entire proof of its existence remains to be given.73

In January of the following year (1909), Sambon replied to Looss' s criticisms in a long article with the same title as that used by Looss 105. He began by saying that he ought to have refuted Looss's "critical", "violent" and "ill-considered" paper at once, but he had delayed in the hope that someon e would be able to describe distinctive morphological features for adul t S. mansoni. Since this had not yet been done, he now found it necessary t o

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reply lest his silence be interpre ted wrongly. Sambon let it be clear that he had the utmost regard for the eminent scientist who had studied helminthology in Egypt during the previous 25 years, but tempered this by remarking that : "Respect for authority is one thing, slavish submission to authority i s another"105. Sambon then proceeded to counter Looss's arguments point b y point. He insisted that the marked differences in the morphology of the eggs were quite sufficient to estab lish a new species, quoted precedents established by zoologists, and asserted that Looss himself had subscribed to new species on much flimsier grounds. Conce rning Bilharz's alleged discovery and Looss's vague confirmation of two forms of egg within the one adult worm, Sambon declared: Until he can show me an actual specimen I am bound to place the worm capable of producing the two kinds of eggs with the phoenix, the chimaera and other mythical monsters.105

He then demolished Looss's dismissal of the different clinico-pathologica l effects associated with the two forms of worms, demonstrating that Looss' s views were a: "multitude of surmises and conjectures more or les s improbable"105 and adding nastily: "But Professor Looss has a theory, an d theories often require a careful selection of the facts" 105. Sambon then re-emphasized the different geographical distributions of S. mansoni and S. haematobium. He noted that large numbers of patients in certain region s passed vast numbers of lateral-spined eggs, yet not a single terminal-spine d ovum could be found, and questioned how this could possibly be consisten t with Looss's idea that they were a product of unfertilized female worms - there would have to be an entire absence of ma le schistosomes. Further, he reasoned that explaining all these lateral spines on the basis of abnormality an d parthenogenesis bordered on absurdity. Next, Sambon showed that he had not distorted the literature; rather, it was likely that the several patients wit h urinary schistosomiasis in America that Looss had referred to, had acquire d their infection in Africa, and there was no doubt that urinary schistosomiasis alone occurred in southern Africa. Finally, he stood his ground and declared: I never for a moment placed myself on the same level in the latter respects (as a helminthologist) with the celebrated professor of Cairo, but at the same time I would say that I have paid some attention to the subject, and cannot abandon my independence of judgement, or my right to give expression to my views. 105

Two years later (1911), stung by Sa mbon's objections, Looss returned to the debate. He had concluded on the basis of further observations that it was not necessary to invoke parthenogenesis. Instead, he postulated that unfertilized eggs are laterally spined, and that after fertilization, there is a "transitio n period" following which the eggs become terminally spined. He had th e impression that once the production of normal (terminal-spined) eggs ha d begun, the others (lateral-spined) were usually evacuated quickly, bu t reiterated: "that the females of S. haematobium can, and do, produce two forms of eggs is beyond question, even now" 74.

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While all this was going on, a number of workers, particularly in th e Americas, had embarked upon a search for characteristic morphologica l features of worms producing lateral-spined eggs which would allow definite distinction of S. mansoni from S. haematobium. Holcomb, an assistant surgeon with the US Navy, in 19 07 examined material from patients in Puerto Rico and thought that the male worms were more brown in colour and had a larger ventral sucker 47. In the following year (1908), Pirajá da Silva in Brazil recovered 24 worms, including both sexes, from the portal venous system of a single cadaver; all these worms produced only lateral-spined eggs. Pirajá da Silva, who was an assistant in internal medicine at the Santa Isabel Hospital in Bahia, described a number of features of the adult worms which he thought were distinctive. These included differences in the outlines of the anterior end of the male worm and the posterior end of female schistosomes, less salien t spinous papillae, a more distal location of the caecum, and subtle differences in the structure of the female reproducti ve organs when compared with Looss's figures of S. haematobium. He first published these opinions in Portuguese in 190892, then amplified them in English 93 and in French 94 in the following year. Also in 1908, Leiper studied material from Uganda and thought that ther e were differences in the shape of the testes 69, although in a letter to Pirajá d a Silva in February 1909 he wrote: I regret that so far I have not been able to separate the Schistosomum haematobium from the Sch. mansoni in the specimens I have received from abroad and I cannot therefore send you types of each. Both forms occur in Egypt and we in Europe get the worms from the portal veins and these may be one or the other of the two forms and so far we know no way of differentiating them. 70

In fact, at that stage, Leiper lea ned towards Looss's unitarian view, for he went on to say: There is a good deal too much theory alike in Looss' as in Sambon's position. I mean they require more facts. I studied for a year under Professor Looss and saw enough of his work to feel more reliance on his observations than on those of Dr. Sambon but I have not yet made up my mind finally on the subject. 70

Similarly, Flu (1911) thought that there were differences in the formation of the anterior part of the gynaecophoric canal of the two parasites 36. To all of this, Looss replied that each and every one of these features could be seen in in Egypt. Pirajá da Silva received the full force of Looss's wrat h when he wrote vitriolically: Thus Pirajá da Silva's 'proof' of the existence of a 'second species' of Schistosomum becomes reduced to a combination of several very elementary mistakes; what the conclusions based on such evidence are worth scientifically, every reader is at liberty to decide for himself. But am I to be blamed if I urge that authors, before they write on parasitological questions, should make themselves acquainted with the parasites they deal with.74

Moreover, Looss tried to ridicule da Silva by claiming that the ova that h e described were nothing more than concretions. In April 1912, Pirajá da Silva presented his findings to the German Society of Tropical Medicine i n

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Hamburg. The subsequent discussion has been published by de Cerquier a Falção who has championed da Silva's cause in a paper entitled "Professo r Pirajá da Silva, incontestable discoverer of 'Schistosoma mansoni'" 18. Parenthetically, it ought to be re marked that while it is true that Pirajá da Silva did discover S. mansoni adult worms in Brazil, de Cerqueira Falção ha s ignored the fact that Holcomb e had described adult S. mansoni in Puerto Rico before Pirajá da Silva, and that many observers had doubtless seen S. mansoni adults in Africa, although they did not recognize them as such. But returning to Pirajá da Silva in Hamburg: "Pirajá faced with courage and firmness the giant Looss stating....'I was afterwards contested with energy by Prof. Looss: the eggs I observed in the uterus of the female Schistosoma were considered by him as mere concretions, although he had never seen my slides. Gentlemen: I am not a zoologist but I have for many years dealt exclusively with helminths; being a physician, I based myself on my own observations. A wrong interpretation of the microscopic aspect of my slides might have occurred. However, in spite of Looss's authority, I am not ready to admit such a mistake to have been made. I have now the pleasure to emphasize that in the course of careful and repeated investigations on some 100 cases of bilharziasis in Bahia, I could never find one single egg bearing a terminal spine....Our best clinicians are unable to report on any bladder affection as being due to Schistosoma....In Bahia, bilharziasis is a disease affecting exclusively the lower portion of the intestines, extending into the liver.95

It is with these last remarks that Pirajá da Silva probably put his finger on the deficiency in Looss's armamentarium that prevented him from seeing the truth. Both Sambon and Pirajá da Silva were physicians and were impressed by the marked pathological, clinical and diagnostic differences between urinary and intestinal schistosomiasis. When put together with the variations in th e morphology of the eggs and in the geographical distributions of the two forms of schistosomiasis, there was no doubt in their minds that there were tw o species of schistosomes. Looss, on the other hand, was not a clinician an d failed utterly to appreciate th e completely different responses of humans to the two species of parasites. Thus, an impasse was reached, and it remained for Leiper in his studies of the life cycle of schistosomes to prove beyond all doubt that the two species were separate.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND THE SNAIL INTERMEDIAT E HOST AND PROOF OF THE EXISTENCE OF S. MANSONI By the middle of 1915, Leiper was convinced that schistosomiasis in Egypt, whether due to one or two species, was transmitted by the mediation of certain snail intermediate hosts. The events that led up to this discovery have bee n described in chapter 8. Furthermore, it was this achievement which enabled him to differentiate definitively between S. mansoni and S. haematobium.

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Shortly before Leiper left Egypt for Europe in July 1915, a mouse which had been infected with cercariae from Planorbis boissyi (now known as Biomphalaria alexandrina) died. This mouse was infected with adult schistosomes, and although only two or three eggs were seen, they were all laterally spined. According to Looss's later theory, they were abnormal products in the transitional phase of young sexually matu re worms of S. haematobium, whereas according to Sambon, they indicated that the adult worm was S. mansoni. On Leiper's reaching London, he found that four monkeys, also infected with cercariae from P. boissyi, also began to pass lateral-spined eggs in August, but they died within a fortnight from an overwhelmingly intense infection . Similarly, in rats infected with P. boissyi-derived cercariae, only laterall y spined eggs were found. Leiper had also infected some animals very lightl y with cercariae from Bulinus (known to Leiper as Bullinus) snails in the hope that some of these animals would live long enough to permit the testing o f potential anthelmintics. Unfortunately, the infection was so light that no worms were found in any of these animals. In October of that year, Leiper reviewed the position and realized that h e needed to infect animals lightly with cercariae from P. boissyi so that they would survive for several months and thus enable the female schistosomes to pass through Looss's hypothetica l "transition period". Secondly, another group of animals had to be infected heavily with cercariae from Bulinus in order to establish the specific nature of this form of parasite. Accordingly, he returned to Egypt in November 1915 and infected monkeys orally and mice, rats and monkeys percutaneously. The smaller animals were killed weekly in order to assess the mode of development. Worms were first recovered 17 days afte r infection from a mouse infected with cercariae obtained from Bulinus; although the parasites were immatur e, they showed differences in the structure of the gut when compared with with those obtained from mice infected with P. boissyi-derived cercariae. Egg production began during the ninth week. He published his findings and conclusions in a preliminary report in the British Medical Journal in March 1916: By submitting individual mice, each on one occasion only, for a limited period to infection with the cercariae from single infected molluscs, it has been possible to demonstrate that those developing in the Bullinus molluscs always produce bilharzia worms which give rise solely to terminal-spined eggs, while those which have developed in Planorbis boissyi always become worms which produce solely lateral-spined eggs.71

He then turned his attention to experiments with monkeys. Two monkeys taken from London to Egypt were infected orall y on the same day, one with cercariae from Planorbis and the other with cercariae from Bulinus. The former monkey began to pass lateral-spined eggs after six weeks and died from dysentery on the sixtieth day. The other monkey had no eggs in the urine or faeces and was killed six weeks after infection; worms were found in the liver and in th e mesenteric veins but no eggs were seen. Meanwhile, a third monkey had been

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infected orally with cercariae from Bulinus. Confusingly, it began to pas s terminal-spined eggs in the faeces after 12 weeks and died five weeks later; at autopsy, no eggs were found in the urine or bladder. At this point, Leiper had determined that cercariae derived from Planorbis produced only terminal-spined eggs. He explained the restriction of infection to the intestine in monkeys as being due to differences in the venous connections of th e bladder in this host. In order to cl inch the matter completely, rats and monkeys were infected lightly with P. boissyi cercariae and kept alive for nine months, i.e. well past Looss's transition period; lateral-spined eggs only were produced during that time. Leiper concluded that: The terminal-spined and lateral-spined eggs found in bilharzial infections are, therefore, the normal and characteristic products of two distinct species, B. haematobium and B. mansoni, and are spread by different intermediary hosts.72

Thus, at one stroke, Leiper confirmed the differentiation of Egyptia n Schistosoma into two species, S. haematobium and S. mansoni, and at the same time demonstrated that Bulinus species were the intermediate hosts of the former worm and Planorbis boissyi (Biomphalaria alexandrina ) was the vector of the latter schistosome. Leiper went on to remark that he ha d examined the only remaining fragment of a male schistosome found in 1857 by Cobbold who had called it B. magna, but was unable to identify whether it was S. haematobium or S. mansoni. Consequently, there was no difficulty in the names of S. haematobium and S. mansoni standing for the worms causing urinary and intestinal schistosomiasis, respectively 72. Shortly afterwards, Manson-Bahr and Fairley studied intestina l schistosomiasis in British Em pire troops of the Egyptian Expeditionary Force. They confirmed Leiper's findings by infecting monkeys with cercariae fro m Planorbis snails then subsequently recovering adult S. mansoni. They infected Planorbis molluscs with S. mansoni miracidia, and confirmed that Bulinus species were resistant to that para site83. Following this, Porter showed in 1920 that in southern Africa that Planorbis pfeifferi (= Biomphalaria pfeifferi ) was a vector of S. mansoni 97. Within a year or two of the publication of Leiper's discoveries, two Sout h Americans working independently confirmed his findings with respect to S. mansoni. In December 1916, Adolpho Lutz reported that certain species o f local Planorbis snails were intermediate hosts of S. mansoni in Brazil. He experimented with five species of Planorbis and found that P. olivaceus = P. bahiensis (now known as Biomphalaria glabrata ) was the species most susceptible to infection with miracidia obtained from laterally spined ova , although development also took place but to a lesser extent in P. ferrugineus and P. tenagrophilus. Cercariae developed after five weeks or so in the same manner as Leiper had described, but he observed that the rate was dependent upon the temperature 75. In the following year, he completed the cycle o f development by infecting guinea pigs and rabbits with cercariae from thes e

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snails then subsequently recovering S. mansoni adult worms 76. Lutz also pointed out that the cercariae of S. mansoni had in fact been seen, but no t recognized as such, by Pirajá da Silva as early as 1912 when the latte r described them and named them Cercaria Blanchardi. Finally, Lutz showed that P. olivaceus was infected naturally with S. mansoni cercariae, and re-examined in detail the kinetics of inf ection in experimentally infected snails. He found that miracidia penetrated the molluscs within 10-15 minutes, th e most usual site of attack being the antenna. Sporocysts were apparent within three to four days then secondary sporocysts were seen migrating into th e visceral sac 20 days after infection. Mature cercariae were found about fiv e weeks after exposure 77. In Caracas, Venezuela, Juan Iturbe (1917) infected P. guadelupensis (now known as Biomphalaria glabrata ) with miracidia obtained from S. mansoni ova51. He observed the transformation of miracidia into sporocysts then th e production of secondary sporocysts then the appearance of cercariae after six to seven weeks. White mice, guinea pigs and newborn puppies were infected percutaneously with these cercariae; two months later, adult S. mansoni were recovered from the portal vein of two mice. Iturbe found, however, that th e most constant success was obtai ned when experimental animals were fed food contaminated with livers of P. guadelupensis containing large numbers o f cercariae. He then found many naturally infected snails of this species in the city. Finally, Ampullaria luteostoma and P. cultratus were infected under laboratory conditions, but he did not regard these as being vectors in nature. Also from South America, Cardoso in 1923 reported that Planorbis centrimetralis was the common intermediate host of the parasite in Sergip e State, Brazil 16. The cycle of transmission was again invest igated by Faust and his colleagues in the early 1930's. They infected the snail they called Heliosoma (Planorbina) guadaloupense (= Biomphalaria glabrata ) with S. mansoni miracidia then produced patent infec tions in a variety of experimental animals. With respect to development of the parasite in the snails, they first identified sporocysts on the eighth day. Cercariae began to emerge after 24-35 days , depending upon the season and continued to be discharged for four months , producing altogether about 100,000 cercariae from a single miracidium 31,32. The taxonomy of the snail vectors of S. mansoni has been a matter of some controversy. Planorbis boissyi described by Potiez and Michaud in 1838 was shown to be identical with Planorbis alexandrinus described by Ehrenberg in 1831; this latter name therefore had priority. A number of other genera were raised, however, to house intermediate hosts of S. mansoni; these included, in addition to the genus Planorbis described by Geoffoy in 1767, Biomphalaria raised by Preston in 1910 98, Tropicorbis enunciated by Pilsbry and Brown in 1914, Afroplanorbis of Thiele, 1931, and Australorbis erected by Pilsbry in 1934. A World Health Organiz ation study group in 1954, however, noted that it had long been recognized that the known species of snails which serve a s

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intermediate hosts for S. mansoni are generically the same, and that they al l have probably been derived from the same stock. They recommended that the name Biomphalaria should be used for all the snail intermediate hosts o f S. mansoni 99. In 1965, the International Commission on Zoological Nomenclature confirmed this view and ruled that the correct generic name for th e following snail vectors of S. mansoni, Armigerus, Planorbina and Taphius, was Biomphalaria 50. In an annotation on an abstract concerning this decision, Wright noted that it had not been necessary to consider Australorbis and Tropicorbis since they were both junior synonyms of Biomphalaria 123. The correct names for the major African vectors of schistosomiasis mansoni ar e therefore Biomphalaria alexandrina and B. pfeifferi. Concerning the South American molluscan vectors, Martins in 193 8 considered that Planorbis centrimetralis , P. guadaloupensis, P. immunis, P. nigricans, P. olivaceus and perhaps P. peregrinus were all synonyms given to members of a variable species properly known as Australorbis glabratus 85 . As already noted, the proper name for Australorbis is Biomphalaria, therefore the correct name for the major South American vector o f schistosomiasis mansoni is Biomphalaria glabrata .

MIGRATION OF WORMS IN THE DEFINITIVE HOST In 1919, Iturbe and Gonzalez in Venezuela studied the migration of S. mansoni through the tissues of experimental animals and found that the event s were similar to those that had already been described for S. japonicum ( see chapter 10). They observed that cercariae penetrated the skin within fiv e minutes, lost their tails in the process, then the resultant schistosomula passed via the bloodstream through the hea rt and lungs to the liver. Male worms were found in the portal veins 18 days after infection, but female worms were not identified until one month after exposure 52. In the same year, Fairley repor ted his observations in monkeys infected with S. mansoni. He observed that the worms inhabited chiefly the inferior an d superior mesenteric veins and tributaries of the portal vein in the liver. Fairley then went on to describe the mechanism of egg-laying by female worms in the distal tributaries of the portal venous system; this was the same as has already been recounted for S. haematobium (see chapter 8). A few years later, Faust and his colleagues re-investigated the route an d kinetics of migration in rats, rabbi ts and monkeys infected experimentally with a Puerto Rican strain of S. mansoni. They noted that schistosomula had left the skin within 16-20 hours of infection, and pas sed mainly via the veins but partly through the lymphatics to the lung capillaries where they were first seen at 20 hours. By the third day. they had reached the systemic circulation, and on the fourth day, they were discovered within the hepatic radicles of the portal vein where they were believed to feed for the first time. Larvae were found in the

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lungs up to 19 days after infection, and peak numbers of worms in the live r were reached on the thirteenth day. Mature worms were first seen in th e colonic venules 35-40 days after infection 32,33. Adult worms may live in the portal venous syst em of humans for many years. One patient has been recorded who, at least 26 years after infection, was still passing eggs containing living miracidia 116. Epidemiological evidence , however, suggests that the average life span for these worms is between five and ten years 120.

CORRELATION OF INFECTION WITH PATHOLOGY AND INVESTIGATIONS OF PATHOGENESIS The pathological changes in schistosomiasis mansoni were described b y Bilharz and Griesinger soon after the discovery of S. haematobium, although neither of these investigators realized that the pathological changes they saw in the large bowel were caused by S. mansoni infection. On 15 March 1852, Bilharz and Griesinger performed an autopsy on a boy who had died fro m meningitis. In addition to urinary sch istosomiasis, disease of the intestinal tract was discovered: From the middle of the transverse colon to the anus, the mucosa was somewhat swollen and delicate; it was markedly congested and covered with reddish mucus. In the region of sigmoid colon and in the rectum were superficial erosions....Between these hyperemic, inflamed areas were both more coarsely congested and almost or completely normal stretches of mucosa.13

As has been discussed earlier, Bilharz found clumps of eggs as well as eg g shells which he thought were S. haematobium "capsules" in this intestine . Several days later, Griesinger discovered eggs with lateral spines containing miracidia in dysenteric large intestine: In a black-pigmented large intestine showing scars of healed ulcerations and many warts and spines, I found (19 March 1852) an enormous number of Distoma shells (eggs?) (sic) provided with a lateral spine. I was fortunate enough to see massive hatching of the organisms.43

When Griesinger found a number of such patients, he wondered whether these trematodes might not be the cause of both the acute and chronic diseases of the large intestine that abounded in E gypt. Against this, however, was the fact that during the short time that he had left in the country, Griesinger did not always find eggs in cases of dysentery, despite the most assiduous searching . Consequently, he reached the conclusion that most of the dysenteries aros e from causes other than schistosomiasis, but that "distomiasis of the larg e intestine.... is only one, but nevertheless a highly important complication o f these diseases" 43. He did, however, add a caveat: But I do consider it possible that, in some cases, Distoma alone can effect changes in the large intestine which, at least to the naked eye, seem very similar to those of true dysentery.43

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These changes were then studied in more detail in histological sections . Thus, Zancarol (1882) demonstrated that colonic vegetations, which in th e fresh state had the appearance of internal haemorrhoids, were in fact folds of mucous membrane which were stuffed wi th schistosome eggs 124. Several years later, Belleli described the histological characteristics of a tumour, the size of a small apple, removed from the rectum of a patient in Egypt; it had th e appearance of an ordinary ad enomatous polyp, but groups of ova were seen in the connective tissues 8. This gave rise to speculation that irritation by parasites may play a part in tumour formation 3, but Ferguson was later to remark that the rarity of malignant neoplasia in intestinal schistosomiasis stood out in contrast with that seen in the urinary infection 34. These polyps were recognize d frequently in Egyptian schistosomiasis but rarely elsewhere. Thei r manifestations and the resulting complications were described by Maddern: The most common seat of infection is the lower part of the small intestine and the large intestine generally. The most common lesion in the intestinal tract is the presence of papillomata of varying sizes and characters along the whole length of the intestine from the ileum to the anus, sometimes thickly scattered or again sparsely distributed throughout the mucous membrane....Over quite extensive areas of certain parts of the large intestine, the papillomata have necrosed and separated off at their pedicles, resulting in ulcers of dysenteric appearance....Sometimes, again, certain lengths of the large intestine become infiltrated, together with their peritoneal attachments, with hard bilharzial tissue. There is an enormous thickening of the walls of the gut, a dense packing of its interior with papillomata, and deposits of bilharza tissues in the appendices epiploicae and on the serous surface of the gut, and a fixing of the intestine with massive deposits behind it and between the layers of its peritoneal attachments.79

Although Bilharz originally found adult s chistosomes in the portal vein close to the liver, S Kartulis in 1885 was the first person to report the deposition of eggs in the liver55. As his patient suffered from both urinary and intestina l schistosomiasis, it is not now possible to be certain whether Kartulis saw ova of S. mansoni, S. haematobium or both. In 1904, William St. Clair Symmers published the results of his observations on liver pathology during a five year period in Cairo. From time to time, he had n oticed that the liver had an unusual appearance: On section, the liver presents a remarkable appearance due to an enormous increase of the fibrous tissue (Glisson's capsule) which normally surrounds the portal canals.... When a portal canal is cut transversely, the mouths of the contained vessels and bile ducts are seen embedded in the centre of a circular or slightly oval area of white connective tissue, the diameter of the mass being....from a sixth to a quarter of an inch; whereas, longitudinal sections of the canals reveal elongated masses of similar appearance and thickness, so that the cut surface of the liver looks as if a number of white clay-pipe stems had been thrust at various angles through the organ. 110

Microscopical examination of six of these livers revealed that this periportal firosis was associated with the presence of schistosome ova: Among this tissue are seen ova of the Bilharzia haematobia, often in considerable numbers. ...A small blood vessel may often be seen running up to, and widening into,

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such a mass of concentrically arranged young fibrous tissue, and lying in the centre of the newly formed mass, as if it had become impacted in the vessel, and had by its presence produced the proliferation of tissue which resulted in cirrhosis, an ovum. 110

Although he entitled his paper "Note on a new form of liver cirrhosis due to the presence of the ova of Bilharzia haematobia", it is clear that he was visualizing eggs of S. mansoni, for he remarked that most of the ova wer e laterally spined. Most of the eggs were dead with merely the shell remaining and were surrounded by fibrou s tissue, but he occasionally observed fresh ova which were filled with a mass of inflammatory cells. Symmers thought that all of these changes were indicative of a cirrhosis of the liver caused b y schistosome ova. Cirrhosis of the liver and splenomegaly with ascites have long bee n recognized as being frequent in Egypt. Indeed, an attempt has been made to link the abdominal distension and gy naecomastia seen on several reliefs on the tomb of Mehou, a notable of the VIth Dynasty, to hepatic involvement i n schistosomiasis 46. Certainly, this form of liver disease accounted for 4% of the admissions to the medical wards of the Kasr-el-Aini Hospital in Cairo during the early part of this century. In 1909, Day and Ferguson reported thei r experience with this problem and concluded that it was not due t o schistosomiasis 23. Fifteen years later, however, Day changed his position when ova were discovered at liver biopsy in a series of patients subjected t o splenectomy. He regarded splenomeg aly as an early and often transient feature of S. haematobium infection, but concluded that progressive and lastin g splenomegaly may accompany hepatic schistosomiasis mansoni, even whe n infection of the intestinal tract was slight. Day believed that there were tw o types of "cirrhosis". If the numbers of eggs were small, a diffuse multilobular cirrhosis was established, but if they were numerous, the dense periporta l (pipestem) fibrosis of Symmers was found 22. The paucity of eggs in the liver and the recovery of male worms alone from the portal vein, however, led Girges in his review to conclude that: Egyptian splenomegaly is a disabling endemic parasitic syndrome caused by male Schistosoma mansoni infestation of the liver and portal vein....It presents an absolutely different picture from the ordinary type of schistosomiasis mansoni. There is very little or no alimentary disturbance or implication of the gut, the brunt of the infection being inflicted upon the viscera.40

Subsequently, the view was promulgated that these features were very similar to Banti's syndrome and "before falling back on this obscure diagnosis in the future, the question of schistosomiasis....will have to be considered" 4. Nevertheless, the genesis of these liver changes remained a matter o f controversy for many years. Thus, in 1959, Carter and Shaldon wrote: the importance and extent of the infiltration of the liver by ova, and the nature and causes of the fibrosis found in the livers of patients with schistosomiasis, are still disputed.17

Experimental studies, however, eventually placed beyond any doubt tha t when splenomegaly and ascites were due to schistosomiasis of the liver, they

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were the result of presinusoidal hypertension caused by obstruction to blood flow as a result of granulomas around the eggs. Thus, infections with worms in the portal system but without eggs in the liver failed to induce significan t changes in the haemodynamics of the portal venous system in experimenta l animals. Further, the eggs themselves were calculated to contribute less than 5% of the obstruction, the great proportion of obstruction being generated by granulomas117. Progressive understanding of the genesis and evolution of these lesions led to a solidification of the concept that the condition described b y Symmers was not cirrhosis, as defined by liver parenchymal cell death, nodular regeneration and sclerosis, but a simple hepatic fibrosis. Thus, in retrospect, it is apparent that schistosomiasis with heavy egg deposition and subsequent granulomatous inflammation may cause portal hypertension, splenomegaly , ascites and oesophageal varices. It is now clear that in those instance s described by the early investigators in which cirrhosis was associated with a minimal number of eggs, the patients had cirrhosis resulting from one of the many other causes, known and unknown, of that condition together wit h coincidental light schistosome infections. Griesinger's postulate that eggs might sometimes be carried in th e circulation to organs outside of the portal venous system was borne out when Belleli7 reported the finding by Mackie in 1885 of numerous small, fibrosing abscesses containing schistosome eggs in the lungs of a man who had die d from the complications of urinary schistosomiasis. In 1905, Symmer s described the recovery of a pair of copulating worms from the left lung of a 35 year old person who had died from intestinal schistosomiasis 111. Pulmonary schistosomiasis was then investigated intensively by Shaw and Ghareeb who examined 282 cadavers of persons with schistosomiasis mansoni an d schistosomiasis haematobia in Egypt and found that in 2%, death was du e directly to lung damage caused by these parasites. Moreover, one third of all these patients had schistosomal pulmonary emboli; 10% of these emboli were due to the adult worms themselves, whereas the rest were due to eggs. The ova caused necrosis of the vessel walls and passed into the alveolar spaces an d were associated with a chronic inflammatory re action, sometimes accompanied by endothelial thickening of the arterioles, resulting in cor pulmonale 107. Following delineation of the pathology of schistosomiasis, attempts wer e made to comprehend the genesis of these changes. Crucial to such a n understanding was the realization that the primary inflammatory reactio n around schistosome worms and eggs in the tissues was of a non-suppurative nature. Fairley in 1919 described "tubercles" containing many eosinophili c leucocytes around eggs in monkeys infected experimentally with S. haematobium and S. mansoni 26,29. Hutchinson in 1928 detailed thi s phenomenon more clearly, showing that ova were at first surrounded b y fibroblasts and foreign body giant cells to form a granuloma which he called a "bilharzial pseudotubercle" 48. This was echoed by Koppisan who described the pseudotubercle as the fundamental histopathological unit o f

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schistosomiasis mansoni. He also portrayed an evolutionary process in which an infiltration of eosinophils and neutrophils around ova in the tissues wa s followed by the appearance of ep ithelioid cells which were in turn replaced by fibrosis65. Eventually, KS Warren and a number of other investigators showed that these granulomas were the consequence of cell-mediated immun e reactions to schistosome egg antigens 117,119. Whether or not resistance to reinfection is generated by prior exposure t o infection has been a vexed and controversial topic. Reductions in frequenc y and intensity of infection in older age groups have been put forward as a n indication of the acquisition of such resistance, but Warren, in his majo r review118, concluded that these effects were more probably explained o n ecological grounds, particularly behavioural influences on contact wit h contaminated water.

RECOGNITION OF THE CLINICAL FEATURES The dysenteric symptoms of schistosomiasis were emphasized by Mackie in Alexandria in 1882. He noted that many Egyptians suffering from thi s condition complained of a feeling of a constant weight and discomfort about the rectum, pain in the hypogastrium, and a frequent desire to defaecate, but that straining at stool resulted only in the passage of a little mucus and blood. These symptoms had often been present for months. The patients wer e sometimes emaciated, and rectal ex amination disclosed firm nodules about the size of a small bean in the rectal mucosa 78. These features were reiterated by Maddern, also in Egypt, a few years later. He wrote that the most commo n lesions in the intestinal tract were papillomas in the large bowel associate d with symptoms ranging from minimal to diarrhoea, tenesmus, and passage of blood and mucus, as in dysentery 79. The early manifestations of infection w ere reported by Lawton in 1917, soon after the differentiation of S. mansoni as a separate entity by Leiper in 1916. Lawton described the clinical features of a group of 24 Australian soldiers who had been infected at a freshwater canal at Tel-el-Kebir during World War I. Several of the men had noticed itching when coming out of the water afte r bathing. The incubation period was uncertain, but between four weeks an d three months later, there was a gradual onset of anorexia, headache, myalgia, dizziness, cough, fever, rigors, sweats and abdominal pain. Generalize d urticaria was always present, usually during the second and third week of the clinical illness, and lasted for 12-48 hours. Diarrhoea was only an occasional and transitory feature. Examination revealed abdominal tenderness, partic ularly in the right upper quadrant and over the descending colon, as well a s enlargement of the liver and spleen 67. In 1922, Girges reviewed the clinical aspects of schistosomiasis on the basis of his observations of 4,000 cas es of S. mansoni infection at Tanta on the Nile

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delta40. He divided them into two types - the intestinal and hepatic. Intestinal schistosomiasis was in turn divided into four phases following "Baoonah itch" (indicating cercarial invasion) and a laten t period: (1) febrile or toxaemic stage lasting three to six weeks - this was seen in 3% of his patients and was marked by the sudden or insidious onset of fever, hepatosplenomegaly, occasiona l urticaria, indigestion, diarrhoea and tendern ess in the right hypochondrium; (2) dysenteric stage lasting two to three years - this was seen in nearly three fifths of his patients and coincided with the ap pearance of eggs in the faeces and was characterized by exacerbations of dysentery every 15-20 days associated with fever; (3) intestinal or papillomatous stage - this was seen in one third of his patients and was typified by thickening of the lower bowel which was ofte n palpable through the abdominal wall, and the appearance of papillae in th e rectum. (4) final stage or "stage of repair" was seen in only 0.2% of hi s patients - Girges considered it the terminal stage of infection with marke d sclerosis and contraction of the tissues and with only a few atrophie d papillomata left. The manifestations of hepatic schistosomiasis (which Girges considered as being synonymous with Egyptian splenomegaly) were initially the same as those in intestinal schistosomiasis. The second stage was marked by the appearance of an enlarged, hard, o ften tender liver and spleen. The third stage was indicated by the appearance of ascites. Ova were typically absen t from the stools. As already indicated, it is now probable that this conditio n frequently had nothing whatever to do with schistosomiasis. Similar syndromes to these were described a few years later by Pons i n Puerto Rico96. They were reiterated again by Gelfand in Southern Rhodesi a (Zimbabwe) who recognized three clinical varieties: (1) an acute phase o f fever and urticaria, often associated with malaise, anorexia and cough; (2 ) chronic abdominal pain and periodic mild diarrhoea with occasional blood and mucus in the stools; (3) a late form with cirrhosis and splenomegaly 39. In many endemic areas, not only is polyparasitism present, but infection s with gastrointestinal bacterial and viral pathogens are common. Thi s frequently makes it difficult to discern which features are due to schisto somiasis and which are due to other pathogens. In recent years, a number of community studies have shed some light on this problem by relating th e clinical manifestations to the int ensity of infection. A controlled study by Cook and his colleagues of schistosomiasis in the West Indian island of St. Luci a showed that gastrointestinal symptoms were no more frequent in infected than in non-infected individuals, but that hepatomegaly and splenomegaly wer e more common in the moderately and heavily infected children, as defined by the numbers of eggs excreted in the faeces 20. Similar observations were then made in Kenya 109 and in Brazil 68. These findings confirmed views on the prognosis in schistosomiasi s mansoni. Although severe and sometimes fatal infections with S. mansoni were well-described in the nineteenth century, it was recognized that such an outcome was uncommon. Before elucidation of the life cycle, there was some

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speculation that autoinfection might occur, and that this could influence th e prognosis. When it was realized that infection was acquired from infecte d snails and that adult worms did not multiply in the human host, it seeme d probable that continuing exposure was necessary for the development o f severe disease. This concept was supported by the observation that expatriate troops infected during World War I did not develop progressive disease when they were removed from the endemic areas 27. In the last several decades, some longitudinal studies of the effects o f schistosomiasis have been carried out, although they have tended to con centrate on the more heavily infected individuals. Thus, Katz and his col leagues in Brazil followed up 112 patients fo r ten years; two patients died from haematemesis, seven had evolved towards hepatosplenomegaly, but most of the others showed little progres s in the severity of the disease 58. Rather similar results were reported by Kloetzel, also in Brazil, who observed 105 patients infected with S. mansoni for five years and found that only seven had died 63. Thus, schistosomiasis mansoni, although it may be a cause of considerabl e morbidity, is not a major cause of death.

DEVELOPMENT OF DIAGNOSTIC METHODS Although Bilharz and Griesinger discover ed that urinary schistosomiasis could be diagnosed in life by finding eggs in the uri ne, and were aware that ova could be found in the intestinal mucosa at post-mortem examination, they do no t appear to have paid much attention to diagnosing schistosomiasis by finding eggs in the stools. It is true that Bilharz did write to von Siebold in Augus t 1852; "I have also found eggs in the stool of a patient with acute dysentery" 12. This was almost a throw-away line, however, and neither Bilharz no r Griesinger developed the idea that this phenomenon could be utilized i n diagnosis. This presumably devolved from thei r failure to differentiate between laterally and terminally-spined eggs, their belief that urinary schistosomiasis was of greater importance, and the relative ease of examining urine compared with faeces. This concept was accepted by various commentators in thei r textbooks; they all recommended examining the urine in order to make th e diagnosis. Thirty years after Bilharz disc overed the worms, Mackie reported that rectal nodules common in Egyptians with schistosomiasis could be twisted off with haemorrhoidal forceps, then the characteristic ova could be demonstrate d microscopically. He even added that no ova could be seen in the urine despite careful and repeated micoscopical examination, but made no mention of any similar examination of the faeces 78. As late as 1903, Milton, in an extensiv e review of schistosomiasis which encompassed clinical and therapeutic aspects of both urinary and intestinal forms of the disease, discussed diagnosis b y examination of the urine for eggs, but omitted any reference to a simila r

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examination of the stools 87. It is uncertain who first began routine microscopical examination of th e faeces in order to diagnose schistosomiasis mansoni, although it is clear that Manson in 1902 serendipitously found laterally-spined eggs while looking for hookworm ova in the stools 81; indeed, it was this discovery which, as already described, initiated the debate that led to the delineation of S. mansoni as a separate species. Following this report, however, examination of the faece s became a frequent, then a standard, inves tigation in both clinical situations and in epidemiological studies. Much attention then turned to developin g laboratory techniques for maximizing the chances of detecting ova in th e stools6,30,100,106,115,122. With the realization that it was important to determine the intensity of infection, however, these techniques largely fell out favour an d were replaced by quantitative methods, the most important of which is th e Kato technique, originally described by Kato and Miura in 1954 57, then modified by Komiya and Kobayashi 64, adapted for quantitative diagnosis by Martin and Beaver84, simplified by several workers 14,59, then developed into a "Quick Kato Smear" suitable for rapid quantification of schistosome eggs under field conditions 91. The introduction of the proctoscope and sigmoidoscope provided a tool for visualizing the intestinal lesions induced by S. mansoni. Thus, Bercowitz and his colleagues examined proctoscopi cally 155 Puerto Rican army recruits who had eggs in the faeces, and found that two thirds of them had small, sharpl y demarcated ulcers, pinpoint or linear in shape and up to several millimetres in width10. Subsequently, Greany in the Sudan sigmoidoscoped 38 patients with schistosomiasis and found that the most frequent lesions were yellow-whit e pinhead dots; hyperaemia and friabil ity were common, ulcers were seen in one third, and polyps were rarely met 42. Da Cunha and his colleagues sigmoid oscoped over 2,000 patients with schistosomiasis in Brazil and found tha t congestion was the commonest lesion, rectal polyps were rare, yellowis h nodules of ova could be visualized, and varices were frequent in patients with hepatosplenic schistosomiasis 21. Even though polyps containing eggs were rare in regions outside of Egypt, it was found that eggs could often be found in biopsies of rectal mucosa 45. Similarly, eggs may be found in the liver in schistosomiasis; thus in one study, ova were seen in liver biopsies in 21 out of 45 cases 25. Structural damage to the large intestine can be displayed by radiographi c barium enema examination24. Similarly, effects on the liver and portal venous system can be investigated radiologically, manometrically, and using nuclear medicine techniques 1,5,88,89. In most instances of hepatic schistosomiasis, it was found that liver function tests were only mildly or moderately impaired 89,101. There have been many efforts to develop immu nological assays for the diagnosis of schistosomiasis mansoni. Fairley described the employment of a complement fixation assay for antischistosomal antibodies in 1919 28, while Taliaferro and his colleagues described a precipitation reaction 113 and an

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intradermal test114, but immunoassays have remained much less useful tha n parasitological diagnostic techniques.

THE SEARCH FOR EFFECTIVE TREATMENT The anthelmintic therapy of schistosomiasis mansoni is broadly similar to that of schistosomiasis haematobia and has been detailed in chapter 8. There are, however, some differences. As already indicated, niridazole was shown to be less effective against S. mansoni than against S. haematobium and metrifonate was found to be of no value at all. On the other hand, oxamniquine is a useful addition to the therapeutic armamentarium in schistosomiasis mansoni. This drug was shown by Foster and coll eagues in 1973 to be active against S. mansoni in rodents and in monkeys, but had no effects on S. haematobium or S. japonicum 37. In the same year, Katz and co-workers tested oral and intra muscular administration of the drug i n 24 adults in Brazil with schistosomiasis mansoni and found that the latter route was preferable 60. Subsequent studies confirmed the efficacy of the drug against S. mansoni, although it appeared to be more useful against the South American than the African strains of th e parasite112. In 1903, Milton reviewed the surgic al management of schistosomiasis of the rectum. He recommended enemas of starch and opium or copper sulphate in the early stages. He advised removal of polyps, but this was frequently no t possible because they were either too numerous or were too high in th e rectum. He found that excision of the rectum was rarely necessary 87. Splenectomy was undertaken for "Egyptian splenomegaly" in the earl y 1920's, and this was said to be sometimes attended by considerable improvement22. Noya Benitez performed 22 splenectomies in patients with schisto somiasis and reported in 1947 that it may relieve portal hypertension i f undertaken before liver damag e was excessive 90. Ligation of the hepatic artery had its advocates 49,62 but sometimes had devastating consequences and did not find lasting recognition. Various shunt procedures such as portocaval anastomosis and lieno-renal anastomosis were assessed from time to time 38,54,89,108. It was thought initially that patients with schistosomal portal hypertensio n were not likely to develop po rtosystemic encephalopathy as liver function was held to be relatively undisturbed. There were reports, however, that hepati c dysfunction did supervene 121 and the operation gradually lost favour with many surgeons. An ingenious procedure for removal of adult worms from the portal venous system by extracorporeal filtration of blood was described by Goldsmith and colleagues in 1965 41. They removed 148 to 800 worms from three patients, but the technique did not live up to expectations and was abandoned.

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UNDERSTANDING THE EPIDEMIOLOGY Early ideas concerning the epidemio logy of schistosomiasis before S. mansoni and S. haematobium were distinguished have been recounted in chapter 8 . Central to the understanding of the epidemiology of schistosomiasis mansoni was the demonstration by Leiper that this infection was transmitted by certain species of snails. This was followed by the delineation of the geographica l distribution of S. mansoni, with the realization that this infection but no t S. haematobium infection also occurred in the Western Hemisphere. This was followed by the identification o f the various species of snail intermediate hosts of the parasite in different parts of the world. Over the next few decades, much effort was expended on defining the frequency of the infection and severity of disease in a large number of endemic areas. Although humans have proven to be the major reservoir of infection, S. mansoni infection in nonhumans wa s first reported by Cameron in 1928 after he found that monkeys on the Wes t Indian island of St. Kitts were infected naturally 15. Subsequently, the occurrence of natural infections in rodents in Egypt 66 and in South America 86 was shown. As with schistosomiasis haematobia, the main determinants of the prev alence and intensity of infection are the presence and density of vector snails, and the behavioural habits of the human population which determine both the contamination of water sources with infected faeces and the exposure t o cercaria-laden water. Like schistosomiasis haematobia, schistosomiasi s mansoni has been spreading wit h the advent of new irrigation systems and has increased in frequency along the Nile downstream from the Aswan High Dam (see chapter 8).

INTRODUCTION OF SCHISTOSOMA MANSONI INTO THE WESTERN HEMISPHERE In 1902, Manson wrote that with the exception of Mesopotamia, Cyprus and Mauritius, schistosomiasis had hitherto been supposed to be peculiar to Africa. He then reported the instance of an Englishman who had been infected with schistosomes producing laterally spined eggs while residing in the Wes t Indies. Its occurrence in a white man suggested to Manson that the infection must be not uncommon among the indigenous inhabitants. He then dre w attention to the parallels betwee n schistosomiasis and another African disease, Guinea worm infection, which had been at one time prevalent in parts o f Central and South America, and noted that the latter condition had no w disappeared. Although he did not specifical ly say so, Manson implied that both of these infections had been introduced from Africa, and with remarkabl e precision and foresight wrote: "It is evident that the distribution of this an d similar parasitic diseases depends on the presence or absence of the efficient

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intermediaries" 81. This form of schistosomiasis wa s indeed found to be common in parts of the Americas. In 1908, Pirajá da Silva wrote that the worm was probabl y introduced into the New World from Af rica by West African slaves, beginning in 1550. Infection was particularly common in the environs of Bahia, Brazil from where da Silva was writing. That city was at one time one of the mai n entry ports during the times of the slave trade. He postulated that these people were the carriers of schistosomes from Africa, and that the schistosome eggs found climatic conditions in America favourable for development 92. More recently, it has been suggested that Recife in Brazil may have been the most important entry point, particularly during the Dutch administratio n (1630-1654), since the Dutch brought in an in ordinately high number of slaves during this period 2. Although laterally spined eggs were common in South America in the early parts of this century, haematuria and terminally spined eggs were not, eve n though the latter disease was frequent in parts of Africa and may have been at some time in the past in the Western Hemisphere. This became explicabl e when Leiper proved that S. mansoni and S. haematobium were different species and required different molluscan vectors. Snails susceptible t o S. mansoni were found in various regions of the Americas, although they were usually different species from those seen in Africa, but snails susceptible t o S. haematobium were absent. While indigenous American snails wer e susceptible to S. mansoni and are most important in transmission, there may also have been a small-scale introduction of African vectors. For example , Biomphalaria alexandrina pfeifferi and Bulinus tropicus were found in the municipal gardens and in ditches about the city of São Paulo, Brazil. It wa s suggested that these species may have been introduced in water barrel s brought from Africa during the slave trade times, and had been left behin d when the barrels were washed out and refilled with fresh water 9. Further support for the slave trade theory was provided by the demonstration tha t infection was common in those places where slaves from endemic areas o f Africa had been imported, such as northe astern Brazil. This infection may now be becoming zoonotic, for Martins in Brazil in 1958 found that natura l infections were common in wild and domestic rodents 86. While it is the view of the vast majority of investigators that S. mansoni was introduced from Africa, a few workers believe that this worm was autochthonous in Brazil. Magalhães and Dia s, for example, reached this opinion on the basis of reports of a disease with symptoms similar to that seen in schisto somiasis mansoni which was said to have existed along the rivers before the arrival of the Portuguese 80.

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THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Measures for the prevention and control of intestinal schistosomiasis ar e similar in many respects to those used in S. haematobium infections. The development of such techniques has already been outlined in chapter 8. The greatest success has attended a multidisciplinary approach. For example , Biaggi reported forty years ago that the prevalence of S. mansoni infection in a rural area of Puerto Rico had been reduced from 44.6% to 4.5% by a combination of treatment, installation of efficient latrines, improvements i n water supply and attempts at biological control of snails, but he commente d that these measures were too expensive to be applied to the whole island 11. Similarly, schistosomiasis was once common in St. Kitts, West Indies, with the prevalence of infection as late as 1932 being estimated to be as high as 25%. The infection has now disappeared, presumably as a result of unplanne d environmental improvements 35. Various methods for the control of schistosomiasis mansoni have bee n assessed in various parts of the world, but perhaps the most elegant of these studies were carried out on the West Indian island of St. Lucia by Jordan and his colleagues. The efficacies of different control techniques including snai l control, chemotherapy and provision of safe water supplies were investigated. Although all methods produced similar results, it was concluded that chemotherapy (hycanthone plus or minus oxamniquine) was the cheapest and most rapidly effective method of achieving transmission control and also provided disease control. Snail control (with Bayluscide), however, did not requir e either population cooperation or a stable community. Installation of safe water supplies was the costliest technique and required education and cooperation of the population, but provided other social and medical benefits 53. These techniques are being used in varying combinations, as far as practicable and economically feasible, in various parts of the world.

REFERENCES 1. ALMEIDA FC, LUZ FF. Direct operative portography in hepatosplenic schistosomiasis mansoni. Gazeta Médica da Bahia 70: 1-15, 1970 2. ALMEIDA MACHADO P. The Brazilian program for schistosomiasis contro l 1975-1979. American Journal of Tropical Medicine and Hygiene 31: 76-86, 1982 3. ANONYMOUS. Parasites and tumours. Lancet ii: 300, 1885 4. ANONYMOUS. Schistosomiasis or Banti's Syndrome? Lancet i: 642, 1937 5. ARAFA MA, BIBAWA E, RAFAAT A. The portal pressure in hepatic fibrosi s associated with bilharziasis. American Journal of Tropical Medicine and Hygiene 6 : 108-113, 1957 6. BELL DR. A new method for counting Schistosoma mansoni eggs in faeces. Bulletin of the World Health Organization 29: 525-530, 1963 7. BELLELI. Les oeufs de Bilharzia, &c., dans les poumons. Union Médicale d'Egypt e

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Nos. 22-23, pp 1-3, 1885 8. BELLELI V. Du rôle des parasites dans le développement de certaines tumeurs ; fibro-adénome du rectum produit par les oeufs du Distomum haematobium . Progrès Médical 13: 54-56, 1885 9. BEQUAERT JC, de LUCENA DT. Introdução no Brasil de duas espécies africanas de caramujos transmissores da e squistossomose - Bulinus tropicus (Krauss) e Biomphalaria alexandrina pfeifferi (Krauss). Revista Brasileira Medica 8: 167-170, 1951 10. BERCOWITZ ZT, RODRIGUEZ-MOLINA R, HARGRAVE D W, DICKE JD, GREEN CE. Studies on human Schistosoma mansoni infections. I. Proctoscopic picture i n asymptomatic schistosomiasis mansoni infections. Journal of the American Medica l Association 125: 961-963, 1944 11. BIAGGI N. The fight against schistosomiasis. Puerto Rico Journal of Public Health and Tropical Medicine 26: 101-109, 1950 12. BILHARZ T. Fernere Mittheilungen über Distomum haematobium . Zeitschrift für wissenschaftliche Zoologie 4: 454-456, 1853. Partly translated in 61 13. BILHARZ T, von SIEBOLD CT. Ein Beitrag zur Helminthographia humana, au s brieflichen Mittheilungen des Dr. Bilharz in Cairo, nebst Bemerkungen von Prof. C. Th. von Siebold in Breslau. Zeitschrift für wissenschaftliche Zoologie 4: 53-76, 1852 Partly translated in 61 14. BORDA CE, PELLEGRINO J. An improved st ool thick-smear technique for quantitative diagnosis of Schistosoma mansoni . Revista do Instituto de Medicine Tropical de Sã o Paulo 13: 71-75, 1971 15. CAMERON TW. A new definitive host for Schistosoma mansoni . Journal of Helminthology 6: 219-222, 1928 16. CARDOSO E. Contribuição ao estudo da schistosome no Estado de Sergipe. Brazi l Medico ii: 239-240, 1923 17. CARTER RA, SHALDON S. The liver in schistosomiasis. Lancet ii: 1003-1008, 1959 18. de CERQUEIRA FALÇÃO E. Professor Pirajá da Silva, incontestable discoverer o f "Schistosoma mansoni". Zeitschrift für Tropenmedizin und Hygiene 10: 146-153, 1959 19. COBBOLD TS. Cases of haematuria due to Bilharzia. British Medical Journal i : 1096-1097, 1885 20. COOK JA, BAKER ST, WARREN KS, JORDAN P. A controlled study of morbidity of schistosomiasis mansoni in St. Lucian children, based on quantitative egg excretion. American Journal of Tropical Medicine and Hygiene 23: 625-633, 1974 21. da CUNHA AS, CANCADO J R, PELLEGRINO J, de OLIVERIA CA. Valor oograma para a seleção e avaliação de medicamentos da esquistossomose mansoni. Revista d o Instituto de Medicina Tropical de São Paulo 5: 75-84, 1963 22. DAY HB. The etiology of Egyptian splenomegaly and hepatic cirrhosis. Transactions of the Royal Society of Tropical Medicine and Hygiene 18: 121-130, 1924 23. DAY HB, FERGUSON AR. An account of a form of splenomegaly with hepati c cirrhosis endemic in Egypt. Annals of Tropical Medicine and Parasitology 3: 379-394, 1909 24. di EGIDIO M. Osservazione radiologiche sulla bilharziosi intestinale nello Yemen . Archivio Italiano di Scienze Mediche Tropicali e Parassitologia 38: 311-327, 1957 25. ERFAN M, TALAAT S. Demonstration of Schistosoma ova in the liver by biopsy . Journal of the Royal Egyptian Medical Association 30: 663-664, 1947 26. FAIRLEY NH. Bilharziasis: some recent advances in our knowledge. Lancet i : 1016-1021, 1919 27. FAIRLEY NH. Observations on the clinical appearances of bilharziasis in Australia n troops, and the significance of the symptoms noted. Quarterly Journal of Medicine 12: 391-403, 1919. 28. FAIRLEY NH, The discovery of a specific complement fixation test for bilharziosis and its practical application to clinical medicine. Journal of the Royal Army Medical Corps 32: 449-460, 1919

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29. FAIRLEY NH. A comparative study of experimental bilharziasis in monkeys contrasted with the hitherto described lesions in Man. Journal of Pathology and Bacteriology 23 : 289-314, 1920 30. FAUST EC, D'ANTONI JS, ODOM V, MILLER MJ, PERES C, SAWITZ W , THOMEN LF, TOBIE J, WALKER JH. A critical study of clinical laboratory technics for the diagnosis of protozoan cysts and helminth eggs in feces. American Journal o f Tropical Medicine 18: 169-183, 1938 31. FAUST EC, HOFFMAN WA, JONES CA. Life history of Manson's blood fluk e (Schistosoma mansoni). I. Extramammalian phase of the cycle. Proceedings of th e Society of Experimental Biology and Medicine 31: 474-476, 1934 32. FAUST EC, HOFFMAN WA, JONES CA. Life history of Manson's blood fluk e (Schistosoma mansoni). II. The mammalian phase of the cycle. Proceedings of th e Society of Experimental Biology and Medicine 31: 476-478, 1934 33. FAUST EC, JONES CA, HOFFMAN WA. Studies on schistosomiasis mansoni in Puerto Rico. III. Biological studies. 2. The mammalian phase of the life cycle. Puerto Ric o Journal of Public Health and Tropical Medicine 10: 133-196, 1934 34. FERGUSON AR. Associated bilharziasis and primary malignant disease of the urinary bladder, with observations on a series of forty cases. Journal of Pathology an d Bacteriology 16: 76-94, 1911 35. FERGUSON FF, RICHARDS CS, SEBASTIAN CT, BUCHANAN IC. Natura l abatement of schistosomiasis mansoni in St. Kitts, British West Indies. Public Health 74: 261-265, 1960 36. FLU PC. Beitrag zur Lösung der Frage, ob Schistosomum mansoni , identisch ist mit Schistosomum haematobium. Centralblatt für Bakteriologie, Parasitenkunde un d Infektionskrankheiten, Abteilung originale 61: 389-403, 1911 37. FOSTER R, CHEETHAM BL, KING DF. Studies with the schistosomicide oxamniquine (UK-4271). I. Activity in rodents and in vitro. Transactions of the Royal Society o f Tropical Medicine and Hygiene 67: 685-693, 1973 38. GARCÍA-PALMIERI MR, RAFFUCI FL, DÍAZ-BONNET LA, BERNAL-ROSA JF. Shunt surgery for portal hypertension due to Schistosoma mansoni . Evaluation and management in fortyone cases. Journal of the American Medical Association 171 : 268-271, 1959 39. GELFAND M. The clinical features of intestinal bilharziasis ( S. mansoni). Clinical Proceedings, Cape Town 1: 247-252, 1942 40. GIRGES R. The aetiology of "Egyptian spleno megaly". Journal of Tropical Medicine and Hygiene 35: 86-90, 99-105, 1929 41. GOLDSMITH EI, LUZ FF, PRATA A, KEAN BH. Surgical recovery of schistosomes from the portal blood. Treatment of parasitization in man. Journal of the America n Medical Association 199: 235-240, 1967 42. GREANY WH. Schistosomiasis in the Gezira irrigated area of the Anglo-Egyptia n Sudan. II. Clinical study of schistosomiasis mansoni. Annals of Tropical Medicine and Parasitology 46: 298-310, 1952 43. GRIESINGER W. Klinische und anat omische Beobachtungen. Über die Krankheiten von Egypten. Archiv für Physiologie Heilkunde 13: 528-575, 1854. Partly translated in 61 44. HARLEY J. On the endemic haema turia of the Cape of Good Hope. Medico-Chirurgical Transactions 47: 55-72, 1864. Abstracted in Lancet i: 156-157, 1864 45. HERNÁNDEZ MORALES F, MALDONADO JF, PRATT CK. The diagnosis o f schistosomiasis by a rectal biopsy technique. American Journal of Tropical Medicine 26: 811-820, 1946 46. HOEPPLI R. Parasitic disease in Africa and the Western Hemisphere. D. Helmint h infections. Acta Tropica, Supplement 10: 111-150, 1969 47. HOLCOMB RC. The West Indian bilharziosis in its relation to the Schistosomum mansoni (Sambon 1907), with memoranda on ten cases. United States Naval Medica l Bulletin 1: 55-80, 1907

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48. HUTCHINSON HS. The pathology of bilharziasis. American Journal of Pathology 4 : 1-16, 1928 49. IBRAHIM H. Combined ligation of hepatic and splenic arteries in Egyptia n splenomegaly. Journal of the Egyptian Medical Association 40: 253-269, 1957 50. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE. Opinion 735. Biomphalaria Preston, 1910 (Gastropoda): Grant under the plenary powers o f precedence over Planorbina Haldeman, 1842, Taphius H. and A. Adams, 1855, an d Armigerus Clessin, 1884. Bulletin of Zoological Nomenclature 22: 94-99, 1965 51. ITURBE J. Intermediate host of Schistosoma mansoni in Venezuela. Journal of Tropical Medicine and Hygiene 20: 130-131, 1917 52. ITURBE J, GONZALEZ E. Quelques observations sur les cercaires de la vallée d e Caracas (Première partie). Laboratorio Iturbe, pp 18, 1919. Abstracted in Tropica l Diseases Bulletin 14: 142-143, 1919 53. JORDAN P. Schistosomiasis - research to control. American Journal of Tropica l Medicine and Hygiene 26: 877-886, 1977 54. JUSTINIANO RT. Portocaval shunt in the treatment of bleeding esophageal varices due to schistosomiasis. (preliminary report). Boletín de la Asociación Médica de Puerto Rico 55: 266-270, 1963 55. KARTULIS S. Ueber das vorkommen der Eier des Distomum haematobium Bilharz, in den Unterleibsorganen. Archiv für pathologische Anatomie und Physiologie und fü r klinische Medicin (Virchow) 99: 139-145, 1885 56. KARTULIS S. Bilharzia. Lancet ii: 364, 1885 57. KATO I, MIURA M. Comparative examin ations. Japanese Journal of Parasitology 3: 35, 1954 58. KATZ N, BRENER Z. Evolução clínica de 112 casos de esquistossomose manson i observados após 10 anos de permanência em focos endêmicos de Minais Gerais. Revista do Instituto de Medicina Tropical de São Paulo 8: 139-142, 1966 59. KATZ N, CHAVES A, PELLEGRINO J. A simple device for quantitative stoo l thick-smear technique in schistosomiasis mansoni. Revista do Instituto de Medicin a Tropical de São Paulo 14: 397-400, 1972 60 KATZ N, PELLEGRINO J, GRINBAUM E, CHAVES A, ZICKER F. Preliminary trials with oxamniquine, a new antischistosomal agent. Revista do Insituto de Medicin a Tropical de São Paulo 15: 25-29, 1973 61. KEAN BH, MOTT JE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 62. KHAIRY M. Hepatic artery ligature for liver cirrhosis in Egypt. Journal of the Egyptian Medical Association 40: 396-409, 1957 63. KLOETZEL K. Mortality in chronic splenomegaly due to schistosomiasis mansoni : follow-up study in a Brazilian population. Transactions of the Royal Society of Tropical Medicine and Hygiene 61: 803-805, 1967 64. KOMIYA Y, KOBAYASHI A. Evaluation of Kato's thick smear technic with a cellophane cover for helminth eggs in feces. Japanese Journal of Medical Science an d Biology 19: 59-64, 1966 65. KOPPISAN E. Studies on schistosomiasis in Puerto Rico. VI. Morbid anatomy of th e disease as found in Puerto Ricans. Puerto Rico Journal of Public Health and Tropica l Medicine 16: 395-455, 1941 66. KUNTZ RE. Natural infection of an Egyptian gerbil with Schistosoma mansoni . Proceedings of the Helminthological Society of Washington 19: 123-124, 1952 67. LAWTON FB. The early symptoms following infection by Schistosoma mansoni . Medical Journal of Australia ii: 247-250, 1917 68. LEHMAN JS, MOTT KE, MORROW RH, MUNIZ TM, BOYER MH. The intensity and effects of infection with Schistosoma mansoni in a rural community in northeas t Brazil. American Journal of Tropical Medicine and Hygiene 25: 285-294, 1976 69. LEIPER RT. Half yearly report to the Colonial Office, May 1908. Cited in 72

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70. LEIPER RT. Letter to P. da Silva (February 1909). Cited in 18 71. LEIPER RT. On the relation between the terminal-spined and lateral-spined eggs o f Bilharzia. British Medical Journal i: 411, 1916 72. LEIPER RT. Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 30: 235-260, 1918 73. LOOSS A. What is "Schistosomum mansoni" Sambon 1907? Annals of Tropica l Medicine and Parasitology 2: 153-191, 1908 74. LOOSS A. Some notes on the Egyptian Schistosoma haematobium and allied forms. Journal of Tropical Medicine and Hygiene 14: 177-182, 1911 75. LUTZ A. Observações sobre a evolução do Schistosomum mansoni . Nota previa. Brazil Medico 30: 385-387, 1916 76. LUTZ A. Observações sobre a evolução do Schistosomum mansoni . Brazil Medico 31: 81, 89, 1917 77. LUTZ A. O Schistosomum mansoni e schistosomose segundo observações feitas n o Brazil. Memorias do Instituto Oswaldo Cruz 11: 121-155, 1919 78. MACKIE J. Bilharzia haematobia in connexion with a form of dysentery in Egypt . British Medical Journal ii: 661, 1882 79. MADDERN FC. The incidence of bilharziosis in Egypt and its clinical manifestations. British Medical Journal ii: 965-969, 1910 80. MAGALHÃES BF, DIAS CB. Esquistossomose de Manson. Estudo Memorias d o Instituto Oswaldo Cruz 41: 363-446, 1944 81. MANSON P. Report of a case of Bilharzia from the West Indies. British Medical Journal ii: 18941895, 1902 82. MANSON P. Tropical diseases. A manual of the disease of warm climates. third edition, Cassell and Co., pp 756, 1903 83. MANSON-BAHR P, FAIRLEY NH. Observations on bilharziasis amongst the Egyptian Expeditionary Force. Parasitology 12: 33-71, 1920 84. MARTIN LK, BEAVER PC. Evaluation of Kato thick-smear technique for quantitative diagnosis of helminth infections. Ameri can Journal of Tropical Medicine and Hygiene 17: 382-391, 1968 85. MARTINS A V. Contribuçã o ao estudo do gênero Australorbis Pilsbry 1934. Memórias do Instituto Ezequiel Dias 2: 5-61, 1938 86. MARTINS AV. Non-human vertebrate hosts of Schistosoma haematobium and Schistosoma mansoni . Bulletin of the World Health Organization 18: 931-944, 1958 87. MILTON F. Bilharziosis surgically considered. Lancet i: 866-869, 1903 88. MOUSA AH, EL-GAREM A, SAIF M, EL-ABDIN AZ. The significance of estimating the hepatic blood flow in hepatosplenic bilharzial cases by the radiogold clearance and uptake methods and its value in determining the extent of porta-systemic collaterals . Journal of Tropical Medicine and Hygiene 70: 55-59, 1967 89. NEL CJ, HONIBALL PJ, VAN WYK FA. Portal hypertension in schistosomiasis. South African Journal of Surgery 12: 233-239, 1974 90. NOYA BENITEZ J. Splenectomy in schistosomiasis. Preliminary report. Puerto Ric o Journal of Public Health and Tropical Medicine 23: 247-255, 1947 91. PETERS PA, EL ALAMY M, WARR EN KS, MAHMOUD AA. Quick Kato smear for field quantification of Schistosoma mansoni eggs. American Journal of Tropical Medicine and Hygiene 29: 217-219, 1980 92. PIRAJÁ da SILVA M A. Contribução para o estudo da schistosomiasis na Bahia. Brazil Medico 22: 281-283, 441-444, 451-454, 1908. Partly translated in 61 93. PIRAJÁ da SILVA M A (cited as da SILVA P). Contribution to the study o f schistosomiasis in Bahia, Bra zil. Journal of Tropical Medicine and Hygiene 12: 159-163, 1909 94. PIRAJÁ da SILVA M A. La schistosomose à Bahia. Archives de Parasitologie 13 : 283-302, 1909 95. PIRAJÁ da SILVA M A. Cited in 18

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96. PONS JA. Studies on schistosomiasis mansoni in Puerto Rico. V. Clinical aspects o f schistosomiasis in Puerto Rico. Puerto Rico Journal of Public Health and Tropica l Medicine 13: 171-254, 1937 97. PORTER A. The invertebrate (molluscan) hosts of Schistosoma mansoni and Fasciola hepatica in South Africa. Medical Journal of South Africa 16: 75-76, 1920 98. PRESTON. Annals and Magazine of Natural History 6: 535, 1910 99. REPORT OF A STUDY GROU P. Bilharzia snail vector identification and classification (Equatorial and South Africa). World Health Organization Technical Report Series, No. 90, pp 1-22, 1954 100. RITCHIE LS. An ether sediment ation technique for routine stool examinations. Bulletin of the United States Army Medical Department 8: 326, 1948 101. RODRIGUEZ HF. Schistosomal hepa tosplenomegaly. Boletín de la Asociación Médica de Puerto Rico 48: 393-403, 1956 102. SAMBON LW. Descriptions of some new species of animal parasites. Proceedings of the Zoological Society of London. No. 19, pp 282-283, 1907 103. SAMBON LW. New or little known African entozoa. Journal of Tropical Medicine and Hygiene 10: 117, 1907 104. SAMBON LW. Remarks on Schistosomum mansoni . Journal of Tropical Medicine and Hygiene 10: 303-304, 1907 105. SAMBON LW. What is "Schistosomum mansoni" Sambon 1907? Journal of Tropical Medicine and Hygiene 12: 1-11, 1909 106. SCOTT JA. Dilution egg counting in comparison with other methods for determining the incidence of Schistosoma mansoni. American Journal of Hygiene 25: 546-565, 1937 107. SHAW AF, GHAREEB AA. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza's disease. Journal of Pathology and Bacteriology 46: 401-424, 1938 108. SHIROMA M, OKUMURA M, MEIRA JA, FERREIRA JM. Cirurgia da hipertensão portal na esquitossomose mansônica hepatosplênica. Avaliação clínica de 150 casos de anastomose espleno-renal. Revista do Hospital das Clínicas; Faculdade de Medicina , Universidade de São Paulo 22: 309-337, 1967 109. SIONGOK TK, MAHMOUD AA, OUMA JH, WARREN KS, MULLER AS , HANOKA AK, HOUSER HB. Morbidity in schistosomiasis mansoni in relation t o intensity of infection: study of a community in Machakos, Kenya. American Journal of Tropical Medicine and Hygiene 25: 273-284, 1976 110. SYMMERS WStC. Note on a new form of liver cirrhosis due to the presence of ova of Bilharzia haematobia . Journal of Pathology and Bacteriology 9: 237-239, 1904 111. SYMMERS WStC. A note on a case of bilharzial worms in the pulmonary blood in a case of bilharzial colitis. Lancet i: 22, 1905 112. SYMPOSIUM DE OXAMNIQUINE. Rio de Janeiro, Brasil, Junho, 1973. Revista do Instituto de Medicina Tropical de São Paulo 15: Supplement, pp 1-175, 1973 113. TALIAFERRO WH, HOFFMAN WA, COOK DH. A precipitin test in intestina l schistosomiasis. Journal of Preventive Medicine 2: 395-414, 1928 114. TALIAFERRO WH, TALIAFERRO LG. Skin reactions in persons infected wit h Schistosoma mansoni. Porto Rico Journal of Public Health and Tropical Medicine 7 : 23-35, 1931 115. TOMB JW, HELMY MM. The diagnosis of in testinal schistosomiasis by sedimentation. Transactions of the Royal Society o f Tropical Medicine and Hygiene 25: 181-185, 1931 116. WALLERSTEIN RS. Longevity of Schistosoma mansoni: observations based on a case. American Journal of Tropical Medicine 29: 717-721, 1949 117. WARREN KS. The immunopathogenesis of schistosomiasis: a multidisciplinar y approach. Transactions of the Royal Society of Tropical Medicine and Hygiene 66 : 417-434, 1972 118. WARREN KS. Regulation of the prevalence and intensity of schistosomiasis in man: immunology of ecology? Journal of Infectious Diseases 127: 595-609, 1973

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119. WARREN KS. The pathology, pathobiology and pathogenesis of schistosomiasis . Nature, London 273: 609-612, 1978 120. WARREN KS, MAHMOUD AA, CUMMINGS P, MURPHY DJ, HOUSER H B . Schistosomiasis mansoni in Yemeni in California: duration of infection, presence o f disease, therapeutic management. American Journal of Tropical Medicine and Hygiene 23: 902-909, 1974 121. WARREN KS, REBOUÇAS G, BAPTISTA AG. Ammonia metabolism and hepati c coma in hepatosplenic schistosomiasis: patie nts studied before and after portacaval shunt. Annals of Internal Medicine 62: 1113-1133, 1965 122. WELLER TH, DAMMIN GJ. The acid-ether centri fugation and the zinc sulfate flotation techniques as methods for the recovery of eggs of Schistosoma mansoni . American Journal of Tropical Medicine 25: 367-374, 1945 123. WRIGHT CA. Tropical Diseases Bulletin 63: 862, 1966 124. ZANCAROL G. A specimen of Bilharzia, &c., with ova in the tissues of the bladder and large intestine. Transactions of the Pathological Society of London 33: 410-412, 1882. Abstracted in British Medical Journal i: 13, 1882 and Lancet i: 16, 1882

Table 9.1. Landmarks in schistosomiasis mansoni __________________________________________________________________ 1851 1882

Bilharz saw but did not recognize adult worms Zancarol and Mackie remarked that in Egyptian schistosomiasis, eggs found in the bladder had terminal spines while those in the bowel had lateral spines 1882 Mackie emphasized the dysenteric symptoms of many patients with Egyptian schistosomiasis 1885 Kartulis described schistosome eggs in the liver 1902 Manson reported a patient with schistosomiasis acquired in the Western Hemisphere; the eggs were in the stools, not in the urine, and had lateral spines 1904 Symmers described clay-pipe stem fibrosis of the liver 1907 Sambon gave the name Schistosoma mansoni to the worm producing laterally spined eggs 1916 Leiper discovered the molluscan vectors of Egyptian schistosomiasis and proved the specific identities of S. mansoni and S. haematobium 1918 Christopherson reported the efficacy of tartar emetic 1940+ Kikuth and Gönnert showed that miracil D had schistosomicidal activity in experimentally infected animals 1947 Blair, Hawking and Ross introduced therapy with miracil D 1964 Lambert and Ferreira reported that niridazole was active 1967 Pellegrino, Katz and Scherrer showed that hycanthone was effective 1973 Oxamniquine was reported by various workers to be effective in treatment 1977 Praziquantel was reported by various investigators to be effective in experimental animals 1979 Katz, Rocha and Chaves reported that praziquantel was effective in humans __________________________________________________________________

Chapter 10

Schistosoma japonicum and SCHISTOSOMIASI S JAPONICA

SYNOPSIS Common name: Oriental blood fluke, causes Oriental schistosomiasis Major synonyms: Bilharzia japonica, Schistosoma cattoi Distribution: China, Philippines, Indonesia, (Japan) Life cycle: similar to S. mansoni except that the vectors belong to the genus Oncomelania Definitive hosts: humans, dogs, cats, rodents, water buffalo, pigs, horses, sheep Major clinical features: similar to schistosomiasis mansoni; also epilepsy Diagnosis: demonstration of eggs in faeces, rectal mucosa, or liver biopsy Treatment: niridazole, praziquantel, (tartar emetic)

DISCOVERY OF THE EGG Ova of the parasite now known as Schistosoma japonicum were first discovered in 1888 by Tokuho Majima (pen-name, Naganori) in Japan when he made a postmortem examination of a man who had been suffering with ascites and peripheral oedema. Majima noted that the spleen of this patient wa s enlarged to five times the normal weight but that the liver was shrunken an d contracted. The liver, moreover, had granular nodules both on its surface and in the parenchyma amongst thickened connective tissue. When histologica l sections of the liver were prepared: It was found most surprisingly and unexpectedly that with the thickened interlobular tissue there were countless parasite eggs, and these were located only in the connective tissue....these eggs were oval....in shape and varied in size from 0.065 to 0.06 mm in length and 0.05 to 0.04 mm in diameter. The shells of the eggs did not possess small covers (opercula). There were two kinds of eggs; the first type was pale yellow in color with contents of a granular nature streaked with brownish-black pigment....The second type had only the egg shell with no contents and were, therefore, colorless and transparent.72

Majima wondered where the eggs came from, and with excellent logic bu t miserable luck, opened the bile duct and the portal vein in the hope of finding adult worms. He was unsuccessful - if he had been, he would have anticipated the discovery of S. japonicum by 16 years. Majima was not able to examine the faeces of this patient but predicted that eggs might have been found there . 263

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Finally, he explained why he had reported this case: I have set down my experience in the hope that in a parasite-ridden country like Japan, a summary of the microscopic observations and clinical record might be useful to students in the future.72

Similar eggs were found subsequently by Yamagiwa (1890) 119, Kurimoto (1893)55, Kanamori (1898) and Fujinami (1904) in various organs, especially the liver, of patients who had died in parts of Japan where an illnes s characterized by hepatosplenomeg aly, diarrhoea, anaemia, wasting, ascites and peripheral oedema was common. Some of these authors believed that the ova played a role in the genesis of this disease, as did Kawanishi (pen-name Kasai), who in 1902 was the first to find eggs in the faeces of patients 52. In April 1904, Fujiro Katsurada, professor of medicine at Okayama Medical College in Japan went to Yamanashi Prefecture Hospital and examined twelve patients with this syndrome. In five of these persons, he found ova of th e parasite now known as S. japonicum in the faeces. Although he is quoted a s saying in one paper "Until now, the eggs have been unknown to the medica l world"49 this appears to be a mistranslation for two reasons. Firstly, later in the same paper, he refers to earlier discoveries of the same kind of eggs b y Yamagiwa and Kanamori. Secondly, in a subsequent paper and translated by a different person, the following passage appears: Yamagiwa, Kurimoto, Fujinami and others observed cases in which in several organs....in cadavers from infected areas, numerous eggs of a hitherto unknown parasite were found.50

In any event, Katsurada described the eggs in detail, noting that they were oval in shape, gave their dimensions, commented upon a transparent membran e inside the shell, mentioned that the egg shells were devoid of any spine similar to that seen in S. haematobium eggs, and described the miracidium which was often seen within an egg. In one paper, he stated that the egg had a n operculum 49, but later corrected this error 50. In an attempt to find ova with morphological characteristics similar to those of these eggs, Katsurada reviewed e very known parasite and concluded that the most similar eggs were produced by the trematode, S. haematobium, but realized that the eggs he had found were shorter and had no spine. When h e studied the miracidia from his specimens and compared them with th e descriptions given for the miracidia of S. haematobium, he could discern little difference between the two parasites, except that he could find no evidence of the two large gland cells in the anterior part of the body of the miracidium that were said by Looss to be typical of S. haematobium. Consequently, Katsurada wrote "therefore, I cannot but help conclude that the egg which I discovere d and that of Bilharzia haematobium are similar, but not exactly the same" 49. For a number of years it was thought that, in contradistinction to th e terminally spined ova of S. haematobium and the lateral-spined eggs of S. mansoni, S. japonicum ova did not have a spine. In 1910, however, Leipe r examined 50 eggs from four human cases and three infections in dogs an d

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discovered by rolling them around on a micr oscope slide that a small, knob-like projection was always present 60. Evidence of the antiquity of schistosomiasis ja ponica in eastern Asia has been provided recently by finding typical eggs in human tissue. In 1971, a corps e which had been buried 2,100 years pr eviously in Hunan Province of China was exhumed and characteristic S. japonicum eggs were recovered from digested liver. Four years later, eggs were found similarly in a corpse which had been buried 100 years earlier than the previous one 75.

DISCOVERY OF THE ADULT WORMS Following his initial observations, Katsurada hypothesized that, since thes e eggs were not found in the faeces of every patient with the endemic syndrome, and as greater numbers of eggs were recovered from purged stools, it wa s unlikely that the adult worms dwelt within the gastrointestinal tract or an y lumen connected directly with it. It was more probable that the worms resided in the walls of the gut or in the visc era connected closely with it. It was obvious to him that the only way to find these parasites and clarify the pathology of the infection was to perform an autopsy on a patient with the endemic disease . Unfortunately, Katsurada had no opportunity to undertake such a post-mortem examination, but he was able to review specimens of three livers and on e intestine obtained at autopsy a few years earlier by Drs. Shimohira ( = Shimodaira) and Muramatsu. In this material, he found similar eggs. Thi s evidence, together with the observations of earlier investigators, particularl y Kanamori who had found similar ova in a rectal tumour and in a cirrhotic liver, left Katsurada in little doubt that not only was this parasite the cause of th e syndrome, but that it was most likely that the adult worms lived in the porta l venous system. As Katsurada knew that some ot her trematodes endemic in humans in Japan, such as Clonorchis sinensis and Paragonimus westermani, could also be found in cats and dogs, he killed a cat an d two dogs obtained from one of the endemic areas. He noted nothing relevant in the dogs, but in the cat, killed on 9 Apri l 1904, Katsurada found two kinds of parasitic eggs in the liver, one of whic h was the same as he had seen in human faeces an d in the specimens of liver from three human autopsies. But in addition to the ova, he found adult worms: white pieces of parasites were found in the large branch of the portal vein in the portal system. After being suitably prepared, these worms were studied microscopically. They were males, probably of the Bilharz's Schistosoma haematobia (or belonging to the same genus) and had not been seen in Japan before. 49

In June 1904 Katsurada published all his f indings to that time. He described the eggs and the male worms, and concluded tha t the eggs and worms were directly related, as a child to its parent 48. This view was disputed by a scholar of the subject, so Katsurada obtained a

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second cat from the same village (Okamada in Yamanashi Prefecture) an d found 24 male and eight female adult worms in the portal and mesenteric veins of this animal. He then described both sexes of the worm in detail, including the appearances of the eggs within the female worms, and emphasized th e differences between the parasite that he had found and S. haematobium. These results appeared in his second paper published in August 1904. At this time, he called the parasite Schistosoma haematobium japonicum : "for the time being, I want to call the parasite that I discovered, and which belongs to th e genus Schistosoma, 'Schistosoma haematobium japonicum'" 49. In October 1904, he wrote a third account, which was also published in German i n December 1904 then translated into English in April of the following year, the worm on this occasion being labelled Schistosoma japonicum 50. Katsurada's discovery was confirmed later in the same year by other Japanese workers. In May 1904, Fujinami in Hiroshima (who had earlier found eggs in the viscera of the first fatal case of Katayama disease that he had encountered), discovered a partly damaged female worm in a branch of the portal vein of a second patient who had died. He regarded this worm as a Distoma haematobium and apparently believed initially that it was the first suc h specimen to be found in Japan. In this patient, he also found the characteristic ova in the liver, intestinal wall, mesenteric glands and pancreas 33. Soon thereafter, Tsuchiya in Yamanashi found the parasite in cats, dogs an d humans109. These observations were all either unpublished or inaccessible to him in the Japanese literature when the Englishman, John Catto, discovered worms of the same type in 1904. Catto was res ident medical officer at St. John's Island quarantine station in Singapore when cholera broke out on a passenger ship from China. One of the travellers, a man from Fukien, died from cholera, but wa s noted during life to have hepatosplenomegaly. At autopsy, the rectovesica l pouch was almost obliterated by adhesions, the mesentery was thickened and contained enlarged lymph nodes, the l iver was enlarged and cirrhotic, the colon was thickened with the mucosa being swollen, hyperaemic, friable an d ulcerated, and the spleen was pigmented. Portions of the liver, mesenteri c lymph nodes and bowel were preserved and histol ogical sections were prepared in Singapore by Dr Finlayson and at the Kuala Lumpur Research Institute by Dr Daniels. These disclosed "numerous small, oval bodies having a smooth , stout capsule"17 but opinions differed as to whether they were coccidia or the ova of some unknown parasite. In the event, the case was published in th e Journal of the Malaya Branch of the British Medical Association as one of human coccidiosis. Catto then returned to England and re-examined th e material at the London School of Tropical Medicine. This time, it becam e evident that there were not only ova but also filariform larvae (? Strongyloides - author) in the large intestinal mucosa. The sections were shown at th e Medical Research Club in London but no definite conclusion was reached, so

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samples were sent to an eminent German authority who considered that the y were neither coccidia nor trematode ova, but the eggs of a nematode o f unrecognizable species. At Patrick Manson's suggestion, Catto began to section systematically all the preserved tissues. He found nematode larvae in smear s prepared from the large intestine, a minute adult nematode in an artery of the mesorectum, and a nematode larva in a mesenteric lymph node. Stimulated by these observations, and no doubt misled by the German opinion, Manson and Catto presented the case to a meeting of the British Medical Association i n Oxford in July 1904 as that of an infection with a new nematode: "The parasite would seem to be an oviparous nematode of minute dimensions and o f unknown species" 74. Catto continued his dissections and eventually found male and female adult trematode worms in the mesenteric vessels, although neither he nor exper t pathologists could be certain whether they were arteries or veins. Within th e bodies of the female worms Catto now saw ova corresponding to the ova l bodies in the viscera and realized that he was dealing with concomitan t nematode and trematode infections. Manson then sent specimens to the International Zoological Congress at Berne, Swi tzerland, where they were examined by Blanchard, Looss, Ward, Stiles, Grassi and others, all of whom agreed that the parasite was a schistosome and new to science. Catto then presented a n updated version of his findings, describing both the autopsy features and th e adult worms, to a meeting of the Pathological Society of London on 1 5 November 190416. Blanchard subsequently named the parasite Schistosoma cattoi in Catto's honour, then Catto published a detailed record of the parasite under that name in the British Medical Journal of 7 January 1905 17. Further investigations revealed the identity of this parasite with the on e described by Katsurada so, by the law of priority, Katsurada's designation , Schistosoma japonicum, stands as the correct name for this helminth. Thus, the worm was discovered independently by several workers. Faust and Melene y have placed these events in perspective well: As has frequently been the case in many important contributions to science, several workers attack the same problem contemporaneously, but without knowledge of each other's investigations. Only the circumstance of time gives one the honor which the other quite equally deserves. Such is the case with Schistosoma japonicum Katsurada.29

Katsurada in Yamanashi attacked the problem logically and systematically; he began with patients with a particular clinical syndrome, found eggs in thei r stools, confirmed their presence in the viscera of other patients, surmised that adult worms must live in the portal veno us system, found the male worm in that position in a naturally-infected cat, then pursued the quest relentlessly until he found female worms in another animal. Fujinami in Hiroshima, having earlier found the eggs in another of his patients, was beaten to the punch by a mer e month or so, but was without doubt t he first to find the female adult worm, and the first to find an adult schistosome in a human being. Finally, Catto i n

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Singapore and England, and completely unaware of the Japanese discoveries, was tenacious enough, after meandering dow n several false alleys, to eventually find adult worms a matter of several months after the Japanese researchers . Furthermore, although the exact time sequence is unclear, it is probable tha t Catto, or possibly Tsuchiya in Japan, was the first person to find male adul t schistosomes in a human being.

DISCOVERY OF THE PERCUTANEOUS ROUTE OF INFECTION When the adult forms of S. japonicum were discovered, it was clear that th e infection must be transmitted in a fashion similar to that of S. haematobium. But, as already discussed in chapter 8, the life cycle of that parasite too wa s quite obscure, with protagonists of the direct infection theory and th e intermediate host school each ardently defend ing their own particular view. The speed with which the Japanese investigators worked out the life cycle of S. japonicum is little short of remarkable, considering that it took only nine years from Katsurada's discovery of the adult worms until Miyairi and Suzuk i demonstrated transmission through snail intermediate hosts. This contrast s starkly with the 64 years between Bilharz's discovery of S. haematobium and Leiper's elucidation of the life cycle of that worm - and that largely followed the precedent set by the Japanese. In defence of the European investigators , however, it must be remarked that two factors worked in favour of the Oriental scientists. Firstly, Miyairi and Suzuki found snails susceptible to infection and naturally infected with S. japonicum at almost their first attempt, whereas a number of European investigators examined many different species with a conspicuous lack of success. Secondly, although animals can be infecte d experimentally with S. haematobium and S. mansoni, occidental schistosomiasis in nature is principally a disease of humans. Oriental schistosomiasis, on the other hand, is a major zoonosis with humans and animals being equally infected; this was known as early as 1847 for Fujii then wrote that even th e cattle and horses were not immune to the affliction 32. This facilitated research enormously for simple animal models were th erefore available for experimental elucidation of the life cycle. Fujinami recognized this when he looked back on the early years of schistosomiasis research in Japan: animal experiments have been easily carried on, as the subjects of the experiment could be infected by immersing them in water of the ditches in the endemic area. The animal experiments have led to the solution of many interesting problems in the pathology of the disease.34

Animal experimentation was indeed the key to success, but the key had first to be found. It was Fujinami himself, in collaboration with Nakamura, a n assistant professor of pathology at Kyoto Unive rsity, who made the fundamental discovery. Because the adult schistosomes lived in the portal venous syste m and were often found in the intestinal wall, many Japanese investigators thought

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it likely that infection was acquired via the gastrointestinal tract, possibly by the ingestion of worms in contaminat ed water. On the other hand, the development of leg rashes and subsequent disease in farme rs working in rice fields suggested that infection might occur through the skin. Fujinami and Nakamura therefore devised an experiment to test the various hypotheses. They decided to use cows since these animals were not onl y susceptible to infection, but they were also large and docile enough to be made to stand in water with only the hooves be ing soaked and without water touching the anus and genitalia, thus avoiding the possibility of infection via the mucous membranes of these organs. They used 17 cows up to one year of age an d which had been obtained in Hiroshima ci ty where the infection was absent. The experiment was begun on 7 June 1909 with the beasts being divided into a number of groups. The first gr oup of six calves was given only boiled food and water, and except on these occasions, th eir mouths remained covered. Each day they were taken out of the barn and stood in water, three of them in the mud of a rice paddy and the other three in a river which received great volumes o f water from the rice fields. All of these animals became infected with S. japonicum, but much larger numbers of adult worms were found in the cows that had been allowed into the rice fields. A second group of seven calves had their legs washed with soap and alcohol, then oiled and covered wit h water-proof, protective leg bags. Four o f these animals ate and drank in the rice fields, while three of them were taken to the river banks to feed. Six of these cows remained uninfected, and a solitary worm pair was recovered from th e seventh animal. A third group of two cows was fed and watered like the first group. One cow was confined to the barn; no infection developed. The other animal was placed in an irrigation canal for nearly five and a half hours on one day only, nevertheless, it became infected with 31 worms. Finally, no special measures were taken for a fourth group of two cows which were permitted to roam freely; both animals became infected. Fujinami and Nakamura therefore concluded that infection was acquired by penetration of the skin 35,36: The great difference between the findings for group A and B is obvious - like snow and charcoal - and we feel that the problem of the mode of entry of the infection, which has vexed scientists for so long, has at last been incontrovertibly solved" 35

Further, they deduced that infection could be acquired easily in a short space of time by contact with contaminated water, but that the risk of infection was greater in the stagnant waters of the paddy fields and small irrigation canal s than in the fast-flowing waters of the rivers. The two researchers found schistosome s in different stages of growth in most animals. One cow, however, had been exp osed on only one occasion, and when it was killed 26 days later, small mal e and female worms were found in copula. Although no eggs were detected, this observation led Fujinami and Nakamura to write that: "the time required for the parasite to grow is comparativel y short"36. This conclusion was verified by experiments which they undertoo k

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concurrently with dogs. These animals were kept secluded in cages an d provided with uncontaminated food and water. At various intervals, they were allowed outdoors into the rice fields and river. They were killed 23 or 54 days later. In the dog killed after 23 days, small (4-5 mm) but mature male an d female worms in copula were found, but again, no eggs were seen. In the dog killed 54 days after infection, schistosomes 1 .0-1.3 cm long were recovered and the female worms contained eggs. Similar results were obtained with rabbits, and when the results from the three spec ies were compared, it became apparent that ova were first produced five to six weeks after exposure, with egg s appearing in the faeces shortly thereafter. Thus, Fujinami and Nakamura proved that infection occurred via the skin , but they recognized that how it happened, and the nature of the antecedent and subsequent events still remained unclear: The life cycle before they (adult worms) are found in the portal circulation is not yet known. The connection between the small worm (miracidium) which during the warm season leaves the egg shell which had been deposited in the soil and water and the very young, immature worms in the portal vein must await serious study in the future.36

The demonstration by Fujinami and Nakamura that infection was effected by penetration of the skin was confirmed later that year by Katsurada an d Hasegawa who, in another district of Japan, infected a dog and a cat. It was also demonstrated unexpectedly by Matsuura who had the misfortune to becom e infected accidentally while wading in foul water. As will be discussed later , microscopical confirmation of t he direct penetration of the skin by schistosome larvae, albeit of uncertain specificity, was provided in 1912 by Miyagawa 81.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE LARVAL STAGES AND THE SNAIL INTERMEDIAT E HOSTS The answer to the part of Fujinami and Nakamura's question concerning th e events leading up to percutaneous infection was provided four years later b y Keinosuke Miyairi and Masatsagu Suzuki, both of Kyoto University. They published their results first in Japanese in 1913 86 (an English abstract of this paper appeared in the March 1914 issue of the Tropical Diseases Bulletin ), then a German version was published in 1914 87. It had been known for a number of years that when eggs hatched, miracidia were released. In 1904, Kawanishi had reported that when: provided with a little warmth, it (the larva) immediately comes out of its shell....When they first leave the shell, the larvae look like wine bottles. After one day they become larger and assume many different shapes.52

Consequently, Miyairi and Suzuki began wi th the question as to what happened to schistosome ova deposited in animal and human excrements in the open air.

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They found a small ox infected with schistosomes which provided a constant source of material for their exper iments. First, they observed the motions of the miracidium within each egg, then they studied the hatching of the larva. At a village called Kisi-mura of Miyoki-gun in Saga Prefecture, they found S. japonicum eggs in human faeces left on the roadside. They therefore searched carefully in the surrounding area and eventually: succeeded in finding a certain species of snail in a little ditch by a rice field in the village. The snail which apparently had no lungs had a brownish yellow shell which was very smooth on the surface and was turning in a clockwise direction. The shell could be easily crushed and had seven whorls....As amateurs, we couldn't tell the exact name of the snail.86

Miyairi and Suzuki collected these snails and kept them alive in receptacle s containing fresh water and cabbage leaves. They then took young snails which proved to be free of naturally-acquired infect ion and mixed them in a basin with miracidia freshly prepared from S. japonicum ova. They described graphically the subsequent course of events: The way a fresh miracidium rushes up to its host can be compared to that of a hungry tiger coming out his cage to hunt for something to eat" 86. The miracidia attached themselves to the free body surface of the snails then penetrated to the interior: the animal (miracidium) makes its head sucker as thin as possible, pushes it between the snail's epidermal cells, and stretches its cylindrical body as long as possible. With a jerk it pulls itself together so that the base of the inserted proboscis cone and the epidermal slit becomes wider. Repeated efforts, alternate stretching and contraction of the body, push the cone further and further inside. 87

Miyairi and Suzuki were uncertain how each miracidium lost its ciliar y covering but noted that the larvae tended to congregate in the gills, the wall of the digestive organ, the salivary glands and near the nerves. The parasites then became immobile and transformed in to small, spherical sporocysts which grew daily. By twelve days after infection, Miyairi and Suzuki found secon d generation sporocysts (they called them rediae) within the primary sporocysts: the redia is a strange animal which, in open movement, can stretch out then contract again into an oval form....Its head is thickly covered with fine spines. The mouth is often wide open as though the animal intended to bite something. Very little can be seen of the digestive tract. The entire abdominal content consists of rather large, pale cells which, in the course of time, divide to form large and small cell aggregates. 87

The secondary sporocysts migrated into the liver where they grew lengthwise. Seven weeks after infection of the snails, Miyairi and Suzuki found cercariae within the secondary sporocysts. They wrote that "a cercaria is provided with a powerful caudal tail and this is split, in its distal third, into two parts. Th e body and the caudal tail are covered with spines" 87. then went on to provid e details of the anatomical organization of the cercaria. The next step was to complete the life cycle of the worm by infecting mice with these cercariae. Attempts to infect mice with cercariae raised in snails in the laboratory were unsuccessful, so Miyairi and Suzuki used older, naturallyinfected molluscs. These snails had three types of cercariae, one of whic h

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resembled those raised in laboratory snails exposed experimentally to S. japonicum miracidia. A mouse was placed together with the snails for three hours each day for three days. Three weeks later, the mouse was killed by anothe r mouse, but on examination, the investigators found male and female schist osomes in its internal organs. This experiment was repeated on a number o f occasions with more mice, and they were always found to be infected. Thus, Miyairi and Suzuki were able to demonstrate that a certain species of mollusc was naturally infected with the larval stages of a worm which matured into adult S. japonicum in experimental mice. Further, they were able to infect clean snails with miracidia obtained from S. japonicum eggs and produce these same larval forms. Although they did not complete the whole life cycle with the same worms under laboratory conditions, there was nevertheless no doubt that Miyairi and Suzuki had found an intermediate host and had described th e various stages of metamorphosis and reprod uction of larval S. japonicum. They were unable to identify the snails exactly, but concluded that the mollusc s probably belonged to the family Hydrobiidae, remarking that precise species identification must be left to the specialist. At the same time as Miyairi and Suzuki were ca rrying out their studies, Miyagawa was working independently on the same prob lem. By a series of exclusion experiments, he identified in snails the fork-tailed cercariae which developed into adult schistosomes in experimental animals. Moreover, he demonstrated the much closer morphological relationship between these latter two stages of the parasite than between the miracidium and the cercariae 81-83. It has been remarked that Miyairi received none of the international honours he deserved89, but the same cannot be said, on this occasion at least, for Robert Leiper. On 20 February 1914, Leiper and Staff Surgeon Edward Atkinson of the Royal Navy left London for eastern Asia accompanied by an editoria l fanfare in the Journal of Tropical Medicine and Hygiene : The departure of the expedition....is an event which must prove of considerable scientific importance....The primary object of the expedition is to ascertain the mode of spread of the trematode diseases of man.3

Leiper and Atkinson arrived in Shanghai at the end of March and were granted good laboratory facilities. This site had the added advantage of providing them with ready access by road and water to endemic areas of schistosomiasis. They investigated a number of parasites including Clonorchis, Metagonimus, Diphyllobothrium, Echinochasma, Metorchis, Fasciolopsis and Ancylostoma, but their main attention was centred on S. japonicum 61. Their first objective was to find a patient with schistosomiasis who could provide them with a steady source of eggs for experiments, but despite travelling 1,000 miles b y boat, train and rickshaw over the space of three months, they failed to find a suitable and cooperative person. By this time, unfortunately, the two principal players, Leiper and Atkinson, had fallen out. Nelson, in his entertaining review of this affair, quotes passages of letters written by Atkinson to Cherry-Garrard,

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a zoologist who was to have worked with them: I don't really think old chap that you can fully realise how perfectly damnable this man can be. This fellow has really been too damnable for words. I ought to give him a sound thrashing, tell him what he is for the good of his soul and then leave him.5

In the event, Leiper and Atkin son gave up their search for infected humans and borrowed a dog, the faeces of which were loaded with S. japonicum eggs, from a customs officer in Yanchow. They used miracidia hatched from these eggs to infect all the available local snails, an experiment which they termed th e "blunderbuss method". None of the molluscs, however, were attractive to the larvae. Impatient with the tardiness of their progress, Leiper set off for Japan where he first visited Fujinami, then journeyed to Katayama and collected a batch of snails to take back with him to Shanghai. On his return to China, he tested the snails with S. japonicum miracidia and found that one species, the same as that of Miyairi and Suzuki, showed an extraordinarily marke d attraction for the miracidia. This snail was identified subsequently by G C Robson of the British Museum as a species of a new genus of hydrobii d mollusc which he named Katayama nosophora 95. Furthermore, Leiper an d Atkinson found the liver of these snails "ramified with long intertwinin g delicate tubes bluntly rounded at the extremities and containing cercariae with bifid tails"63. They believed that these tubes were not rediae but secondar y sporocysts. Encouraged by this success, Leiper returned to Katayama an d collected another supply of these molluscs. Many died on the return journey , but sufficient survived to provide cercaria e with which to infect laboratory-bred mice. Meanwhile, however, World War I had b roken out, so the expedition was aborted and Leiper and Atkinson returned to Britain with their specimens. Most of the mice died before Hong Kong was reached, but in one putrescent animal, a single male schistosome was found. At Aden, the few remaining snails were sacrificed and used to infect the last remaining mouse. One month later, male and female worms in copula were found in the portal vessels at autopsy i n London. This led Leiper and Atkinson to conclude in their report published in January 1915: The marked attraction of the mollusc for the miracidium, the peculiar morphological characters of the cercaria and the successful infection of a laboratory-bred mouse from cercariae obtained from Katayama molluscs after several weeks' captivity at sea leave no room for doubt that the schistosome has a life-cycle similar to that of other trematodes.63

It has been suggested that one of Atkinson's main quarrels with Leiper was over scientific priority. Nelson has postulated that the publication of tw o papers, with Leiper as senior author, on t he parasites that Atkinson had brought back from Antarctica may have started the row between the tw o parasitologists 89. Similarly, Atkinson may have felt that Leiper gave insufficient credit to the pioneering work of the Japanese scientists with inadequat e

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reference to them in his publications. Thus, in their paper of January 191 5 (which was probably written largely if not entirely by Leiper as Atkinson was on active service), there is only a sketchy outline of the Japanese discoveries and no specific references are given. Concerning Miyairi and Suzuki's work, it is merely recorded that there is a note in a paper by Katsurada in December 1913 "to the effect that he is informed in a private letter from a colleague that Mr. Miyairi of Kiushu had just found a reproductive stage of Schistosoma in a Lymnaeus species"63. Indeed, the paper concludes: It would appear that the above results confirm Miyairi's main conclusion as to the transmission of Schistosoma japonicum. Unfortunately, his paper is inaccessible....The only information at present available to workers is an annotation by Kumagawa in the Tropical Diseases Bulletin for March 30th, 1914. 63

Nelson has written that it must have been a great shock to Leiper when h e visited Fujinami in Japan and the latter revealed to him the full details of th e work of Miyairi and Suzuki. It seems quite likely, however, that Leiper knew more about this work, even bef ore he left for the Far East, than he let on. In the Tropical Diseases Bulletin of March 1914 (p. 290), Leiper provided a n abstract of the paper by Katsurada of December 1913 in which Miyairi an d Suzuki's work is alluded to. More imp ortantly, the preceding abstract, prepared by Fleet Surgeon Kumagawa of the Tokyo Naval Medical College, wa s concerned with Miyairi and Suzuki's definitive paper written in Japanese; this abstract was referred to with the words "see above" in the text of Leiper' s abstract (although it is possible that the comment was inserted in an editorial capacity by someone else). Further, Leiper in the 1915 paper with Atkinso n made no mention of the German version of Miyairi and Suzuki's pape r published in 191487; it seems inconceivable that he did not know of it s publication, particularly as he had discussed the Japanese investigators ' observations with Fujinami who would have known of its imminent or actual publication. Finally, no ment ion at all was made of the Japanese studies among the 532 references on schistosomiasis that Leiper published in 1915 i n connection with his studies of the life cycle of S. haematobium. Leiper may have been stung by such complaints as those attributed to Atkinson, for three years later, in the final part of his report on his studies of S. haematobium in Egypt, he harked back to his Japanese experience and took some pains t o emphasize what he then felt had been his main contribution and the guidin g principle behind the establishment of the expedition to the East: a morphological clue might be established by which the bulk of cercariae of unknown origin could be excluded microscopically; thus bringing the experimental use of monkeys (for infection with S. haematobium) within practical limits.62

This morphological clue, he suspected, might be the absence of a muscula r pharynx in schistosome cercariae compared w ith cercariae of most other flukes, for adult schistosomes, in contrast to these trematodes, had no pharynx. In this surmise Leiper was right, and he then went on to acknowledge the work o f Miyairi and Suzuki (but, again, without giving a reference), and reiterated the

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importance of the morphology of the cercaria for his own studies of the lif e cycle of S. haematobium: In the meantime, however, Miyairi and Suzuki....had succeeded by another method of approach in tracing the metamorphosis in a closely allied, if not identical, snail in the South Island of Japan. My own observations therefore confirmed generally the results of these workers, apart from establishing my chief, ulterior object, which was to provide a simple and reliable means of attacking the complex problems of B. haematobia.62

The life cycle of S. japonicum was then confirmed in another geographical area by S. Yokogawa. In February 1914, adult schistosomes were found in a pig in Taiwan, then subsequent surveys disc losed them in dogs, pigs, goats, and cattle. Yokogawa therefore collected snails and examined them for cercaria e resembling those described by Miyairi. Eventually he succeeded in finding an infected snail, obtained the cercariae and rubbed them on to the skin of a rabbit. Eighteen days later, he killed the animal and recovered young schistosomes 5 mm long from the portal venous system 122. Many years later, Hsü and Hs ü showed with human volunteers that the Formosan strain of S. japonicum is a non-human, zoophilic strain wh ich develops for a short period in the viscera of humans but does not reach maturity 42. Attention then turned to China when Faust and Meleney investigated schistosomiasis and its transmission on the Chinese mainland. Their first step was to obtain some snail vectors, known at that time as Blanfordia nosophora , from S Yoshida in Osaka, Japan. In February 1922, they showed that these snail s were susceptible to S. japonicum miracidia from a Chinese patient whereas the usual molluscs in the Peking area, including Viviparus, Planorbis and Lymnaea species could not be infected. Fa ust and Meleney therefore postulated that the same or a similar species of mollusc must be the intermediate host in China. In August 1922, Meleney found some similar snails near Soochow in the lower Chang Jiang (Yangtze) Valley on river banks near the water's edge and on water grass stalks. When dissected in the hospital laboratory, 28% of these snails (which were identified subsequently as Oncomelania (Hemibia) hupensis by Bryant Walker of Detroit, Michigan, USA) contained schistosome cercariae. These cercariae were then used to infect laboratory mice and S. japonicum adult worms were eventually obtained 78. Another batch of snails which was not naturally infected was infected under experimental conditions with S. japonicum miracidia of Chinese origin and the metamorphoses of the larvae were observed. Cercariae, which were produced nine weeks afte r exposure of the snails, were used to infect experimental dogs 28. Finally, O. hupensis was infected successfully with S. japonicum of Japanese origin 27. In 1932, Tubangui demonstrated that a snail identified by J Bequaert o f Harvard University as Blanfordia quadrasi (now known as Oncomelania quadrasi) was the intermediate host of S. japonicum in the Philippines 111. Meanwhile, in an appendix to Faust and Meleney's monograph o n schistosomiasis japonica which appeared in 1924, Nelson Annandale of th e

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Zoological Survey of India and the Indian Museum, Calcutta, had reviewed the status of the molluscan intermediate hosts of S. japonicum. He concluded that there were three species which transmitted the worm, nosophora, formosana and hupensis, all of which belonged to the genus Oncomelania Gredler 1881, which was quite distinct from the genus Blanfordia 2.

STUDIES OF THE MIGRATION AND DEVELOPMENT OF LARVAE Once Fujinami, Nakamura and others had shown that infection was acquired by the percutaneous route, Yoneji Miyagawa turn ed his attention to both tracing the route of migration of the worms from the skin to the portal venous system, and determining the structures of the various developmental forms. He went to Yamanashi province of Japan in the summer of 1911. Initially, he looked for worms in the portal venous blood. Experimental animals, especially dogs and rabbits, were immersed in water in areas where the disease was rampant, then he collected blood between two and twenty four hours later. In these samples, Miyagawa managed to find schistosomula. He then identified similar worms in the skin and concluded that they had penetrated the skin partly directly an d partly via the hair follicles, then entered the vascular system and possibly the lymphatics, and were carried to the portal veins. He examined the anatomy of these skin worms in detail and compared them with adult worms in the portal vein and free-living miracidia, and found that they resembled adul t schistosomes more than miracidia. This led him to conclude (before Miyair i and Suzuki's proof) that the change in appearance must have occurred in a n intermediate host: On comparing the youngest described worms with the miracidia originating from eggs, I found a considerable difference. I assume, therefore, that S. japonicum very probably has an intermediate host.81

In a subsequent study, Miyagawa reported that he had found schistomula i n thoracic duct lymph of infected dogs and in the draining lymph nodes. Because of the paucity of numbers of worms in the lymph, however, he believed tha t most worms passed directly via the bloodstream 82. Soon afterwards, Ogat a made use of Miyairi and Suzuki's discovery t o confirm Miyagawa's findings. He applied cercariae to the skin of experimental animals and observed thei r passage through the integument via the bloodstream to the lungs 91. Two schools of thought then arose as to the means by which worms reached the portal system from the lungs. Narabayashi proposed that the parasite s entered the pleural space then passed through the diaphragm to the liver and portal circulation 88. He was supported in this view by Suyeyasu who studie d serial sections of mice 104, but Miyagawa and Takemoto contended tha t schistomula left the lungs via the systemic arterial circulation and were carried to the gastrointestinal tract where they then found their way to the porta l

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venules. Miyagawa and Takemoto based this view on their failure to fin d worms penetrating the diaphragm or in the liver parenchyma, wherea s parasites were seen in the intr ahepatic blood vessels of experimentally infected animals84. Shortly thereafter, Cort examined the development of these worms in detail. He noted that soon after penetrating the skin, the tail of the cercaria was los t and the cephalic glands dege nerated. By the twelfth day, the majority of worms had reached the liver. There was little increase in size until the larvae reached this organ, although the digestive system became more organized and the oral sucker assumed its adult character. Cort was unable to distinguish between the sexes in the earliest liver stages, but began to discern differences when the y reached 0.3-0.4 mm in length. Growth continued after sexual maturity but at a slower rate. As growth continued, he observed that the body of th e female worms became rounded on cross-section while that of the male worms flattened gradually and the sides grew up to form the gynaecophoric canal. Pari passu with these events, the suckers grew and the digestive system becam e horse-shoe shaped and distended with food. Differentiation of th e reproductive organs came relatively late and they only became clearl y distinguishable when the male and female worms attained lengths of 1.5 an d 2.0 mm, respectively 22. A year or two later, Meleney and Faust re-examined both of these aspects . They observed the process of invasion by cerca riae, noting that during invasion, if not before, the tail of the organism dropped off, and determined that invasion might be effected within several hours but could take up to two days. Within two to three days of exposure of e xperimental animals, most schistosomula had reached the lungs. Although a few worm s were side-tracked in heavy infections and reached the pleural cavity where they degenerated, most larvae passe d through the lungs into the systemic circulation. Meleney and Faust agreed with Miyagawa's contention, for they recovered worms at this stage of the infection, not only from mesenteric artery, but also from the renal, splenic and a variety of peripheral arteries79. They found that those worms which reached the portal venous system were able to grow and develop, with sexual differentiatio n occurring as early as the seventeenth day, although sexual maturity was no t reached until after four weeks. By this time, the worms had migrated retrograde from the liver to the distal mesenteric venules where they laid eggs 28,29. In 1932, Goto attempted to settle the argument over the two routes of migration. He found that washing out of the organs and tissues of dogs infected with S. japonicum supported the systemic arterial migration theory of Miyagawa and Takemoto while serial sections of decalcified mice indicated direct migration as espoused by Narabayashi and Suyeyasu. Consequently, Goto concluded that the results obtained depended upon the technique used 39. Once within the portal system, worms may live for many years, continuing infections being reported 32 years 76 and 47 years40 after the last possible

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exposure.

CORRELATION OF INFECTION WITH PATHOLOGY The pathological changes produced by S. japonicum were recognized by Majima simultaneously with his discovery of the eggs in 1888. The gros s morbid anatomical changes he found have already been alluded to, as has his description of the ova. In addition, however, Majima provided a luci d exposition of the histological appearances, emphasizing that the eggs occurred only in the portal tracts and not within the lobules, discussing the inflammatory infiltration, and remarking upon the interlobular fibrosis: these parasite eggs....were in peculiar locations in the connective tissues, mostly with great numbers of eggs in large groups. Around the ends of these groups of eggs....a marked infiltration of round cells was observed....There were indications in various places of a new interlobular connective tissue; in these areas with increased interlobular connective tissue there was marked round cell infiltration as well as swelling and proliferation of the bile ducts....Because of the pressure by the new connective tissue, atrophy was seen likewise in a small number of cells. 72

Katsurada in 1904 described the pathological consequences of infection in both the liver and intestine, and remarked upon the absence of lesions in th e rectum. He concluded that female worms released eggs which embolized t o several organs where they excited inflammation and fibrotic reactions. Wit h respect to the liver, he wrote: "In consequence of this the liver sooner or later shrinks, and a kind of cirrhosis results, whereby the capsule of the live r becomes granular, thickened and irregular" 50 and concerning the bowel , Katsurada remarked: in most cases, eggs are found in the intestinal mucosa and submucosa, especially in the large intestine. The deposition of eggs induces more or less severe inflammation, which leads in parts to tissue disturbance, in parts to tissue growth; infiltration in the bowel wall follows, and that frequently terminates in ulceration of the mucous membrane.50

These features were reiterated by Catto who described deposition of ova, not only in the liver and large intestine, but also in the gall bladder, mesentery and small bowel, and wrote that "Where ova accumulate they provoke at certai n places a small-celled infiltration, wh ich gives place later to a great proliferation of fibrous tissue" 17. In 1924, Faust and Meleney reviewed the p athological anatomy 29. They noted that the invading cercariae produced a local reaction in the skin characterized histologically by oedema, congestion and leucocytic infiltration. In thei r passage through the lungs and later i n the gut, the chief lesions produced by the young worms were haemorrhages. In massive infections, there was hepati c parenchymal cell necrosis and degeneration of the convoluted tubules of th e kidneys, presumably as a result of released toxins. Polymorphonuclea r

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leucocytes, and particularly eosino phils, congregated around eggs in the tissues and abscesses formed; these tended to break outwards by small openings into the intestinal mucosa. Thrombosis of the lar ger mesenteric and portal veins was frequently seen in later cases. In the liver, there was, in addition to th e inflammatory lesions produced by degeneration of eggs, a general pipeste m fibrosis. The spleen varied in size, but was sometimes hypertrophie d enormously. Faust and Meleney were unimpressed by lung lesions, but noted that eggs might sometimes be seen in the brain.

RECOGNITION OF THE CLINICAL FEATURES Japanese clinicians became aware gradually of a syndrome characterized b y hepatosplenomegaly, diarrhoea, anorexia, gen eralized oedema and anaemia that was endemic in certain parts of the country. It was particularly prevalent in a village named Katayama, and was, on that ac count, sometimes known as Katayama disease, the villagers ascribing the condition to a lacqueur said to hav e been released from a ship wrecked nearby in a storm years before. The first recorded clinical description of schistosomiasis was by a physician, Dairo Fujii (pen name, Yoshinao), who visited the region in 1847 and wrote a report which remained largely unknown for man y years. It was eventually found in the possession of a descenda nt, Yaekichi Fujii, and Fujinami arranged for its publication. Fujii did not know what type of disease it was, but described the initial cutaneous manifestations, considered the onset as being not unlike that of consumption (wasting disease, tuberculosis, although that infection was not yet defined bacteriologically), and concluded that in its terminal stages, th e condition was really an "abdominal swelling": the native people who waded in the water to till the fields developed on their lower legs small papules which were extremely pruritic....the clinical manifestations in severe cases - pallor, sunken yellow facies, night sweats with muscle wasting, a rapid and feeble pulse - were similar to those of consumption. Some people had watery diarrhea and some had tenesmus. Others had a bloody or mucoid diarhhea. Later wasting of the extremities occurred and the abdomen became swollen, like a drum. Below the breasts the abdominal veins were dilated and the umbilicus herniated outward. In advanced cases, the abdominal skin became shiny, even reflective, anasarca usually ensued and the patient died.32

In the early 1880's, Erwin Baelz, a German professor at the Imperia l University of Tokyo, visited the endemic area at Okayama. He found that 20% of the population were afflicted with hepatosplenomegaly, bloody diarrhoea , anaemia, fever, ascites and oedema. Baelz attributed these findings t o Clonorchis sinensis 6, although it now seems much more likely that he wa s dealing with schistosomiasis japonica. Nearly sixty years after Fujii's visit, and being aware of his memoir, Kenj i Kawanishi (Kasai) visited Katayama. He too was familiar with the skin rashes,

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and noted that cows and horses were also affected, writing "Persons who g o into the mud immediately develop red rashes; the associated pruritis (sic) i s said to be unbearable" 52. He then went on to state that the signs of Katayam a disease were "(an) enlarged liver and spleen, sometimes abdominal ascites , anaemia and bloody stools" 52. Although the relationship betwen schistosomiasis japonica and skin rashes was fairly striking, there were some dissenters. For example, Miyagawa (1913) discounted the association on a number of grounds, including variations i n geographical distribution of the two conditions, differences in the histological appearances of the skin, and the absence of eggs in the faeces of many patients with dermatitis 83. In various parts of China, a syndrome of fever with urticaria had been recognized from time to time. This condition was known as Yangtze Fever, Hankow Fever, Kiukang Fever and Urticarial Fever, dep ending upon the region in which it was observed. In 1910, Houghton at Wuhu Hospital in China associated this syndrome with S. japonicum infection69, then this opinion was supported b y other observers. In 1913, Edgar gave an excellent description of the syndrome which usually afflicted children or young men who bathed in creeks or waded in marshy ground in the Chang Jiang (Yangtse) valley; the condition wa s particularly well-recognized in foreign seamen. According to Edgar, malaise was followed by headache, myalgia and fever which was remittent in character and lasted for three to six weeks. Half of the cases had transient or persistent urticaria, and many complained of cough and transitory diarrhoea whic h sometimes developed into dysentery. The illness usually settled down withi n two to three weeks 26. This description was reiterated in the following year by Laning wh o described two further stages in the evolution of the disease 56, a classification which was also adopted by Mann 73. The next stage of illness was associate d with hepatosplenomegaly, dysentery, marked eosinophilia, and the passage of S. japonicum eggs in the stools. A terminal stage which may or may no t supervene was typified by a: cirrhotic liver, sometimes enlarged, sometimes shrunken, ascites, oedematous extremities, marked emaciation, anaemia, weakness, passage of blood and mucus in the stools.56

Interest in the clinical manifestations of schistosomiasis japonica by Western clinicians was rekindled when a number of troops became infected during the invasion of Leyte island in the Philippines in 1944. A number of series o f patients were reported, and these descriptions generally followed the patter n described thirty years earlier in China 30,45,107 With respect to prognosis, it had been apparent from the early times that the severity of illness seemed to be dependent upon the intensity of infection. Longterm observations of expatriates infected in China before and around Worl d War I, and of Allied troops infected in Southe ast Asia during World War II, and who were then removed from the endemic area, indicated that the prognosi s

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was probably good in the absence of reinfection. Whether or not significan t resistance to reinfection develops is uncertain, although Vogel and Minning in 1953 reported that complete resistance to reinfection could be built up i n experimental monkeys infected repeatedly with S. japonicum 116.

DEVELOPMENT OF DIAGNOSTIC METHODS The simplest means of diagnosing schistosomiasis japonica, that is the demonstration of the pathognomonic eggs in the stool, was discovered before th e causative agent was found. Thus, in late 1902, or possibly in early 1903 , Kawanishi discovered what he regarded as a new type of egg in the faeces of a patient from near Katayama. This patient had the typical syndrome common in that area: In the stools.....I found oval-shaped light brown colored eggs, 0.1-0.08 mm in length and 0.077-0.05 in width.....an operculum is not found. The eggs vary in content. 52

Kawanishi therefore went back to the endemic area in March 1903 and found several more patients excreting the same eggs. The value of this diagnosti c technique was confirmed by Katsurada 49,50 in 1904 when he found eggs in the faeces of five such patients and then went o n to discover the adult worms. Since that time, considerable attention has been paid to improving techniques fo r demonstrating and quantifying eggs in faeces (see chapter 9). The introduction of sigmoidoscopy provided a means of assessing structural damage to the large bowel and permi tted an alternative method of finding eggs. Thus, Johnson and Berry (1945) reported that small yellow nodular lesion s could be seen on sigmoidoscopy, particularly at the rectosigmoid junction, and that biopsy of these lesions revealed the presence of the characteristic eggs 45. Diagnosis of schistosomiasis japonica by liver biopsy, which also provides an assessment of structural damage in the live r, appears to have been first reported by Stransky and Pesigan in 1953 101. Later, Kurata showed that liver functio n tests may provide an index of hepatic damage 54. Many attempts have been made to dev elop immunodiagnostic procedures for use in schistosomiasis japonica. In 1910, Yoshimoto was probably the firs t person to introduce a complement fixation assay 123, while Miyairi and Imai in 1928 described a precipitin test 85. In 1936, Kan described an intradermal test 46.

THE SEARCH FOR EFFECTIVE TREATMENT Details of the development of drugs which have been used in the therapy o f schistosomiasis japonica have been described in chapter 8. Initially, quinine 110 and arsenicals were tried, particula rly in Japan, but these drugs did not pass the test of time and proved of little use. In 1913, Hutcheson reported that emetine

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was useful in patients with dysentery 43. In view of the efficacy claimed for the drug in other forms of schistosomiasis, there may have been some activit y against S. japonicum, but it is also possible that the patients had concurren t amoebic dysentery which responded to the drug. There was dispute over th e effectiveness of emetine during the next few years 51,94,112, but interest in it largely waned in favour of tartar emetic. Following the introduction of antimonials for the treatment of schistosomiasis in Africa, the drug was tried in Chin a and Japan against S. japonicum. In 1921, Sanders and Priston reported that intravenous injection of antimony was efficacious in three patients; there was a great reduction in the numbers of ov a excreted and those that were present in the faeces were not viable 97. On the other hand, Libby, in a small series of cases, found that tartar emetic was not particularly active and this led to suggestions that this drug was less effective in schistosomiasis japonica than in other forms of human schistosomiasis 65. In a later and more extensive study, the same author concluded that while tartar emetic was useful in mild and moderate cases, it was of little value for patients with severe infections where there was hepatosplenomegaly 66. Nevertheless, Meleney and his colleagues regarded the drug as curative when a total dose of 1.5-2.0 grams of antimony was given over a period of 18-20 days 29,80. Moreover, Nishi investigated the actions of the drug in experimentally infected dogs and found that sodium antimony tartrate was able to kill youn g schistosomes and affected eggs in tissues 90. In 1951, Pesigan and his colleagues showed that lucanthone, when used in doses recommended for other forms of schistosomiasis, was ineffective in the treatment of S. japonicum infections93. Likewise, metrifonate and oxamniquine were found to be inactive. At a symposium on niridazole held in Lisbon i n 1965, there were suggestions that this drug may be less effective i n schistosomiasis japonica than in the treatment of S. mansoni and S. haematobium infections. This question was investigated further by Santos and hi s colleagues in the Philippines; they found that the cure rate in 106 patient s treated with various regimens of niridaz ole ranged between 48% and 85% 98. Sy then treated 237 persons and managed to follow up just over half of them one month later; 55% were cured, the egg count wa s reduced in 18%, and there was no response in the remaining 27% of patients 105. Praziquantel now looks to be the drug of choice in the treatment of schistosomiasis japonica. Th e introduction of this drug has been described in chapter 8. Suffice it to say here that Santos and his colleagues studied the effects of different dosage regimens in 128 Filipino patients and found that praziquantel was very effective; onl y 24% of patients treated for three days and reviewed 12 months later were still passing ova in the faeces 99.

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UNDERSTANDING THE EPIDEMIOLOGY The syndrome known as Katayama disease and w hich turned out to be caused by S. japonicum, was associated with water long before the causative agent was identified. Thus, Fujii in 1847 related the condition to wading in the padd y fields, and by making use of the appearance of a rash on the legs, was able to pinpoint the time of the year at which infection was acquired to the seaso n between spring and summer 32. The same connection between working in rice fields and Katayama disease was recognized by Kawanishi who, in 1904 , provided a concise description of the locale. At that time, Katayama was a village of 190 inhabitants and 36 houses situated at the foot of a hill 80 fee t high. The paddy fields were several feet lower than the level of the river, thus making it very difficult to drain the stagnant water, particularly during th e prolonged rainy season, and it was in these fields that workers developed the erythematous eruption on their legs 52. Furthermore, it was in these people that Kawanishi found S. japonicum eggs, thus bringing the nature of the affliction closer to clarification. Fujii also recognized the focal nature of the condition, the locations an d boundaries of which were gradually extended by a number of Japanes e clinicians over the next sixty years. The discoveries by Catto in 1904 o f S. japonicum in a man from Fukien province of China16,17, and in an 18 year old male in Hunan province, China, by Logan in the following year 68 widened knowledge of the geographical distribution considerably, as did the report by Wooley in 1906 of schistosomiasis japonica in the Philippines 118. Many years later (1937), Brug and Tesch discovered an endemic focus of infection i n Sulawesi, Indonesia12. From time to time, weather conditions led to epidemics of schistosomiasis in new areas as, for example, occurred when the summe r floods in the Chang Jiang (Yangtse) valley in 1931 brought the infection from the upper part of the system down to the delta 47, or when major floods occurred in China in 1954 67. The reason for the association with water fell into place, of course, with the discovery that certain species of snails were the vectors of infections. Attention then turned to investigating the behaviour and ecology of these long, narrow, operculated snails. The amphibious snails were most numerous in wet, moist soil near water and thick grass. The population was densest along irrigatio n ditches and became progressively thinner on the banks of rivers and canals, in rice beds, and in paddy fields. It was shown that they were most active at night, but crawled only at a rate of about three metres a month. If the surface of the earth became dry, the snails dug down into the deeper, wetter reaches, and by closing the operculum, survived for three months or so, although infecte d molluscs tended to die earlier. Mating was found to occur throughout the year, but was at a maximum in the spri ng and early summer and at a minimum in the early winter, with many snails hibernating during the depths of winter. Th e average life span was determined at around five years or so, wit h

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newly-hatched snails taking up to a year to reach maturity 21,29,103. Finally, it was realized from the beginning that this form of schistosomiasis was an extensive zoonosis, for a wide range of animals were found to b e infected in nature, beginning with Katsurada's discovery of adult worms in cats in 190449,50. These included dogs, rats, mice, cattle, water buffalo, pigs, horses, sheep and goats.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Hopes for the control or, better, the eradication of schistosomiasis have been held for many years. Over a century ago, Fujii left a memoir expressing thi s desire: I recently read my manuscripts and found the script of 'Katayama Memoir'. Thirty years have passed....By knowing (what causes it), we can treat it. In this way, the mysterious disease which has existed for many years can be eliminated easily. This would be good for the people.32

Once Fujinami and Nakamura had shown that infection was acquired whe n parasites penetrated the skin , they were able to suggest several means whereby the infection could be contained: (1) the faeces which contain the eggs must be disinfected. (2) in order to prevent the growth of the causative agent, constructions on land and water must be renovated; (3) in order to prevent the causative agents penetrating the body, contact with contaminated water should be avoided.36

The first of these points was overvalued to some extent, for it took no account of the excretion of eggs by infect ed animals, while the last proposal was clearly impossible for the many peasants whose livelihood depended upon working in the paddy fields. The discovery of the snail intermediate host by Miyairi an d Suzuki, however, provided another point at which the cycle of transmissio n could be attacked. This seemed the simplest approach, so attention in Japa n centred upon the evaluation of various molluscicides. Of all the chemical s tested, lime was found to be the surest and most economical agent 34,37. This chemical was available readily in Japan and the farmers used it for fertilizing the rice fields. Lime was therefore spread on the banks of infested canals and drainage ditches, and in the water contained in them. Alternatively, Fujinami and Fukutuni showed that burying the snails in wet, but not dry, soil kille d them. In 1928, Todokoro reported on the effectiveness of a combination o f measures in Hiroshima prefecture in Japan. These included the destruction of snails with lime, the installation of pit latrines, the replacement of cattle b y horses (which are less susceptible to infection 34) for ploughing, the repression of wild rats, and educating the local inhabitants about the dangers of immersing skin in water. The results were highly encouraging, with the incidence of skin rashes decreasing and the prevalence of infection in cattle and the numbers of

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snails dropping markedly 108. Since that time, and occurring pari passu with improving economic conditions, as well as the introduction of specifi c measures such as the cement lining of irrigation ditches and the availability of more effective molluscicides, the infection has almost disappeared i n Japan120,121. Similar excellent results have not been achieved in the Philippines o r Indonesia where the paucity of economic resources has militated agains t attempts to control the infection. The situation in China is somewhat less clear. In 1924, after reviewing the biological and technical problems in volved, Faust canvassed some of the social and political factors that would affect control measures: One more fact must be kept in mind in considering such an undertaking so intimately concerning the native farming class - namely, their suspicion that only harm can result from any stranger tresspassing on their domain. Coupled with this is the improbability of securing any government cooperation at the present time in China. 27

Then, with truly prophetic foresight, he went on to add: In spite of these unpleasant facts, the problem of eradicating schistosomiasis from China is a hopeful one. One must bear in mind that China is an ancient country, that she moves slowly and deliberately, but that she moves surely. The next fifty years will bring much in the way of reorganization and development in China. It seems not too much to expect that public health and preventive medicine will follow closely upon the steps of improved agriculture and commerce, and that in this scheme of affairs, schistosomiasis will not long be allowed to remain an uncontrolled infection in the heart of the country.27

Schistosomiasis was regarded in China as a serious parasitic disease with a major economic impact. By the middle of the 1950's, a nationwide contro l scheme was evolved and put into operation. Maegraith visited the country a year or two after the inititiation of this programme and has recorded hi s impressions 71. The extent of infection at that time was not fully known, but it was estimated that over 11 million people were infected in the fertile region of the Yangtse valley. The three major components of the control scheme wer e mass treatment of overt infections (with the two-fold aim of bringing clinical relief and a reduction in the contamination of the environment with eggs) , preventing the pollution of water by infected human and animal faeces, an d destruction of the snail intermediate hosts. Schistosomiasis centres wer e established for the purpose of mass treatment, propaganda and administrative control, while the actual field work was done by local farming and villag e communities. The year 1970 was set as the target for effective control. Th e most commonly used anthelmintic was sodium or potassium antimony tartrate, given intravenously, initially in seven or 20 day courses, but later in a three day regimen of treatment. Educational campaigns were set up to limit promiscuous defaecation; arrangements were made to collect and store faeces for one week in order to allow the ammonia that was generated to destroy the ova whic h otherwise would survive for several months, but problems were encountered in dealing with animal faeces. Snail control with molluscicides was instituted

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with Paris green or calcium arsenate being used most commonly at first, bu t later sodium pentachlorophenate be came the most popular chemical; they were sprayed on land within two metres of the water level. Physical methods were also employed; these included burning of grass in summer and the manua l removal and burial of snail-containing mud in winter. In 1977, an American delegation visited China in order to assess the impact of these various measures on the prevalence of schistosomiasis 4. The members of the delegation noted that by 1959, 25,000 communal health units concerned with schistosomiasis control had been set up. Between 1958 and 1962 , 5,000,000 people were treat ed with schistosomicides. The campaign to reduce the numbers of Oncomelania hupensis , however, was the most importan t feature of the control efforts. The delegation considered that there had been a reduction by two thirds in the prevalence of human schistosomiasis. Th e success of the programme was ascribed to China's economic, social an d political organization which permitted disciplined mass participation, a n approach which would be very difficu lt for any other nation to emulate. Finally, it was also concluded that in addition to the effects of the various specifi c control measures, the reduction in schistosomiasis transmission was probably also consequent upon a general improvement in socio-economic conditions.

SCHISTOSOME DERMATITIS (SWIMMER'S ITCH, BATHER' S ITCH) Cases of dermatitis of unknown aetiology had occurred for a number of years in persons wading in the freshwater Douglas Lake in Michigan, USA, whil e collecting biological specimens for the Michigan Biological Station. Simila r cases had also occurred in people at several holiday resorts in the region. I n 1928, WW Cort, while collecting molluscs, ( Lymnaea emarginata-angulata ) discovered accidentally that cercariae of a non-human schistosome, Cercaria elvae (now known as the cercaria of Trichobilharzia ocellata ), produced a severe, prickly sensation on the wrists and that this was followed by th e appearance of papules which evolved into a pustular eruption with intens e itching within 48 hours 23. Soon afterwards, Christenson and Greene confirmed this observation a t several lakes in Minnesota, finding C. elvae in Lymnaea stagnalis opressa 20. Later that year, a similar outbreak occurred in people bathing in an artificia l lake in Cardiff, Wales, and this was shown to be due to the same parasite 77. In 1930, Taylor and Baylis pointed out that C. elvae was identical with C. ocellata. They further remarked that although the adult form was not known, the cercariae resembled closely Bilharziella polonica which inhabited the mesenteric veins of ducks 106. This was confirmed in the following year b y

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Brumpt who placed four ducks in a vessel containing C. ocellata then recovered subsequently eggs and adult forms of B. polonica 14. In 1940, Brackett (who had been exposed naturally on many occasions) infected himself deliberately with C. stagnicola and C. ocellata then excised the lesions 29 and 50 hours later, respectively; no cercariae were seen but intense inflammation was noted11. Subsequently, similar cases of dermatitis caused by cercariae o f Trichobilharzia, Gigantobilharzia and Ornithobilharzia species, the definitive hosts being birds and the vectors including species of Chilina, Physa, Planorbis, Polypis and Stagnicola were reported from many parts of the world. A second form of cercarial dermatitis acquired in fresh water was shown to be due to penetration of human skin by cercariae of schistosomes whic h develop in mammals other than man. This was first reported by Buckley i n 1938 who found that dermatitis in workers in paddy fields was a consequence of infection with S. spindale cercariae15. Similar effects have since bee n recognized as being caused by S. bovis 9, S. douthitti 24, S. mattheei 1 Heterobilharzia americana 58 and Orientobilharzia turkestanicum 96. Finally, cercarial dermatitis may also be acquired while bathing in salt water, as was first reported by Penner in 1950. Seabirds serve as the definitive hosts while marine molluscs are the vectors of the worms. Penner described a new avian schistosome larva, Cercaria littorinalinae from the marine snail, Littorina planaxis, found on the coast of southern California 92. Two years later, Stunkard and Hinchcliffe described a s imilar affliction on the beaches of Rhode Island, USA102. Parasites now known to cause this condition include Bilharzia variglandis 102 and Gigantobilharzia huttoni 59.

OTHER SPECIES OF SCHISTOSOMA S. BOVIS This species was first described in 1876 by Sonsino when he recovered th e worms from cattle in Egypt100. The eggs are longer and narrower than those of S. haematobium, thus facilitating delineation of the species. Bulinus species are molluscan intermediate hosts. There have been isolated but doubtful reports the occurrence of this worm in humans. S. INCOGNITUM The distinctive eggs of this parasite were recovered from the faeces of tw o human patients by Chandler in 1926. He proposed the name S. incognitum as the parent worms were unknown 18. Later, the adult worms were found in pigs and dogs in India8, then subsequently in rodents in southeast Asia. The egg s have a short, pointed, terminal spine.

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S. INTERCALATUM In 1908, GC Low stated that when he was in Uganda, schistosomiasis wa s almost entirely of the intestinal form, yet he only found terminal-spined ova in the stools70. A similar observation was made in 1923 by CC Chesterman in the Belgian Congo (Zaire) 19. In 1934, also in Zaire, AC Fisher found severa l hundred such cases and erected a new species, S. intercalatum, to designate this parasite31. Like S. haematobium, Bulinus species of snails are the intermediate hosts of this worm. It resembles S. haematobium morphologically and may be merely a strain of that helminth. S. MARGREBOWIEI This schistosome was discovered in ruminants by Le Roux in 1933 64. The egg has a small, terminal spine. A human infection was reported by Lapierre and Hien in 1973 57. S. MATTHEEI This schistosome was originally described in a sheep by Veglia and Le Roux in 1929113. The eggs are terminally spined and Bulinus species of snails are the intermediate hosts. The first definitive report of the occurrence of the infection in humans was by Blackie in 1932 following a survey in Southern Rhodesi a (Zimbabwe) 10. S. MEKONGI The first case of human schis tosomiasis of southeast Asian origin was reported in 1957 not from Asia but from Paris when Vic-Dupont and colleagues dis covered the condition in an 18 year old Eurasian with hepatosplenomegaly and haematemesis; the early part of the patient's childhood had been spent o n Khong island in the Mekong river between Laos and Cambodia 114. Between 1963 and 1966, Barbier, also in Paris, saw four more Indochinese students who were infected similarly; enquiry revealed that they had all lived on Khon g island7. Alerted by these observations, a World Health Organization team was sent to the island and found that schistosomiasis was endemic there 44. Subsequent surveys indicated that the infection was endemic in some regions of Thailand. Shortly thereafter, the intermediate host was identified as a n aquatic, not amphibious mollusc, Lithoglyphopsis aperta 41, now known as Tricula aperta 25. In 1978, Voge and her colleagues erected a new species, S. mekongi, for this parasite, on the grounds that the eggs were smaller, th e prepatent period in mice was l onger, and the intermediate host was different 115.

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S. RODHAINI This parasite of African wild rodents was described by Brumpt in 1931 13. The eggs have a subterminal spine. It is transmit ted by Biomphalaria snails. Human infection was reported in Zaire in 1954 by Gillet and Wolfs 38.

REFERENCES 1. ALVES W. Experimental cercarial dermatitis in man due to cercariae of Schistosoma mattheei. Transactions of the Royal Society of Tropical Medicine and Hygiene 47: 272, 1953 2. ANNANDALE N. Supplement on the molluscan hosts of the human blood fluke in China and Japan and species liable to be confused with them. In, Studies on schistosomiasis japonica, by EC Faust and HE Meleney, American Journal of Hygiene Monograph Series, No. 3, pp 361, 1924 3. ANONYMOUS. Helminthological investigations. Journal of Tropical Medicine and Hygiene 17: 84-85, 1914 4. ANONYMOUS. Report of the American schistosomiasis delegation to the People's Republic of China. American Journal of Tropical Medicine and Hygiene 26: 427-462, 1977 5. ATKINSON EL. cited in 89 6. BAELZ E. Ueber einige neue Parasiten des Menschen. Berliner klinische Wochenschrift 20: 234238, 1883 7. BARBIER M. Détermination d'un foyer de bilharziose artério-veineuse au sud-Laos (Province de Sithadone). Bulletin de la Société de Pathologie Exotique 59: 974-983, 1966 8. BHALERAO G. On the occurrence of Schistosoma japonicum Katsurada in India. Indian Journal of Veterinary Science and Animal Husbandry 4: 148-151, 1934 9. BIOCCA E. Osservazione sulla morfologia e biologia del ceppo sardo di schistisome bovis e sulla dermatitie umana da esso provocato. Parassitologia 2: 47-54, 1960 10. BLACKIE WK. A helminthological survey of southern Rhodesia. Memoir Series of the London School of Hygiene and Tropical Medicine, No. 5, pp 1-91, 1932 11. BRACKETT S. Pathology of schistosome dermatitis. Archives of Dermatology and Syphilis 42: 410-418, 1940 12. BRUG SL, TESCH JW. Parasitaire wormen aan het Lindoe Meer (Ou. Paloe, Celebes). Geneeskundig Tijdschrift voor Nederlandsch-Indië 77: 2151-2158, 1937 13. BRUMPT E. Description de deux bilharzies de mammifères africaines, Schistosoma curassoni sp. inquir. et Schistosoma rodhaini n. sp. Annales de Parasitologie Humaine et Comparée 9: 325-338, 1931 14. BRUMPT E. Cercaria ocellata déterminant la dermatite des nageurs provient d'une bilharzie des canards. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 193: 612-614, 1931 15. BUCKLEY JJ. On a dermatitis in Malaya caused by the cercariae ofSchistosoma spindale Montgomery, 1906. Journal of Helminthology 16: 117-120, 1938 16. CATTO J. A new blood fluke of man. Transactions of the Pathological Society of London 56: 179189, 1905. Abstracted in Lancet ii: 1499, 1904 17. CATTO J. Schistosoma cattoi, a new blood fluke of man. British Medical Journal i: 11-13, 1905 18. CHANDLER AC. A new schistosome infection in man, with notes on other human fluke infestations in India. Indian Journal of Medical Research 14: 179-183, 1926 19. CHESTERMAN CC. Note sur la bilharziose de la région de Stanleyville (Congo Belge). Annales de Société Belge de Médecine Tropicale 3: 73-75, 1923 20. CHRISTENSON RO, GREEN WP. Studies on biological and medical aspects of "swimmers itch". Schistosome dermatitis in Minnesota. Minnesota Medicine 11: 573-575, 1928 21. CORT WW. On the resistance to dessication of the intermediate host of Schistosoma

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japonicum Katsurada. Journal of Parasitology 6: 84-88, 1919 22. CORT WW. The development of the Japanese blood-fluke, Schistosoma japonicum Katsurada, in its final host. American Journal of Hygiene 1: 1-38, 1921 23. CORT WW. Schistosome dermatitis in the United States (Michigan). Journal of the American Medical Association 90: 1027-1029, 1928 24. CORT WW. Studies on schistosome dermatitis. American Journal of Hygiene 52: 251-307, 1950 25. DAVIS GM. Snail hosts of African Schistosoma infecting Man: evolution and co-evolution. In, The Mekong schistosome, JI Bruce and S Sornmani (Editors), Whitmore Lake, Michigan, Malacological Review Supplement 2: 195-238, 1980 26. EDGAR WH. Yangtze fever. Journal of State Medicine 21: 542-553, 1913 27. FAUST EC. Schistosomiasis in China: biological and practical aspects. Lancet i: 21-24, 1924 28. FAUST EC, MELENEY HE. The life history of Schistosoma japonicum Katsurada. China Medical Journal 37: 726-734, 1923 29. FAUST EC, MELENEY HE. Studies on schistosomiasis japonica. American Journal of Hygiene Monograph Series No. 3, pp 326, 1924 30. FAUST EC, WRIGHT WH, McMULLEN DB, HUNTER GW. The diagnosis of schistosomiasis japonica. I. The symptoms, signs and physical findings characteristic of schistosomiasis japonica at different stages in the development of the disease. American Journal of Tropical Medicine 26: 87-112, 1946 31. FISHER AC. A study of schistosomiasis in the Stanleyville district of the Belgian Congo. Transactions of the Royal Society of Tropical Medicine and Hygiene 28: 277-306, 1934 32. FUJII D (pen name, YOSHINAO). (An account of a journey to Katayama.) Chugai Iji Shinpo No. 691, pp 55-56, 1909. (Originally published in 1847). In Japanese. Translated in 53, 117 33. FUJINAMI A. (Ueber die pathologische Anatomie, und ueber den bom Verfasser entdeckten weiblichen Parasiten des Schistosomum japonicum.) Kyoto Igakkai Zasshi 1: No. 1, 1904. In Japanese, with German summary 34. FUJINAMI A. Historical review of scientific investigations on the pathology of schistosomiasis in Japan, and efforts for the eradication of this disease. Japan Medical World 6: 304-308, 1926 35. FUJINAMI A, NAKAMURA H (The mode of transmission of Katayama disease of Hiroshima Prefecture, Japanese schistosomiasis, the development of its causative worm, and the disease in animals caused by it.) Hiroshima Iji Geppo 132: 324-341, 1909. In Japanese. Abstracted in 117 36. FUJINAMI A, NAKAMURA H. (Route of infection, development of the worm in the host and animals in Katayama disease in Hiroshima Prefecture [Japanese blood sucking worm disease - schistosomiasis japonica].) Kyoto Igaku Zasshi 6: 224-252, 1909. In Japanese. Translated in 53. 37. FUJINAMI A, SUYEYASU Y. (Prophylaxis in schistosomiasis japonica.) Nishin Igaku (special number), November-December 1919. In Japanese. 38. GILLET J, WOLFS J. Human schistosomiasis in the Belgian Congo and in Ruanda-Urundi. Bulletin of the World Health Organization 10: 319-419, 1954 39. GOTO T. Beiträge zur Kenntnis der Migrations-route von Schistosoma japonicum in den Endwirten. Fukuoka Ikwadaigaku Zasshi 25, No, 3, 1932. In Japanese; German summary pp 11-13 40. HALL SC, KEHOE EL. Prolonged survival of Schistosoma japonicum. California Medicine 113: 75-77, 1970 41. HARINASUTA C, SORNMANI S, KITIKOON V,SCHNEIDER CR, PATHAMMAVONG O. Infection of aquatic hydrobiid snails and animals with Schistosoma japonicum-like parasites from Khong Island, Southern Laos. Transactions of the Royal Society of Tropical Medicine and Hygiene 66: 184, 1972 42. HSÜ H F, HSÜ S Y. On the infectivity of the Formosan strain ofSchistosoma japonicum in Homo sapiens. American Journal of Tropical Medicine and Hygiene 5: 521-528, 1956 43. HUTCHESON AC. Results in thirteen casesof dysentery treated with emetine. China Medical Journal 27: 243-245, 1913 44. IJIMA T, GARCIA EG. Preliminary survey for schistosomiasis in South Laos. World Health

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Organization Document, WHO/BILH/67.64, 1967 45. JOHNSON AS, BERRY MG. Asiatic schistosomiasis: clinical features, sigmoidoscopic picture and treatment of early infections. War Medicine 8: 156-162, 1945 46. KAN HC. Intracutaneous test with Schistosoma japonicum antigen. Chinese Medical Journal Supplement 1: 387-393, 1936 47. KASTEIN J. Beobachtungen von gehäuftem Auftreten von "Schistosomum japonicum"-Erkrankungen in Shanghai. Archiv für Schiffs- und Tropen-Hygiene 36: 1-4, 1932 48. KATSURADA F. (Ueber eine endemische Krankheit in der Provinz Yamanashi.) Mittheilungen aus der medizinischen Gesellschaft zu Okayama No. 173, 1904. In Japanese, with German summary. 49. KATSURADA (The etiology of a parasitic disease.) Iji Shimbun No. 669, pp 1325-1332, 1904. In Japanese. Translated in 53 50. KATSURADA F. Schistosomum japonicum, ein neuer menschlicher Parasit, durch welchen eine endemische Krankheit in verschiedenen Gegenden Japans verusacht wird. Annotationes Zoologicae Japonenses 5: 146-160, 1904. Translated as, Schistosomum japonicum, a new human parasite which gives rise to an endemic disease in different parts of Japan. Journal of Tropical Medicine and Hygiene 8: 108-111, 1905 51. KAWAMURA R, KAZAMA Y, TANAKA S. (On the therapeutic treatment of schistosomiasis japonica.) Saikingaku Zasshi Nos. 336-337, 1924. In Japanese. Abstracted in Japan Medical World 4: 132-133, 1924 52. KAWANISHI K (pen name Kasai). (A report on a study of the "Katayama disease" in Higino-kuni. Tokyo Igakkai Zasshi, 18 (3): 31-48, 1904. In Japanese. Partly translated in 53. 53. KEAN BH, MOTT JE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 54. KURATA M. Pathological physiology of schistosomiasis japonica. Kurume Medical Journal 10: 137-161, 1963 55. KURIMOTO T. (Ueber die Eier eines neuen Parasiten.) Mittheilungen aus der medizinischen Gesellschaft zu Tokyo 7 (22): 1-6, 1893. In Japanese, with German summary 56. LANING RH. Schistosomiasis on the YangtzeRiver, with report of cases. United States Naval Medical Bulletin 8: 16-36, 1914 57. LAPIERRE J, HIEN TV. Un cas de triple infestation bilharzienne àSchistosoma mansoni, S. haematobium et Rhodobilharzia margrebowiei? Annales de Parasitologie Humaine et Comparée 48: 301-306, 1973 58. LEE HF. Susceptibility of mammalian hosts to experimental infection withHeterobilharzia americana. Journal of Parasitology 48: 740-745, 1962 59. LEIGH WH. The morphology of Gigantobilharzia huttoni (Leigh, 1953), an avian schistosome with marine dermatitis-producing larvae. Journal of Parasitology 41: 262-269, 1955 60. LEIPER RT. Note on the presence of a lateral spine in the eggs ofSchistosoma japonicum. Transactions of the Royal Society of Tropical Medicine and Hygiene 4: 133-135, 1911 61. LEIPER RT. Report on an expedition to China to study the trematode infections of man. Unpublished report to the Colonial Office, pp 4, 15 January 1915. Abstracted in Tropical Diseases Bulletin 6: 295-296, 1915 62. LEIPER RT. Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 30: 235-260, 1918 63. LEIPER RT, ATKINSON EL. Observations on the spread of Asiatic schistosomiasis. British Medical Journal i: 201-203, 1915 64. LE ROUX PL. A preliminary note on Bilharzia margrebowiei - a new parasite of ruminants and possibly of man in Northern Rhodesia. Journal of Helminthology 11: 57-62, 1933 65. LIBBY WE. Tartar emetic in schistosomiasis japonica. China Medical Journal 37: 158-166, 1923 66. LIBBY WE. A further study in schistosomiasis japonica. China Medical Journal 38: 376-388, 1924 67. LIU J, CHENG WJ, HUANG MH,P'AN JS, CHIANG SC, HSÜ CY, HSÜ PY, T'ANG CY. Acute schistosomiasis japonica. Chinese Medical Journal 76: 229-242, 1958 68. LOGAN OT. A case of dysentery in Hunan province caused by the trematode,Schistosoma

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japonicum. China Missionary Medical Journal 19: 243-245, 1905 69. LOGAN OT. Schistosomiasis (japonicum) and "urticarial fever". A disclaimer of the priority of suggesting that these diseases were identical. China Medical Journal 26: 240-241, 1912. 70. LOW GC. Discussion on "The part played by metozoan parasites in tropical pathology" by L W Sambon. Transactions of the Society of Tropical Medicine and Hygiene 2: 45, 1908 71. MAEGRAITH BG. Schistosomiasis in China. Lancet i: 208-214, 1958 72. MAJIMA T (pen name Naganori). (A strange case of liver cirrhosis caused by parasitic ova). Tokyo Igakkai Zasshi 2 (17): 898-901, 1888. In Japanese. Translated in 53. 73. MANN WL. Some practical aspects of schistosomiasis as found in the Orient. Journal of the American Medical Association 67: 1366-1368, 1916 74. MANSON P, CATTO J. A new nematode. Lancet ii: 615, 1904 75. MAO SHOU-PAI, SHAO BAO-RUO. Schistosomiasis control in the People's Republic of China. American Journal of Tropical Medicine and Hygiene 31: 92-99, 1982 76. MARKEL SF, LOVERDE PT, BRITT EM. Prolonged latent schistosomiasis. Journal of the American Medical Association 240: 1746-1747, 1978 77. MATHESON C. Notes on Cercaria elvae Miller as the probable cause of an outbreak of dermatitis at Cardiff. Transactions of the Royal Society of Tropical Medicine and Hygiene 23: 422-424,. 1930 78. MELENEY HE, FAUST EC. The intermediate host of Schistosoma japonicum. I. Its discovery in the Soochow region. II. Its distribution in China. China Medical Journal 37: 541-554, 1923 79. MELENEY HE, FAUST EC. The route of migration of Schistosoma japonicum in the body of its final host. Proceedings of the Society of Experimental Biology and Medicine 20: 397-398, 1923 80. MELENEY HE, FAUST EC, WASSEL CMcA. A study of intensive antimony therapy ni schistosomiasis japonica. Journal of Tropical Medicine and Hygiene 15: 153-165, 1925 81. MIYAGAWA Y. Ueber den Wanderungsweg des Schistosomum japonicum von der Haut bis zum Pfortadersystem und über die Körperkonstitution der jüngsten Würmer zur Zeit der Hautinvasion. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 66: 406-417, 1912. Partly translated in 53; Abstracted in 117. 82. MIYAGAWA Y. Ueber den Wanderungsweg des Schistosomum japonicum durch Vermittlung des Lymphgefässystems des Wirtes. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 68: 204-206, 1913 83. MIYAGAWA Y. Beziehungen zwischen Schistosomiasis japonica und der Dermatitis, unter Berücksichtigung der Methode der Auffindung von Parasiteneiern in den Faeces, und Beiträge zur Kenntnis der Schistosomum-Infektion. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 69: 132-142, 1913 84. MIYAGAWA Y, TAKEMOTO S. (The mode of infection of Schistosomum japonicum and the principal route of its journey from the skin to the portal vein in the host.) Iji Shimbun No. 1839, 1918. In Japanese. Also, The mode of infection of Schistosomum japonicum and the principal route of its journey from the skin to the portal vein in the host. Journal of Pathology and Bacteriology 24: 168-174, 1921 85. MIYAIRI S, IMAI B. Serologische Studien bei Schistosomiasis japonica. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 106: 237-246, 1928 86. MIYAIRI K, SUZUKI M. (On the development of Schistosoma japonicum.) Tokyo Iji Shinshi No. 1836, pp 1-5, 1913. In Japanese. Abstracted in 117 87. MIYAIRI K, SUZUKI M. Der Zwischenwirt des Schistosomum japonicum Katsurada. Mittheilungen aus der medizinischen Fakultät der kaiserlichen Universität Kyushu Fukuoka 1: 187-197, 1914. Partly translated in 53; Abstracted in 117 88. NARABAYASHI F. (Contribution to the life history of Schistosomum japonicum. The course in the final host from the skin to the portal vein.) Kyoto Igakai Zasshi 22 (3): 1-63, 1916. In Japanese 89. NELSON GS. A milestone on the road to the discovery of the life cycles of the human schistosomes. American Journal of Tropical Medicine and Hygiene 26: 1093-1100, 1977 90. NISHI M. Experimental study of the treatment of schistosomiasis japonica with tartar emetic.

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91.

92. 93.

94. 95. 96.

97. 98. 99.

100. 101. 102.

103.

104. 105. 106.

107. 108. 109. 110.

111. 112. 113.

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Clinical observation, histological investigation and pathological changes on animal intoxicated with tartar emetic. Scientific Reports from the Government Institute for Infectious Diseases, Tokyo 2: 485-501, 1923 OGATA S. Ueber den anatomischen Körperbau der Cercarien des Schistosomum japonicum und die Uebertragungsweise derselben auf Tiere. Verhandlungen der japanischen pathologischen Gesellschaft 48: 121-122, 1914 PENNER LR. Cercaria littorinalinae sp. nov., a dermatitis-producing schistosome larva from the marine snail Littorina planaxis Philippi. Journal of Parasitology 36: 466-472, 1950 PESIGAN TP, PANGALINAN MV, SANIEL VF, GARCIA EG, BANZON TC, PUTONG PB. Field studies on the treatment of schistosomiasis japonica with nilodin. Journal of the Philippine Medical Association 27: 242-247, 1951 REED AC. Schistosomiasis japonica. American Journal of Tropical Diseases and Preventive Medicine 3: 250-273, 1915 ROBSON GC. Note on "Katayama nosophora". British Medical Journal i: 203, 1915 SAHBA GH, MALEK EA. Dermatitis caused by cercariae of Orientobilharzia turkestanicum in the Caspian Sea area of Iran. American Journal of Tropical Medicine and Hygiene 31: 779-784, 1982 SANDERS AA, PRISTON JL. Notes on treatment of some cases of schistosomiasis. Journal of the Royal Naval Medical Service 7: 290-292, 1921 SANTOS AT, BLAS BL, NOSEÑAS JS, PORTILLO GP. Niridazolein the treatment of schistosomiasis japonica. Journal of the Philippine Medical Association 47: 203-207, 1971 SANTOS AT, BLAS BL, NOSEÑAS JS, PORTILLO GP, ORTEGA OM, HAYASHI M, BOEHME K. Preliminary clinical trials with praziquantel in Schistosoma japonicum infections in the Philippines. Bulletin of the World Health Organization 57: 793-799, 1979 SONSINO P. Intorno ad un unovo parasito del Buc Bilharz a bovis. Rendiconti della Reale Accademia di Scienze Fisiche e Matematiche de Napoli 15: 84-87, 1876 STRANSKY E, PESIGAN NE. Liver damage in schistosomiasis in children. Preliminary report. Journal of Tropical Medicine and Hygiene 56: 261-266, 1953 STUNKARD HW, HINCHCLIFFE MC. The morphology and life history of Microbilharzia variglandis (Miller and Northrup, 1926), Stunkard and Hinchcliffe, 1951, avian blood-flukes whose larvae cause "swimmers-itch" of ocean beaches. Journal of Parasitology 38: 248-265, 1952 SUGIURA S. (Studies on the prevention ofschistosomiasis japonica). Mittheilungen aus dem pathologischen Institut der medizinischen Fakultät, Niigata, Japan No. 29, pp 10, 1933. In Japanese, with English summary SUYEYASU Y. (Invasionsweg des Schistosomum japonicum innerholb des Körpers des Wirtes.) Kyoto Igakai Zasshi No. 1: 43-60, 1920. In Japanese, with German summary SY FS. Niridazole in the treatment of schistosomiasis japonica. Journal of the Philippine Medical Association 53: 151-160, 1977 TAYLOR EL, BAYLIS HA. Observations and experiments on a dermatitis-producing cercaria and on another cercaria from Limnaea stagnalis in Great Britain. Transactions of the Royal Society of Tropical Medicine and Hygiene 24: 219-244, 1930 TAYLOR HM, GAGE DP. Symptomatology of early schistosomiasis japonica. Bulletin of the United States Army Medical Department 4: 197-202, 1945 TODOKORA K. History of Japanese schistosomiasis (Katayama Disease) and its prevention in Hiroshima prefecture. Journal of the Public Health Association of Japan 4: 1-9, 1928 TSUCHIYA I. (Yamanishi disease.) Tokyo Iji Shinshi No. 1375, 1904. In Japanese TSUCHIYA I. Clinical, pathological-anatomical, pathogenic, prophylactic and therapeutic study of the schistosomiasis japonica. Sei-i-Kwai Medical Journal 32: 107-109. Abstracted in Tropical Diseases Bulletin 2: 406-407, 1913 TUBANGUI MA. The molluscan intermediate host in the Philippines of the Oriental blood fluke Schistosoma japonicum Katsurada. Philippine Journal of Science 49: 295-304, 1932 TYAU ES. Treatment of Asiatic schistosomiasis. National Medical Journal of China 8: 83-85, 1922 VEGLIA F, LE ROUX PL. On the morphology of a schistosome (Schistosoma mattheei sp. n.) from the sheep in Cape Province. Fifteenth Annual Report, Director of Veterinary Service,

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Union of South Africa, pp 335-346, 1929 114. VIC-DUPONT, BERNARD E, SOUBRANE J, HALLÉ B, RICHIR C. Bilharziose à Schistosoma japonicum à forme hépato-splénique révélée par une grande hématémèse. Bulletins et Mémoires de la Société des Hôpitaux de Paris 73: 933-941, 1957 115. VOGE M, BRUCKNER D, BRUCE JI.Schistosoma mekongi sp. n. from man and animals, compared with four geographical strains of Schistosoma japonicum. Journal of Parasitology 64: 577584, 1978 116. VOGEL H, MINNING W. Über die erworbene Resistenz vonMacacus rhesus gegenüber Schistosoma japonicum. Zeitschrift für Tropenmedizin und Parasitologie 4: 418-505, 1953 117. WARREN KS. Schistosomiasis. The evolution of a medical literature. M.I.T. Press, Cambridge, Mass., pp 1307, 1973 118. WOOLEY PG. The occurrence of Schistosoma japonicum vel cattoi in the Philippine Islands. Philippine Journal of Science 1: 83-89, 1906 119. YAMAGIWA K. (Eggs of an unknown parasite in the human liver.) Mittheilungen der medizinischen Gesellschaft zu Tokyo 4: No. 22, 1890. In Japanese, with German summary 120. YOKOGAWA M. Review of prevalence and distribution of schistosomiasis in Japan. Southeast Asian Journal of Tropical Medicine and Public Health 7: 137-143, 1976 121. YOKOGAWA M. Programme of schistosomiasis control in Japan. Southeast Asian Journal of Tropical Medicine and Public Health 7: 322-329, 1976 122. YOKOGAWA S. (Schistosoma japonicum in Formosa, especially on its intermediate host.) Taiwan Igakkai Zasshi 149: 178-183, 1915. In Japanese. Abstracted in 117 123. YOSHIMOTO M. Ueber die Komplementbindungsreaktion bei der Schistosoma-krankheit in Japan. Zeitschrift für Immunitätsforschung 5: 438-445, 1910

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Table 10.1. Landmarks in schistosomiasis japonica __________________________________________________________________ 1847 1888

Fujii described the clinical syndrome of Katayama disease Majima found ova now known to be those of S. japonicum in human liver and described the pathological appearances 1903 Kawanishi found eggs in human faeces 1904 Kawanishi described hatching of miracidia from eggs Katsurada found male adult worms in the portal vein of a cat (April), then later found male and female worms in another cat, and described the pathological changes in the bowel Fujinami found a female worm in the portal vein of a human (May) Tsuchiya found adult worms in cats, dogs and humans Catto found adult worms in the mesenteric veins of a human and described the pathological appearances 1909 Fujinami and Nakamura showed by experiments with cows that infection was acquired by organisms penetrating the skin 1912 Miyagawa demonstrated schistosomula in histological sections of skin and in blood and lymph 1913 Miyairi and Suzuki described infection of Oncomelania snails with miracidia and the development of miracidia through sporocyst stages to cercariae, then recovered adult worms from mice exposed to cercariae obtained from naturally infected snails 1919 Fujinami controlled the molluscan vectors with lime 1921 Sanders and Priston indicated that tartar emetic may be of some value in treatment 1971 Niridazole was shown to be of value in therapy by Santos and colleagues 1977 Praziquantel was reported to be effective in experimental animals 1979 Praziquantel was shown to be highly effective in humans by Santos and colleagues __________________________________________________________________

Chapter 11

TREMATODE IMPORTANCE

INFECTIONS

OF

LESSER

INFECTION WITH ACHILLURBANIA SPECIES A. NOUVELI This Paragonimus-like fluke was discovered by Dollfus in 1939. He found the worm in an orbital abscess i n a malayan panther (Panthera pardus) which was being kept in a zoo in France 46. In humans, the parasite has bee n recovered from a nodule behind the e ar of a ten year old girl in China by Ch'en in 196537. A. RECONDITA This fluke was found in the maxillary sinuses of a Brazilian opossu m (Didelphus marsupialis) by Travassos in 1942 135. Eggs identified as probably those of A. recondita were found in peritoneal granulomas in a 19 year ol d Honduran male16. The life cycle of both of these worms is not well understood. INFECTION WITH ALARIA SPECIES Flukes of this genus are found in the intestines of birds and mammals, no t including man. Snails are the first intermediate host. Cercariae penetrate the skin of a fish or tadpole then move about f reely in the tissues as mesocercariae. In 1973, an unidentified mesocercaria was observed in the retina of a woman, in Ontario, Canada, who had often prepared frogs' legs for eating 125. A disseminated fatal infection with mesocercariae of A. americana occurred in 1976 in Ontario in a young man who had eaten inadequately cooked frogs ' legs51. Finally, A. marcianae mesocercariae were removed from the skin of a man, in Louisiana, USA, who had eaten baked raccoon 17. DICROCOELIASIS DICROCOELIUM DENDRITICUM This parasite was confused with the common liver fluke, Fasciola hepatica, 297

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for many years. The worm is a common parasite in the biliary passages o f sheep, deer and other herbivorous and omnivorous animals in many parts of the world. It was named Fasciola lanceolata by Rudolphi in 1803 115, then Fasciola dendritica by him in 1819116. In 1899, Looss transferred the worm to the genus Dicrocoelium erected by Dujardin in 1845 47, this name being derived from the Greek words (DIKROOS, DICROOS) and (KOILIA, COELIA), meaning double and cavity, respectively; the parasit e thus became known as D. dendriticum 83. It took many years to elucidate the complete life cycle of D. dendriticum. The eggs are embryonated when passed in the stools, but do not hatch i n water. When ingested by appropriate land snails, metamorphosis occurs with two generations of sporocysts being formed and the eventual production o f cercariae. Many species of land snails act as the first intermediate host , depending upon the geographical region. Cercariae of this worm had in fact been seen and labelled Cercaria vitrina by von Linstow in 1887, but thei r relationship with D. dendriticum was not appreciated at that time. In 1929, two papers appeared in Germany giving accounts of attempts t o solve the problem of the source of this infection. Both investigations wer e based upon intensive epidemiological inves tigations in several heavily infected parts of that country. W. Nöller found that the snail, Zebrina detrita, was heavily parasitized with C. vitrina. Since the distribution of the snail an d dicrocoeliasis did not quite coincide, however, he considered that either C. vitrina may not be the cercaria of D. dendriticum, or else that Z. detrita was not the normal host of the worm. Further searching showed that Torquilla frumentum was host to the same cercaria, and that its distribution did correlate with the presence of infected sheep 97. In another area, Vogel found that Z. detrita and Helicella candidula were infected with von Linstow's cercaria, and he thought it very likely that the latter mollusc might be the intermediate host of D. dendriticum 139. This view was proven to be correct two years later when Cameron infected Helicella by feeding these snails with Dicrocoelium eggs, then raising adult flukes in sheep infected with the cercariae obtained fro m these snails 31. Cercariae of Dicrocoelium aggregate in slime balls and are left on the grass as the snail moves along. In 1952 and 1953, Krull and Mapes in the US A showed that metacercariae develop in the ant, Formica fusca, and that infection of the mammalian host resulted from ingestion of infected ants 70,71. This was confirmed by Vogel and Falção in Germany 142, then the ants, F. cinerea and F. picea, were shown to be the intermediate hosts in the USSR 105. The first description of human infection with this parasite is shrouded i n controversy. The patients described by Bucholz in Germany and Chabert i n France might have been infected with F. hepatica or D. dendriticum (see chapter 4). The same might be said for the nine year old daughter of a shepherd in Bohemia described by Dr Kirchner of Kaplitz and recounted by

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Cobbold39; in this girl, 47 mature worms were found in the gall bladder a t autopsy. This uncertainty flows from the difficulty those observers had i n establishing the identity of the adult fluke. The diagnosis is usually made , however, by finding the distinctive eggs in the faeces. Many of these cases , though, are spurious. Strom showed in 1927 that they result from the ingestion of liver heavily contaminated with eggs 132; in such patients, the excretion o f eggs in the stools is transient compared with patients with true dicrocoeliasis. Most of the infections with this parasite have been reported from the USSR 93. Success has been claimed for thymol and stibophen in the treatment o f dicrocoeliasis121, but subsequent experience has shown that these drugs are not always reliable. Praziquantel may prove to be effective. D. HOSPES This species occurs commonly in cattle in Africa. A number of spuriou s human infections have been encountered, but two genuine human cases have been reported from Ghana by Odei 98.

INFECTION WITH ECHINOCHASMA PERFOLIATUS This species was first described as Echinostomum perfoliatum by von Ratz in 1908111 after he had found it in the small intestine of cats and dogs i n Hungary. Later, it was renamed Echinochasma perfoliatus by Dietz in 1910 45, the generic name being derived from the Greek words (ECHINOS) and µ (CHASMA) meaning "spine" and "hiatus", respectively. Th e worm is a common parasite of cats and dogs in many parts of the world. I n 1922, Tanabe infected himself experimentally by ingesting cercariae in th e gills of freshwater fish 134, then Hirasawa recorded a natural human infection 55.

INFECTION WITH ECHINOPARYPHIUM RECURVATUM This cosmopolitan parasite of the intestine of birds and mammals wa s described by von Linstow in 1873 80, the generic name being derived from the Greek words (ECHINOS) AND (PARYPHE) meaning "spine" and "border", respectively. Infections of humans have been reported a number of times; the first was by Morishita, who named it E. koidzunis, in Taiwan in 192992. Since then, the parasite has been found in humans i n Indonesia and in Egypt. Snails are the first intermediate host and metacercariae encyst in tadpoles and frogs. E. paraulum, a probable synonym of E. recurvatum, was described in a human in the USSR by Skrjabin in 1938 126.

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ECHINOSTOMIASIS E. HORTENSE This parasite was first described by Asada in 1926 11. It was placed in the genus Echinostoma of Rudolphi (1809) and emended by Dietz in 1910 45; the name was derived from a combination of the Greek words (ECHINOS) and µ (STOMA) meaning "spine" and "mouth", respectively. In 1976 , Arizono and his colleagues descr ibed infections in four people who ate loaches (Misgurnus anguillicaudatus). Subsequently, loaches were collected from the same restaurant in which two of the patients had eaten; parasites wer e recovered from the soft tissues adjacent to the gills and a puppy was fed with 40 metacercariae and two humans ingested 10 metacercariae each. Egg s appeared in the faeces after two weeks and the volunteers developed abdominal pain lasting for several days about one month after infection. The dog wa s necropsied after 33 days and five adult worms were recovered from its small intestine9. E. ILOCANUM Eggs of this fluke were first found in the faeces of prisoners in Manila, Phil ippines by Garrison in 1907. He l ater recovered 21 adult worms, 2-6 mm long, after administration of oleoresin of aspidium to one person. Since the prisoner came from the Ilocano region of the Philippines, in 1908 he named i t Fascioletta ilocanum 53. In 1911, Odhner transferred this helminth to the genus Echinostoma 99. The parasite was found subsequently in various parts o f southeast Asia, with first Tubangui (1 931) showing that rats, then Chen finding that dogs, were reservoirs of infection. In 1933, Tubangui and Pasco described the life cycle of the parasite (which they called Euparyphium ilocanum); miracidia penetrated the snails Gyraulus convexiusculus and Hippeutis umbilicus, metamorphosed into rediae, the n produced daughter rediae and cercariae, the latter being liberated and encysting on freshwater molluscs which may be eaten raw 137. G. prashadi was shown subsequently to be the primary intermediate host in India. Worms attach to the intestinal wall and may cause diarrhoea. Recently, Radomyos and colleagues have shown that praziquantel is effective in the treatment of this infection 107. E. LINDOENSE This species was first reported as E. ilocanum by Brug and Tesch in 1937 in the Celebes (Sulawesi), Indonesia 28, but was re-described as E. lindoense by Sandground and Bonne in 1940 119. The parasite was named after the Lak e Lindoe region of Central Celebes where human infection was common, with up

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to 96% of the inhabitants being infected. The molluscan intermediate host s were shown by Bonne to be Anisus sarasinorum and A. convexiusculus, with mussels being important second intermediate hosts 24. He also reported that diarrhoea was induced in experimental human infections. In recent years, the worm has become less prevalent as a result of changes in the eating habits of the population32. The parasite has also been found in Brazil wher e Biomphalaria glabrata is the vector 78. E. MACRORCHIS AND E. CINETORCHIS The metacercariae of these parasites, which were first described by Ando and Ozaki in 19238, encyst in the tissues of tadpoles and frogs. Majima found 66 adult E. macrorchis in the intestines of a boy in Japan in 1927 90. Since then, occasional infections of humans by both species have been reported fro m various parts of southeast Asia 25. E. MALAYANUM This parasite was first found in two Tamil coolies in Singapore and Kual a Lumpur, and was named E. malayanum by Leiper in 1911 74. Species of Lymnaea and Indoplanorbis were shown to be the first intermediate host by Rao110 and then by Lie and Virik 79. E. REVOLUTUM This fluke, which is normally a parasite of t he intestine of various small animals and birds such as musk rats, ducks, geese and fowl, was first described by von Froelich in 1802 as Fasciola revoluta 52, then renamed E. revolutum by Looss in 189983. The first intermediate hosts a re a number of species of snails, and the second intermediate hosts on which encystation occurs are molluscs an d tadpoles. The first infection found in humans was reported by Anazawa i n 1929; he recovered adult worms from the faeces of a Taiwanese woman who had been treated with oleoresin of aspidium 7.

INFECTION WITH EUPARYPHIUM MELIS This fluke, described originally as Fasciola melis by Schrank in 1788 122, is normally a parasite of badgers, hedgehogs and dogs. It was recovered by Leon in 1916 from the stools of a Rumanian patient who had been in Jassy, Iran ; Leon and Ciurea named the worm Echinostoma jassyense in 192276. Hsu57 found two worms in the intestines of a Chinese who had died of chroni c myeloid leukaemia and concluded that they were identical with the wor m

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described by Schrank. That parasite, meanwhile, had been transferred to th e genus Euparyphium. Snails are the first intermediate host and cercariae encyst on tadpoles. INFECTION WITH EURYTREMA PANCREATICUM This fluke is a common parasite of the pancreatic ducts of cattle, buffalo , sheep, goats and hares in Asia and other parts of the world. It was discovered in Japan and became first known to Europeans during the Paris Exhibition of 1889 when Janson from the A gricultural School of Komaba in Japan exhibited a series of parasites, among which was a Distoma pancreaticum from the pancreatic duct of a sheep. The new parasite was referred to in subsequen t years by Railliet (1890) 109 and by Janson (1893) 58 in papers which dealt with the anatomy and pathological significance of the worm, respectively. It wa s then transferred to the genus Eurytrema by Looss in 1907 84. The generic name is possibly derived from a combination of the Greek words (EURYS) and µ (TREMA) meaning "broad" and "hole", respectively. The life cycle of this parasite was determined in 1965 by Basch who fed sporocysts from a snail, Bradybaena similaris, to grasshoppers, Conocephalus maculatus , in which they grew to mature metacercariae; these in turn developed into adul t worms in the pancreas of goats15. Castellani and Chambers in 1919 recorded the presence of eggs of this tr ematode in the faeces of a Chinese coolie 33. Adult worms were found in the pancreatic duct of a 22 year old Chinese man a t autopsy by Chang and Li in 1964 34

INFECTION WITH GASTRODISCOIDES HOMINIS This fluke was first found in the caecum of an Indian patient and designate d Amphistomum hominis by Lewis and McConnell in 187677. Subseqently, it was called Gastrodiscus hominis by Sonsino (1896) 128, then was redescribed i n 1913 by Leiper who renamed it Gastrodiscoides hominis 75. The generic name is derived from the Greek words (GASTER ) and (DISKOS, DISCOS) meaning "belly" and "disc", respectively, with the suffix (EIDOS) indicating "like" or "similar". The worm is common in parts o f northeastern India where more than 40% of the population may be infected 29, but it is also found in other parts of Asia. Pigs are a common reservoir host but various species of monkeys have also been found to be infected. The life cycle is uncertain, but the snail, Helicorbis coenosus, has been infected experimentally 48. Humans may be infected with large numbers of thes e helminths, which are approximately 1 cm long and almost as much wide; 999 worms were recovered from one individual, simply by the administration o f soap and water enemas29. Parasites generally attach to the large bowel and the infection may cause diarrhoea. Mechanical t herapy with soap and water enemas

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is often successful, as is treatment with thymol or tetrachlorethylene. Th e efficacy of praziquantel needs to be evaluated.

INFECTION WITH HAPLORCHIS SPECIES H. pumilio, described by Looss in 1896 82, H. tachui, described by Nishigori in 1924, and H. yokogawai, described by Katsuta in 1932, have all been reported in humans in the Philippines2,3. H. tachui infections have also been reported in Thailand67. The generic name is derived from a combination of the Gree k words (HAPLOOS) and (ORCHIS) meaning "single" an d "testis", respectively.

INFECTION WITH HETEROPHYES SPECIES H. HETEROPHYES This fluke was discovered in 1851 in Cairo by Theodor Bilharz. He wrote to von Siebold in Breslau in Germany (now Wroclaw, Poland) on 1 May 185 1 recounting his discovery: A short while ago, on 26 April, I discovered, in the intestine of a boy' s cadaver a large number of small red dots which, under the microscop e proved to be beautiful fully developed Distoma 1 mm in length and 0.3 mm in width. The red color was due to the red-brown mature eggs which were visible through the body of the worm. 20 In the following year, von Sie bold published Bilharz's letter and added his own comments in which he named the parasite Distoma heterophyes 20. The specific name was derived from a combination of the Gree k words (HETEROS) and (PHYE) meaning "different" and "shape", respectively. The worm s were seen on another occasion by Bilharz, but little more was heard of thi s 81 fluke until Blanchard in 1891 21 then Looss in 1894 once again directed attention to its presence in Egypt. In 1866, Cobbold placed the worm in a distinct genus and named it Heterophyes aegyptiaca, to reflect both the specific name given to it by von Siebold as well as the land of its discovery 40. In 1900, Stiles and Hassal renamed it , according to the nomenclatural law of priority, H. heterophyes 131. In 1915, Onji and Nishio in Japan de scribed a fluke found in human intestine which resembled H. heterophyes but which they believed represented a different species. They called this worm H. nocens 101. Their paper was published in Japanese but Cor t and Yokogawa brought it to the attention of the English-speaking world in 1921 42. The distinction between the two species was based upon small differences in size. This was criticized by Lane in 1922 who noted that all the observed changes could be accounted for by muscula r

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contraction 73. Lane concluded that H. nocens was a synonym of H. heterophyes, a view which has become accepted generally. The second intermediate host of H. heterophyes was identified before the first intermediate host. Onji and Nishio sh owed in 1915 by feeding experiments that cercariae of Heterophyes encysted in the fish, Mugil cephalus (mullet); this observation was not generally appreciated, however, until the appearance of Cort and Yokogawa's translation of Onji and Nishio's work in 1921. Thi s was then soon confirmed for H. heterophyes in Egypt by Harujiro Kobayashi and Mohammed Khalil, working independently. While returning to Japan after a visit to Europe, Kobayashi purchased some Egyptian mullet in Port Said and found in them metacercariae resembling youn g Heterophyes 69. That these were indeed Heterophyes was proven by Khalil who fed encysted cercariae in Mugil cephalus, from Lake Menzaleh near Port Said, to cats then recovered adul t worms eight days later64. He found subsequently that Tilapia nilotica was also infected65, and other investigators showed that Aphanius in Egypt and Acantogobius in Japan were other second intermediate hosts. In 1928, Asada in Japan discovered that a brackish-water snail , Tympanotonus microptera (= Cerithidea cingulata) was the first intermediate host of Heterophyes. He showed that cercariae from these snails encysted i n saltwater fishes but did not complete their development in freshwater fishes . Asada completed the life cycle of Heterophyes by obtaining adult worms after feeding fish, which had been infected in this way, to dogs 12. Subsequently, Khalil in Egypt showed in 1933 t hat cercariae from the snail, Pirenella conica, would encyst in the muscles of the fish, Gambusia affinis, and that when they were fed to a dog, adult H. heterophyes were obtained 65. In addition to humans, H. heterophyes infection has since been found in other mammals includin g cats, dogs and foxes. Heterophyiasis was diagnosed in life for the first time in 1899 in a girl who was a patient of FM Sandwith in Kasr-el-Aini Hospital in Cairo. Adult worms and eggs were both seen when faeces we re being examined microscopically for schistosome ova120. Sandwith also noted that she had no particular symptoms that could be attributed to the infec tion. Nevertheless, the parasite may produce diarrhoea, sometimes associa ted with bleeding from the gastrointestinal tract 65. The parasites occasionally lodge in ect opic locations, for example, adult worms have been found in the brain 43. Filix mas and tetrachlorethylene have been used in the past for the treatment of this condition. H. KATSURADAI This fluke, closely related to H. heterophyes, was described by Ozaki an d Asada in Japan in 1925. The parasites were recovered from humans treate d with thymol. The infection was t ransmitted experimentally from the fish, Mugil cephalus, to a dog102.

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INFECTION WITH HIMASTHLA MUEHLENSI This fluke, described by Vogel in 1933 and named by him after it s discoverer, Mühlens, is a para site of gulls and other birds 140. The generic name (HIMASTHLE) meaning "thong" or is derived from the Greek word µ "strap". The infection has been described in humans only once; Mühlen s obtained five specimens from a German patient who had lived in Colombia for six years, but who may have acquired the infection after eating raw clams i n New York. Marine snails are the first intermediate host and metacercaria e encyst on bivalves such as Mytilus and Mya.

INFECTION WITH HYPODERAEUM CONOIDEA This fluke, first recognized in 1782 by Bloch who named it Distoma conoideum 23, and renamed by Dietz in 1909 44, is a common parasite of birds such as ducks, geese and fowl. The intermediate hosts are Planorbis and Lymnaea snails. The infection is common in some parts of Thailand, where more tha n half of the population may be infected 148.

METAGONIMIASIS The causative agent of this infection, Metagonimus yokogawai , a fluke about 1-2.5 mm long, was first found by H Kobayashi in 1908, but he did not publish his report of the discovery until 10 October 1912, at which time he named it Loxotrema ovatum 68. Not only was the name Loxotrema preoccupied by a genus of the Mollusca, but the designation for the species was pre-empted by Katsurada. In 1911 in Taiwan, S. Yokogawa had found this parasite in humans and in cats and dogs infected experimentally with cysts from the trout , Plectoglossis altivelis. Yokogawa's discovery was reported to the Japanes e Pathological Association by Katsurada at which time he gave the fluke th e name Heterophyes yokogawai; this was duly published on 31 May 1912 60. In the following month (30 June 1912), Katsurada erected a new genus , Metagonimus, in which to place the worm, thus naming it Metagonimus yokogawai 61. Unaware of these publications in Japanese, Leiper, later i n 1913, erected the genus Yokogawa for this parasite 75, then Ciurea in 1915 designated it Loossia. The correct name, Metagonimus yokogawai , was used for the first time in the non-Japanese literature by Yokogawa in Decembe r 1913150. The generic name, Metagonimus, is derived from a combination of the Greek words µ (META) and µ (GONIMOS) meaning "posterior" and "genitalia", respectively. The piscine second intermediate host of M. yokogawai was discovered before the molluscan first intermediate host. In 1912, Yokogawa reported tha t

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encysted cercariae occurred in the freshwater trout, Plectoglossis altivelis, and that eggs appeared in the faeces within one week of the parasites being fed to experimental animals149,150. Subsequent investigations revealed tha t Odontobutis obscurus and Salmo perryi were also vectors of infection. In 1917, Muto demonstrated that Melania (= Semisulcospira) libertina was the first intermediate host. He found that miracidia developed through a sporocyst stage then two generations of rediae. Muto took cercariae from the liver of infected snails and showed that direct infection of experimenta l definitive hosts could not be induced. He then exposed goldfish and carp to the cercariae and proved that they penetrated the skin of the fish and becam e infective after about 20 days. The encysted metacercariae in fish were then fed to cats, with the result that eggs of M. yokogawai appeared in the faeces 1 2 days later95,96. As mentioned earlier, Yokogawa had discovered in 1911 that dogs could be infected experimentally with this parasite. Kobayashi in 1912 68 reported that dogs in Japan were infected with Metagonimus, then Leiper and Atkinso n found that natural infections were common in dogs in Shanghai. Subsequently, other investigators found that many species of fish-eating mammals wer e reservoirs of infection. Clinical studies have indicated that infection occasionally produces diarrhoea particularly if the infection is heavy 123. Yokogawa in 1913 indicated that thymol was effective in the treatment of metagonimiasis 150. Tetrachlorethylene has also been used, while more recently, R im showed that niclosamide was often effective112. Praziquantel may well prove to be a valuable addition to the therapeutic armamentarium.

OPISTHORCHIASIS OPISTHORCHIS FELINEUS This fluke, about 1 cm long, was discovered in the biliary passages of a cat by Rivolta in 1884 and named Distomum felineum by him113, the specific designation reflecting the host in which it was found. In 1895, R Blanchard erected the genus Opisthorchis and placed this fluke in it, the worm thus being known as O. felineus 22. The generic name was derived from a combination of th e Greek words (OPISTHON) and (ORCHIS) meaning "posterior" and "testis", respectively. Several years earlier (1892) in Tomsk, in the Siberian region of the USSR, Winogradoff first reported this infection in humans. He found the parasite i n nine patients and named it Distomum sibiricum 143. Subsequently, Kholokowsky diagnosed the infection in a peasant from near Leningrad but who had travelled extensively in Siberia 66. Askanazy then discovered the worm in five people living in the East Prussian district of Heydekrug. Further studie s

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revealed that a wide range of mammals including dogs, cats, foxes, pigs, rats, rabbits and seals were infected in cent ral and eastern Europe and adjacent parts of the USSR 49. The life cycle of O. felineus was elucidated in fits and starts. Askanazy i n 1905 believed that he had shown that the fishes Idus melanotus (chub) and Leuciscus rutilus (roach) were the intermediate hosts 14. Lühe then indicated that the details of the development of the parasite were known only meagrely, and suggested that an encysted larval worm found in Prussia in the flesh o f L. idus and L. rutilus could be the metacercarial stage and that an earlier phase perhaps passes in the body of a small bivalve mollusc, Dreissena polymorpha 86 . In 1917, Ciurea stated that he believed that Askanazy had been in error and had probably been working with holostomes 38. Ciurea isolated encyste d cercariae from the fishes Tinca tinca and Idus idus, then recovered mature O. felineus twelve days after feeding the parasites to cats and dogs. Subsequent studies by a number of investigators demonstrated that other freshwater fishes of the genera, Abramis, Barbus, Blicca, Cyprinus, and Scardinius, were also hosts of the larval stage of O. felineus. The nature of the first intermediate host of the fluke remained obscure until 1934 when Vogel showed that development of the parasite occurred in th e snail, Bithynia leachi 141. He found that eggs hatched after they were ingested by the snails, then the miracidia mig rated into the tisssues, metamorphosed into first then second generation sporocysts, then produced rediae in which th e cercariae developed after about two months. B. leachi is the only species of snail which has been shown to be susceptible to infection with this parasite . Vogel observed that when cercariae enco untered the fish, they became attached to the scales, dropped their tails, then penetrated into the tissues. Vogel also investigated the route of migration of the worms in the definitive host. He showed that like Clonorchis, but unlike Fasciola, metacercariae of O. felineus excysted in the duodenum, then migrated through the ampulla o f Vater to the distal bile passages wh ere they became attached to the mucosa and matured, beginning the laying of e ggs about three to four weeks after ingestion. Worms in the bile passages may induce inflammation and subsequent fibrosis leading to biliary obstruction and secondary bacterial infection an d cholelithiasis. Clinical studies indicated that the likelihood of significan t damage depended upon the number of worms present. Patients with 50 or so worms usually had no ill-effects, but people with many hundreds of worm s sometimes had severe biliary and hepatic disease. The diagnosis is made by finding eggs in the faeces or duodenal fluid. Hexachloroparaxylol (chloxyl) was claimed to be partially effective in Russia n patients with opisthorchiasis103. Praziquantel has been shown to be effective in the treatment of O. viverrini infections and is presumably also active against O. felineus.

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O. VIVERRINI This fluke was first found in a civet cat (Felis viverrus) by Poirier in 1886 and named Distoma viverrini by him104. It was transferred to the genus Opisth131 orchis of Blanchard 22 by Stiles and Hassal in 1896 . Nevertheless, it is possible that the correct name for this parasite is O. tenuicollis, reflecting the Distoma tenuicollis described by Rudophi in 1819 116. Most early reports of this infection in southeast Asia referred to this parasite as O. felineus 63,106, although Leiper (1911) made a provisional diagnosis of O. viverrini for some flukes from two prisoners in Chiengmai gaol in Thailand that had been sent to him by Dr. Kerr 74. Differentiation between the two species is extremely difficult; Wykoff and colleagues in 1965 could not distinguis h between them on the basis of the appearances o f the adult worms or of the eggs, but found differences in the patterns of the flame cells in the cercariae 146. The infection is now recognized as being common in Thailand, with up to half of the population being infected in some areas 54. The life cycle of this parasite was studied in Thailand by Wykoff and hi s colleagues; they showed that the snail intermediate hosts were Bithynia goniomphalus, B. funiculata and B. laevis, while the most important fis h intermediate hosts were species of Cyclocheilichthys, Hampala and Punteus 146. Early clinical studies suggested a high frequency of diarrhoea, abdomina l pain and jaundice in patients with opisthorchiasis, but these studies were not well-controlled 54,117. Subsequently, Wykoff and co-workers compared th e clinical and biochemical findings in 921 infec ted persons with those in a similar number of uninfected persons in Thailand, and could find no significant dif ferences between the two groups 145. On the other hand, Upatham and col leagues have shown more recently in a study of a village with 309 inhabitants that right upper quadrant abdominal pain was more common in those persons with heavy infections 138. It is possible that there is an association betwee n opisthorchiasis and carcinoma of the bile duct; for example, 5896 worms were found an autopsy of a man who died from this neoplasm 54. The diagnosis is usually made by findi ng eggs in the faeces. Upatham and his collaborators have defined recently the relationship between intensity o f infection and faecal egg excretion138. A number of drugs have been proposed as a treatment for opisthorchiasis viverrini. Partial responsiveness t o dehydroemetine was shown by Muangmanee and co-investigators in 1974 94. Niclofolan was thought to be of some value in patients with light infections 6. Bunnag and Harinasuta showed in 1980 that the infection responded well t o praziquantel; 23 out of 26 patients were cured by a two day course of treatment and toxicity was minimal 30. O. NOVERCA

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This fluke, which is a common parasite of dogs and pigs in India, was firs t found in these animals in that country by Lewis and Cunningham in 1872; i t was named O. noverca by Braun in 1902 26. It has been recorded twice i n humans, on both occasions by McConnell in India. McConnell, like Lewis and Cunningham, considered it to be identical with Distoma conjunctum discovered by TS Cobbold in the liver of an American red fox in 1858. Th e first patient was a Muslim who died in Calcutta in 1876; post-morte m examination revealed small flukes in dilated intrahepatic bile ducts 87. McConnell encountered another patient i n 1878 and on this occasion noted that the flukes were somewhat larger than those described by Cobbold 88. O. GUAYAQUILENSIS Rodriguez, Gomez and Montalvan in Ecuador in 1949 found this parasite in a number of humans and dogs114. According to Artigas and Perez 10, this worm is identical with Amphimerus pseudofelineus described in cats by Ward in 1901. INFECTION WITH PARYPHOSTOMUM SUFRARTYFEX This worm was first obtained from an eight year old girl in Assam, India and named Artyfechinostomum sufrartyfex by Lane in 1915 72. It was later redescribed and transferred to the genus Paryphostomum of Dietz (1909) by Bhalerao in 193119. The generic name is derived from the Greek word s (PARAPHYE) and µ (STOMA) meaning "fringe" and "mouth", respectively. The details of the life cycle are uncertain, but A. mehrai, which is probably a synonym of P. sufrartyfex, utilizes the snail, Indoplanorbis exustus 108 . It is also possible that this species is synonymous with Echinostoma malayanum described by Leiper in 1911.

INFECTION WITH PHILOPHTHALMUS Worms of the genus Philophthalmus mainly parasitize the conjunctival sac of the eyes of birds. The generic name is derived from the Greek words (PHILO-) and µ (OPHTHALMOS) meaning "like" and "eye" , respectively. Parasites of this genus develop in a snail intermediate host and do not require a second intermediate host 4. Human ocular infection was firs t described by Markovic in Belgrade in 1939 91. PLAGIORCHIASIS The genus Plagiorchis was raised by Lühe in 1899 85. It is derived from the (PLAGIA) and (ORCHIS) meaning "oblique" and Greek words "testis", respectively. The species of Plagiorchis normally occur in the

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intestines of a wide range of vertebrates. Snails are the intermediate host s although aquatic mussels may also serve as second intermediate hosts. P. PHILIPPINENSIS Africa and Garcia first found this fluke in 1935 during the autopsy of a man from Ilocano, Philippines, but they left it un-named 1; it was given its curren t name by Sandground in 1940 118. That first patient was also infected wit h Echinostoma ilocanum and Spelotrema brevicaeca . People in this region o f the Philippines were in the habit of eating grubs of certain species of insect s which may be the second intermediate hosts. P. JAVENSIS Sandground in 1940 first found this worm in a Javanese who also had a heavy infection with Echinostoma ilocanum 118. P. MURIS Tanabe described this fluke in 1922 133,134. McMullen in 1937 infected himself experimentally89. A natural infection in a human has been reported only once; it was found in a Japanese patient who was being treated for a heavy , concurrent infection with Metagonimus yokogawai 13.

INFECTION WITH POIKILORCHIS CONGOLENSIS This fluke was described by Fain and Vandepitte in 1957 after they had found it in a retroauricular cyst removed from a boy in Central Africa 50. Eggs similar to those produced by this parasite had been removed previously from near the ear of a man by Yarwood and Elmes in 1943 147. This genus is closely related to, or may be identical with, Achillurbania 16. The generic name is derived from (POIKILOS) and a combination of the Greek words (ORCHIS) meaning "many" or "various" and "testis", respectively.

INFECTION WITH PYGIDIOPSIS SUMMA Onji and Nishio described this fluke in 1915 101. It has been reported in humans in Korea124. The generic name is derived from a combination of the Gree k words (PYGIDION) and (OPSIS) meaning "posterior" o r "rump" and "sight", respectively.

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INFECTION WITH SPELOTREMA BREVICAECA This fluke was first reported a s Heterophyes brevicaeca in 1935 by Africa and Garcia who found it in the intestine of a Filipino male 1. It was renamed Spelotrema brevicaeca by Tubangui and Africa in 1938 136. The complete life cycle is unknown, but encysted metacercariae have been found in the crab , Carcinus maenas 56. In humans, eggs have been observed in the centra l nervous system 2 and in the heart 3.

INFECTION WITH STELLANTCHASMUS FALCATUS This fluke, described by Onji and Nishio in 1915 101, has been reported in humans in Japan, Taiwan and Hawaii 5,59.

INFECTION WITH TROGLOTREMA SALMINCOLA This worm, which lives in the intestinal wall of a number of carnivorou s animals on the northern borders of the Pacific ocean, was described in 1926 by Chapin who named it Nanophyes salmincola 35. It was then renamed Nanophyetus by him in the following year 36. Bennington and Pratt showed in 1960 that the mollusc, Oxytrema silicula, is the first intermediate host 18. The free-living cercariae encyst in the kidneys of certain species of fish, particularly salmon and trout. In lower animals, the worm is a vector of a rickettsia which often produces a fatal, febrile illness In 1931, Skrjabin and Podjapolskaja found that a number of men inhabiting the Amur and Usuri regions of the US SR were infected with a fluke which they named Nanophyetus schikhobalowi 127. In the following year, however , Witenberg concluded that this fluke was identical with the N. salmincola of Chapin, and transferred the parasite to the genus, Troglotrema, of Odhner 100, the parasite thus being designated T. salmincola 144. The generic name is derived from the Greek words (TROGLE) and µ (TREMA) meaning "sunken" and "orifice", respectively. Thymol was found to be effective in the original patients described b y Skrjabin and Podjapolskaja 127. Praziquantel may be more active. INFECTION WITH WATSONIUS WATSONI This parasite was discovered in the intestine of a Nigerian by Watson and sent to Conyngham in London. The flukes were pronounced a new species b y Blanchard, then Conyngham named it Amphistomum watsoni in 190441. The parasite was renamed Watsonius watsoni by Stiles and Goldberger in 1910 129.

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It has been recovered from a human only this once. The life cycle is unknown.

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147. 148.

149. 150.

A History of Human Helminthology dendriticum in Deutschland. Zeitschrift für Tropenmedizin und Parasitologie 5: 275-296, 1954 WINOGRADOFF K (=VINOGRADOV). (On a new species of distomum [Distomum sibiricum] in the human liver.) Izvestia Imperatorskogo Tomskogo Universiteta 4: 116-130, 1892. In Russian. Abstracted in Centralblatt Allgemeine für Pathologie und pathologische Anatomie 3: 910-911, 1892 WITENBERG C. On the anatomy and systematic position of the causative agent of the so-called salmon poisoning. Journal of Parasitology 13: 258-263, 1932 WYKOFF DE, CHITTAKYASOTHORN K, WINN MM. Clinical manifestations of Opisthorchis viverrini infections in Thailand. American Journal of Tropical Medicine and Hygiene 15: 915-918, 1966 WYKOFF DE, HARINASUTA C, JUTTIJUDATA P, WINN MM. Opisthorchis viverrini in Thailand - the life cycle and comparison with O. felineus. Journal of Parasitology 51: 207-214, 1965 YARWOOD GR, ELMES BG. Paragonimus cyst in a West African native. Transactions of the Royal Society of Tropical Medicine and Hygiene 36: 347-351, 1943 YOKOGAWA M, HARINASUTA C, CHAROENLARP P. Hypoderaeum conoideum (Bloch 1782) Dietz 1909, a common intestinal fluke of man in northeast Thailand. Japanese Journal of Parasitology 14: 148-153, 1965 YOKOGAWA S. (A new parasite involving trout as its intermediate host and its new generic name.) Okayama Igakkai Zasshi No. 279, 1912. In Japanese YOKOGAWA S. Ueber einen neuen Parasiten Metagonimus yokogawai, der die Forellenart Plecoglossus altivelis 1(Temminck) zum Zwischenwirt hat. bildung einer neuer Gattung. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 72: 158-179, 1913

Chapter 12

Echinococcus granulosus and ECHINOCOCCOSIS or HYDATID DISEASE

SYNOPSIS Common name: hydatid Major synonym: Taenia echinococcus Distribution: world-wide, particularly in sheep- and cattle-raising countries Life cycle: The adult tapeworms, 3-6 mm long, live in the small intestinal lumen attach ed to the mucosa. They produce eggs which are passed in the faeces. When ingested by an herbivorous or omnivorous animal, each egg hatches a larva (oncosphere) which migrates through the bowel wall then passes via the portal venous system to the liver where many are arrested. Some larvae continue their migration to the lungs where they may either lodge or pass into the systemic circulation and reach other tissues. In the tissues, the larva grows, encysts and the wall differentiates into an outer, non-nucleated, laminated layer and an inner, nucleated, germinal layer. During the ensuing months to years, buds develop from the inner layer and become vacuolated to form brood capsules; these in turn develop protoscolices on their inner surface. The whole cyst is surrounded by a fibrous layer of host origin. When a cyst is ingested by a dog, the protoscolices attach to the small bowel mucosa and develop into adult worms after several weeks Definitive host: dogs and other canines Intermediate hosts: sheep, cattle, pigs, horses, humans Major clinical features: manifestations of a space-occupying lesion, depending upon the location of the cyst Diagnosis: suggested by radiology plus immunological studies; proven at operation Treatment: surgery, where possible; ? mebendazole or albendazole

AWARENESS OF THE ANIMAL NATURE OF HYDATID CYSTS Hydatid cysts have been known since ancient times in both animals an d humans, but the parasitic nature of these "bladders" was long unrecognized . Mention is made in the Talmud of cystic lesions in the viscera of sacrificia l animals. Hippocrates (460-37 9 BC) alluded to tumours filled with water in the lungs of cattle, sheep and pigs. Similarly, in his aphorisms on human medicine, he wrote: "When the liver is filled with water and bursts into the epiploon, in this case the belly is filled with water and the patient dies"(VII,55) 57. In his commentary on the works of Hippocrates, Galen (129-c.200 AD) interpreted this aphorism as describing an hydatid cyst which had burst into the peritoneal 319

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cavity. Galen was also familiar with echinococci and cysticerci (probabl y Cysticercus tenuicollis, the cystic form of the tapeworm, Taenia hydatigena) in the abdomen of butchered animals, for he wrote: "The liver is very muc h inclined to produce hydatids in the surrounding fascia. Sometimes, the liver of slaughtered animals is full of them" 47. Aretaeus of Cappadocia was also aware of hydatid cysts in humans. He recorde d a case in which attempted paracentesis of the abdomen was hindered by blockage of the trocar and cannula wit h vesicles; this circumstance indicated puncture of an echinococcal cys t containing daughter vesicles: Small and numerous bladders, full of fluid, are contained in the place where ascites is found; but they also float in a copious fluid, of which this is the proof; for if you perforate the abdomen so as to evacuate the fluid, after a small discharge of the fluid, a bladder within will block up the passage.8

Hydatid cysts were noted from time to time in medical works of th e succeeding centuries but their true nature was not generally understood. They were usually ascribed to being either (1) excrescences or growths in the viscera produced by collections of serum and mucus, sometimes mixed with pus , between laminae of cellular tissue, (2) enlarged and degenerated glands or, (3) following the discovery of lymphatic glands in the seventeenth century, a s distended and varicous lymphatics. It was not until near the end of the seventeenth century that an awarenes s began to dawn that some of these cysts were animal in nature. Observation s were made on a variety of cysts in animals and humans. First, came th e realization that some of these "bladders" wer e really worms. Once this had been achieved, the various species of cysti c worms, including echinococci, cysticerci and coenuri, were differentiated. The problem was compounded by th e common practice of using the term "hydatid" in medicine to refer to any cystic swelling, with the consequence that echinococcal cysts in humans needed to be separated from similar non-parasitic tumours. The clue that some of these cysts were of animal origin was that many o f them had one of the cardinal att ributes of living animal creatures - spontaneous movement. The Italian, Francisco Redi, appears to have been the first person to both observe and record this phenomenon. Working in Florence in 1684, he found cysts (probably Cysticercus pisiformis ) in the mesentery and also lying free in the peritoneal cavity of a hare. Within each cyst, he observed a retracted neck. Moreover, on watching the cysts closely, he noticed that the free cyst s moved independently. This caused him to comment "quasi animalia foren t proprio motu arta" 98 meaning that the cysts moved about on their own as if they were animals. Redi wondered whether these cysts could possibly be the eggs of the worms, Fasciola hepatica, that he had found in the biliary system of the same rabbit, and had noted previously in the livers of sheep. He thought this was unlikely, however, as the liquid within the cysts did not coagulate when he boiled it, in contrast to his earlier observations on the behaviour of eggs in mammalia n

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ovaries (in which he had found that the enclosed liquid did congeal). Redi also discovered a similar cyst in a marten and, realizing the similarity of thes e various cysts from different animals, grouped them together under the nam e "Glandette o vesichette verminose" meaning "wormy glands or cyst s (vesicles)" 98. In the following year (1685), Philip Hartmann, a professor in the University of Königsberg, East Prussia (now Kaliningrad, USSR), emphasized the animal nature of these cysts and clearly related them to intestinal worms. In th e omentum of a dissected goat, he found cysts that he called "vesicular hydatids" (probably Cysticercus tenuicollis ), the largest being greater in size than a chicken's egg. He noticed a small, white, globular appendage at the extremity of each cyst. When one of these was incised and pressed gently, it was turned inside out. He wrote that at once "the rounded tail of a protruding intestina l worm became evident" 52. Furthermore, he thought that he had noticed som e movement, so he placed the specimen in a container of warm water an d reported that: When it was submerged and clinging to the bottom, I saw not only the proboscis but also the vesicular body begin movement in a marvellous manner; it moved with a singular form of undulation, exhibiting contraction and expansion with rising and falling of its parts.52

The sac itself consisted of nothing beyond a very thin membrane which wa s very smooth on both surfaces and contained a clear liquid lymph within it. On the following day, another goat, which had just died and was still warm, was brought to the dissecting room. In this animal, his students, Thormann an d Litius, found more bladder worms and verified his observations, clearl y demonstrating movements while the cysts were still within the membran e formed by the enclosing omentum 52. In 1688, he was again to find a motile cyst, this time in a pig (Cysticercus cellulosae ; see chapter 13), then in 1694 h e found Cysticercus fasciolaris in a mouse54. These early observations were unknown to the Oxford physician, Edwar d Tyson, when he rediscovered such movements in Cysticercus tenuicollis . In February 1687, he told a meeting of the Royal Society that "Hydatides i n Animalls are a sort of Living creatures" 115. He recounted his observations o n bladders about the size of a pigeon's egg that he had found in the peritonea l cavity of a gazelle brought from Aleppos (now Halab, Syria). He is recorded in the Journal Book of the Royal Society as describing the bladders in th e following terms: They were found involved in two coats like the corion and the Amnion, the innermost having a neck of a more Opake and solid substance that the rest of the Bladder, which neck, (at its first being taken out of the Animall) was observed to move as if alive; the whole bladder being filled with a Limpid water he supposed might be as the stomach to the worm.115

Tyson was said to have come to the conclusion that "(they") are worms sui generis or at least the Embrios of them" 115. This remarkable insight of Tyson's that the cysts loosely termed "hydatids" were worms or at least the embryos of

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them, predated by more than 150 years the experimental demonstration tha t bladders are the "embryonic form" or intermediate stage in the development of tapeworms. Further details of these observatio ns are provided in Tyson's definitive report published in 1891 (the delay being due to difficulty in publishing th e Philosophical Transactions of the Royal Society )116. He observed that whenever a candle was brought near the cyst , the neck, a small, white protruberance, moved. Tyson canvassed the possibility that these cysts represented an egg or embryo of an insect, with the bladder being the amnion and the outer coa t representing the chorion. He thought this unlikely since he had found man y such structures that were all in a similar state when dissecting "rotten sheep", whereas he would have expected that som e of them should have been in a more mature state if they had been a developing insect. He named these cyst s Lumbricus hydropicus in the following words: These Hydatides therefore I cannot but think are a sort of Worms or Insects sui generis, and because they contain so much water in them, and are usually to be met with in rotten Sheep which are usually Hydropical; I call them Lumbrici Hydropici 116

Although less definite on this occasion by including "or Insects" in his opinion on the nature of hydatids, the consensus of his remarks in the text of th e manuscript, together with the title which he gave it, viz.: " Lumbricus hydropicus or an Essay to prove that Hydatides often met with in morbi d Animal bodies, are a Species of Worms, or Imperfect Animals" 116 leaves little doubt that he considered that hydatid cysts were most likely worms. Never theless, he did not think that all such cysts were necessarily verminous i n nature, for he also wrote: "in some I have not observed this Neck and Structure of Parts, but only a transparent bl adder fill with a Lymph, and those I take to be of another kind" 116. Tyson then went on to give his clinical experience wit h hydropical bodies occurring in humans, some of which were undoubtedl y echinococci. Similarly, Marcus Malpighi in 1697, probably unaware of the discoveries of his contempories, recognized the vitality of cysts he found in pigs ( Cysticercus cellulosae), and described accurately the small head within each cyst 81. Despite the major importance of all these observations and the considerable impetus that they could have given to the elucidation of the nature of the cysts and the life cycles of these organisms, more than 60 years were to pass before another significant advance was made. This newly found comprehension of the animal nature of these cysts was largely ignored or forgotten by naturalists and the medical profession until 1760. In that year, Morgagni 84 recalled the researches of Redi, Hartmann and Tyson, and pointed out that th e bladderworms described by various authors were not all of the same kind. Just how long it took for the recognition of the animal nature of hydatid and other verminous cysts to penetrate the general consciousness of the medica l profession is illustrated by the proceedings of the London Medical Societ y published in The Lancet as late as the year 1833:

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Mr. Stephens entered the room in some haste, to exhibit to the Society three or four hydatids which he procured in the course of the afternoon, affording the members an opportunity to personally witness the existence of life in these 'imperfect animalcules' as Baillie terms them, though the hydatids shown on this occasion will almost justify the employment of the less equivocal term 'animal'. The President immediately drew attention to the exhibition. 'This is very interesting,' he observed, 'as it settles a point greatly in dispute. Here is a head as clearly as a head can be. Get a little warm water and see if it will revive the movements.' Mr. Stephens. 'Most probably it will not, for, unfortunately, they are now expiring, but they had this afternoon as free and perfect movement as a lively leech, and though now almost spherical, have assumed an alternately contracted and bulging form.' The President. 'Gentlemen will please to be very careful in examining them lest they break and the fact of life shut from our observation.' 2

Thereupon, warm water was procured and motion was demonstrated when the cysts were placed in it. These cysts, which were not E. granulosus, had been obtained from the mesentery of a sheep and considerable discussion the n ensued as to the relationship between these transparent cysts and the semi opaque, pulpy cysts which members had encountered previously in sheep and in humans.

RECOGNITION OF THE MORPHOLOGICAL SIMILARITIE S BETWEEN CYSTS AND TAPEWORMS, AND THE DIFFER ENTIATION OF SPECIES At almost the same time as Redi, Hartmann and Tyson made the observations already described, a Swiss physician and pathologist, Johann Wepfer, dis covered in 1688 a cyst, later to be known as Cysticercus fasciolaris, in the liver of a mouse121. It is possible that this parasite may have been seen some 20 years earlier by Pecquet 90, but he did not at that time appreciate fully the significance of the observation. Not only did Wepfer r ecognize the animal nature of the cyst, but he also realized that it resembled the tapeworm then known as "lati s lumbricus intestinorum". This interpretation was facilitated by the fact that the caudal vesicle of this cysticercus is relatively small and the head of the worm is not invaginated into it (hence it has has also been called a strobilocercus) . Although Wepfer was the first person to establish a link between any species of tapeworm and its intermediate cystic form, he was completely unaware of the life cycle of the parasite and merely considered C. fasciolaris as an encysted tapeworm. Again, news of this observation was not disseminated widely and it fell into oblivion. In 1766, Peter Pallas made two major contributions to our knowledge o f cystic worms. Firstly, by classifying "hydatids" into non-adherent and adherent forms, he managed to separate cystic worms from serous cysts, respectively . Secondly, he renewed awareness of the morphological similarities betwee n cystic worms and the heads of tapeworms 89. He propounded a theory that al l

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these cystic worms belonged to a single species which he named Taenia hydatigena. Furthermore, he proposed that worms in different animal host s varied in their appearance, especially in the structure of the caudal vesicle. He was aware, for example, that the cysticercus found in the liver of mic e (C. fasciolaris) was reminiscent of the head of the cat tapeworm ( Taenia crassicollis now called T. taeniaeformis). Similarly, he noted the resemblances between the cysts (C. tenuicollis) found in ruminants and the heads of som e tapeworms of dogs and cats (now called T. hydatigena), especially in relation to the circlet of hooks and the sucking pits. Pallas was, however, rathe r perplexed by the cysts we now know as echinococci. He knew that they were found most commonly in the liver and lungs of sheep and oxen, but occurred occasionally in humans as well. He recognized that the cyst walls did no t encompass a distinct neck and head, but contained instead a large number of small bodies or corpuscles, but since he was able to observe them only macroscopically, he was unable to discern their true nature. Even so, Pallas was still convinced that these cysts owed their origin to tapeworms: It seems to me very probable that the incompletely developed water vesicles seen by many observers in the human body, such as those oftenest found in pathological cavities in the liver, are caused by and arise from a worm resembling our own tapeworms.89

Although these cysts appeared to be different in almost every respect from his T. hydatigena, Pallas still believed that they were derived from the latter . Similarly, he considered that the Coenurus of sheep had the same origin. I n fact, he regarded the Coenurus as a many-headed tapeworm, and the Echinococcus as being closely related to if not ident ical with it. Moreover, he surmised that the heads of the coenuri may be but a further development of th e corpuscles or globules that occurred in echinococci. Thus, in re-awakening interest in t hese cysts, Pallas made two major contributions; he differentiated verminous from non-parasitic cysts, and reemphasized the relationship between them and tapewor ms. In doing this and in adopting the nomenclature, Taenia hydatigena, though, he did not mean to imply that these cysts were derived from tapeworms, any more than Tyson would have claimed that they owed their genesis to roundworms or tapeworms when he used th e term, Lumbricus hydropicus , to describe these parasites. Although Pallas regarded echin ococci as being related to tapeworms, he was unable to provide proof to substantiate this view. The requisite evidence was first given in 1782 by Johann Goeze when he described the scolices o f echinococcal cysts and indicate d their similarity to the heads of tapeworms. On 1 November of the previous year, Goeze was given an extremely mutilate d sheep liver that was so permeated with watery vesicles of various sizes that it was almost impossible to see the liver parenchyma. When he pricked some of the vesicles, liquid rushed out like a fountain. Within some of the rather hard and leather-like vesicles, he found smaller, soft, bluish vesicles. When thes e were opened in turn, Goeze disce rned a greyish-white, granular material which

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was connected to a very delicate membrane. When part of this membrane was placed in water, the granules dropped off immediately and appeared to swim around individually. In one of the vesicles, the size of a pigeon's egg, he found many thousands of these granules which were so small that they were hardl y visible to the naked eye. On examining them with a magnifying glass, he saw plainly that they were true tapeworms: he bodies were flat and dotted black; in front four suckers and on the rounded foreshortened proboscis the exceedingly small double-hook crown; however, on each one, posteriorly, was a small, sloping indentation like an anus. 49

Goeze concluded, therefore, that these cysts were a kind of tapeworm whic h were distinct from the coenuri that were found in the brain of giddy sheep . Thus, there was now no doubt that echinococcal cysts were alive, that they were verminous, and that they were related to tapewo rms. Goeze named them Taenia visceralis socialis granulosus, meaning the tapeworm which was found in the viscera and contained a multitude of granules 49. Shortly afterwards (1786) , Batsch renamed the parasite Hydatigera granulosa 13. From this point, unfortunately, progress in the understanding of the nature of cystic worms ceased for more than half a century. Indeed, a genera l retrogression occurred. In 1800, Zeder erected a distinct classificatory group for the cystic worms, thus separating them as a zoological entity from th e tapeworms 122. At first, he called echinococci, Polycephalus hominis 122 , then in 1803, he renamed them Polycephalus echinococcus 123. The problem was then compounded by Laennec (1804) who investigated hydatid cysts i n humans. He could not find the familiar taeniid heads seen in hydatid cysts from sheep and oxen, so concluded that they must either belong to another genus, or else be of a completely different nature. Being less than convinced of thei r animal nature, he gave them the name "acephalocysts" 71. Because of Laennec's authority, this view was generally accepted until Livois showed in 1843 tha t acephalocysts were but ordinary hydatids in which the scolices had not ye t developed 78. The views of Zeder were perpetuated by Rudolphi in his major text of 18081810. He placed the tapeworms in the Order Cestoideorum while the cysti c worms were located in the Order Cysticorum 101. Meanwhile, however, Rudolphi in 1801 had erected the genus Echinococcus 99, which was later to be placed in this latter order. The name was derived from a combination of th e Greek words (ECHINOS) and (KOKKOS/ COCCUS) meaning "spine" and "berry", respectively. The Index Catalogue of Medica l and Veterinary Zoology has cited this parasite as Echinococcus granulosu s ([Goeze 1782]) Batsch 1786) Rudolphi 1805, with Rudolphi in his 180 5 paper100 describing Taenia hydatigena granulosa in swine. Later, Rudolph i divided the genus Echinococcus into three species, E. hominis, E. simiae and E. veterinorum, which he believed infected humans, sub-human primates, and sheep or cattle, respectively 101. In the succeeding decades, there was considerable confusion and disput e

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among helminthologists, some admitting the existence of only a single species, others allowing two, while yet others thought that there was an even greate r number of species. Thus, Bremser, for example, believed that the same kind of scolex was recovered from hy datid cysts of man as was seen in hydatid cysts in animals 19 . This unitarian view was also adopted by Diesing who named th e worm Echinococcus polymorphus 41. The most common practice, however, was to divide echinococcal cysts into two species; E. hominis supposedly occurred in man and had scolices with a single row of hooklets, while E. veterinorum was thought to occur in animals and have a double row of hooklets. Küchenmeister in 1855 considered that this view was untenable for he believed that "E. hominis" had been discovered in cattle by Haubner and Creplin and that von Ammon had found " E. veterinorum" in the human eye. Nevertheless, Küchenmeister believed that tw o species of these cysts could be distinguished on morphological grounds and he divided them into E. scolicipariens in which scolices alone were present, and into E. altricipariens in which daughter cysts were formed as well 69. Rudolf Leuckart at first followed this cl assification and proposed the names E. simplex and E. hydatidosa for these two forms, respectively. In 1863, however, Naunyn showed that adult tapeworms derived from E. altricipariens were identical with those obtained from E. scolicipariens, and concluded that it was no longe r proper to separate the two species 87. Furthermore, it was eventually realize d that, following a single infection, the same animal or human may have cyst s with or without daughter cysts and that the number of hooklets on each scolex is extremely variable and is dependent, to some extent, upon the age or stage of development of the scolices 16. With the recognition that there was but one species of both the cystic form and the adult worm, the parasite was finally named E. granulosus since the genus Echinococcus of Rudolphi remained valid and the specific name reverted to the Taenia visceralis socialis granulosa of Goeze.

DISCOVERY OF THE ADULT WORM AND ELUCIDATION OF THE MODE OF TRANSMISSION THE BACKGROUND The discovery of the life cycle of E. granulosus becomes comprehensible only when viewed in the light of earlier studie s investigating the life cycles of related tapeworms and cystic forms found in a variety of animals. Two ideas wer e required to pave the way for the necessary experimental studies. Firstly, th e morphological similarities between parts of certain cysts and the heads o f various tapeworms had to be recognized and, secondly, the theory of th e alternation of generations needed to be formulated.

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As has already been discussed , the morphological resemblances between the heads of cystic worms and tapeworm heads had been first noted in the latte r part of the seventeenth century by Wepfer, then almost one hundred years later by Pallas and Goeze. Indeed, Goeze came very close to the truth regarding the development of C. fasciolaris when he wrote: On the 13th March, 1780, I found in the liver of the mouse, two clear, crystal vesicles, in each of which there was a pisiform vesicle, but on this as yet, no body. I believe that as regards the production and development of this kind of worm, I have surprised nature in the act.50

Following the same line of thou ght, Goeze's friend, Wagler proposed that tapeworms of cold-blooded animals should be fed to other cold- and warm-blooded animals and vice versa, then watched to see if they became degenerate o r acquired novel properties from their new host. The second impetus was provided in 1842 by Steenstrup when he formulated his theory of the alternation of generations 112 (see chapters 2 and 4). H e conjectured that the cystic worms were early stages in the development o f helminths that were unknown to him. Steenstrup argued, therefore, that these worms should no longer be classified a s a separate group, just as he maintained that certain asexual trematodes such as Cercaria species should also no longer be categorized separately. It is surprising that Steenstrup did not connect the cystic worms with tapeworms as not only had Pallas and Goeze recognized the relationship, but a number o f other authors including Nitzsch, FS Leuckart and F Müller had already recommended the abandon ment of this unnatural cleavage of cystic worms from tapeworms. Küchenmeister summed up the reasons for the general failure of helminthologists to appreciate the connection betwee n cystic worms and tapeworms when he wrote: Naturalists either did not correctly comprehend the true direction of progress, or, for reasons which it is difficult to perceive, they ignored the labours of their predecessors.69

As a consequence of Steenstrup's promulgation of his doctrine of th e alternation of generations, however, a number of investigators re-assessed their ideas. Dujardin in France in 1845 asserted that cystic worms were incompletely developed tapeworms. He surmised that they were formed by the germs o f tapeworms which, instead of going into the intestines of their natural hosts , somehow arrived in the tissues, and under the influence of this unusua l dwelling-place, developed abnormally to become cystic worms; he regarde d them as "une sorte de monstruo sité"42. At around the same time, von Siebold in Breslau, Germany (now Wroclaw in Poland), expressed similar convictions. As he later recounted, von Siebold initially had held the simple (and correct) view that: In its form, its suckers, and its circlet of hooks, the head of the asexual cystic worms possesses such a striking similarity to the heads of certain tapeworms, that one is tempted to believe that the cystic worms are nothing else than undeveloped and larvae-form tapeworms.104

Von Siebold thought that the adult and larval f orms of the worms must be found

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in different animal hosts "since the young brood was so seldom seen near the cestodes"103. He then changed his mind about the development of these cyst s and arrived: at the most decided conviction that the cystic worms are strayed tapeworms which have remained undeveloped and become degenerated, and of which the body grew out in foreign soil into a vesicle, without developing sexual organs. 102

Von Siebold voiced this view repe atedly and vociferously. In another paper, he expounded this theme once more: I finally became convinced that all cystic Entozoa are nothing else than undeveloped or larval tapeworms, which, arrested in their wanderings, have become aberrant and dropsically degenerated.107

This idea was partly engendered by his false belief that, in bladder worms, the scolex end of the larva was formed first th en this developed a posterior (caudal) projection which in turn underwent secondary hydropic degeneration. Vo n Siebold seems to have been unaware that Goeze had already shown in the case of C. fasciolaris of the mouse, that first the cystic caudal end was formed, then the scolex appeared. It was not until the Prague zoologist, von Stein , demonstrated in 1853 a similar development of a small bladderworm in th e larva of the mealworm (Tenebrio molitor) that this sequence of events became generally accepted. Moreover, von Siebold either conveniently forgot, or else, incredibly, was ignorant of the writings of earlier workers, and claimed, even as late as 1853, that he was the first person to draw attention to the similarity between cystic worms and tapeworms 107. This so annoyed Küchenmeister that he went to great lengths in his textbook to demonstrate that von Siebold was decidedly in error in this claim 69. Furthermore, von Siebold's championship of the theory of dropsical or cystic degeneration of tapeworms was to lead to an acrimonious difference of opin ion with Küchenmeister. Thus, according to von Siebold, certain eggs of the tape worm of the cat, T. crassicollis (now known as T. taeniaeformis), frequently strayed into rodents and there degenerate d dropsically (i.e. filled with fluid) into C. fasciolaris, but when their host was devoured by a cat and they became transplanted into their "proper soil", they cast off the degenerated segments, returned to the normal form of T. crassicollis and arrived at sexual maturity. Von Siebold then went further and claimed that with the exception of C. fasciolaris of the mouse, and possibly C. crispus, all of the many other cystercerci have deg enerated so far into a dropsical state, that by virtue of their gross distension, they were no longer fit to return to the state of sexual maturity and consequently they perished without descendents 105,109. In 1850, the Belgian zoologist, PJ van Beneden theorized that the head of a tapeworm (which he named "scolex") is produced from the egg of a tapeworm and conjectured that if the egg reached the gut of a suitable animal host, th e jointed mature tapeworm (which he called "strobila") would develop and grow without interruption. On the other hand, he hypothesized that if the egg found its way into the intestine of an unsuitable host, the head would develop but that the hind part would become inflated and the scolex would sink into it, thu s

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forming a cysticercus 14. Thus, van Beneden deduced that bladderworm s (Cystici), which had hitherto been regarded as a separate class of helminths , were simply larval tapeworms. This correct view was not accepted readil y because the evidence that he advanced was slight. In any case, van Benede n was wrong in thinking that eggs developed directly into tapeworms and tha t bladderworms were an unnecessary stage and appeared only incidentally. This was the state of affairs when Friedrich Küchenmeister in Zittau, (now East) Germany began to investigate the effects of administering various cystic worms to different animals. One cannot but be impressed by the perspicacity of this remarkable man and wonder about the driving forces which impelle d him to seek the truth. Not only did he lack the intellectual milieu in which t o discuss his ideas and concepts, but he found time to pursue his studies in the midst of running his medical practice, despite the absence of laboratory facilities and technical and financial assistance. In the great tradition of Redi , Küchenmeister emphasized the importance of hypothesis and experiment for helminthology and thus became the major figure in the renaissance of this field of scientific endeavour. Küchenmeister began with two of the most easil y accessible cysticerci, C. pisiformis of the rabbit and C. fasciolaris of the mouse. Between 18 March and 9 April 1851. Küchenmeister fed 40 C. pisiformis to a fox then recovered young tapeworms which he called initially Taenia crassiceps 65,66. He then gave C. fasciolaris to a cat and again succeeded in rearing tapeworms that were rapidly approaching maturity 67. Furthermore, he showed that when cy sticerci were fed to an inappropriate host, the cysticerci died and no development took place. He concluded that cysti c worms were not strayed, dropsical tapeworms as claimed by von Siebold, but were tapeworm larvae furnished with a vesicle which probably acted as a reservoir of nutriment. In fact, Küc henmeister indicated that cystic worms were an essential stage in the development and maturation of taeniae. His firs t reports in 1851 65,66, did not meet with universal acclamation, partly because he first identified the tapeworm that he had reared in foxes as T. crassiceps, then as T. serrata, then finally as T. pisiformis n. sp. (which is its current name) . Shortly afterwards, however, he successfully reared tapeworms in dogs from C. tenuicollis of domestic mammals and from Coenurus cerebralis of sheep68. Von Siebold, annoyed that he, an eminent University professor, had bee n upstaged by a mere general practitioner and amateur parasitologist, and en raged by Küchenmeister's treatment of his theory of dropsical degeneration of strayed tapeworms, lost little time in repeating the latter's experiments. In 1852 he confirmed the metamorphoses of C. pisiformis and C. fasciolaris and reported the same phenomenon with Coenurus 106,107. Nevertheless, he clung to his theory: Some individuals of the brood of T. crassicollis go astray in rodents and degenerate into C. fasciolaris; but when their hosts are eaten by cats and the worms are thus transplanted to their fit soil, they cast off their degenerate joints, and returning to the normal form of T. crassicollis, become sexually mature.110

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At the same time, von Siebold embarked upon a personal attack on Küchenmeister and tried to claim credit for himself for the discovery of the phenomenon in two ways. Firstly, he harked back repeatedly to an earlier comment in his article "Parasiten" dated 1844 102 (although it actually appeared in 1845) on the similarity between cystic worms and tapeworms; this, as we have already seen, was not an original observation. Secondly, he tried to impai r Küchenmeister's credibility by asserting that if he had not come to the latter's aid in determining the species of the adult tapeworms, the whole theory of the process of metamorphosis would have been thrown into such a state of con fusion that it could hardly have been corrected 107. To this, Küchenmeister responded in kind saying: "no-one has so grievously offended in the study o f cestodes as the professor of zoology" 70. As we have already seen, Küchenmeister attacked von Siebold's claims t o priority in drawing attention to the relationship between cystic and tapeworms and castigated his theory of dropsical degeneration 69. This in turn, drew the following riposte from von Siebold: "(Küch enmeister) has been led away by his zeal, to depart from that calmness of tone which becomes scientific contro versy."109. When Leuckart came later to review this contre-temps, he sided with von Siebold: "Küchenmeister in his book underrates von Siebold's share in the solution of the problem in a way which is, to every unprejudiced critic, utterly unfair"76. Küchenmeister may have used strong words, but there is no doubt that his experiments opened the door to the t ruth and his interpretation of the results thus obtained were correct. It must also be remarked in passing that not on ly was von Siebold wrong with his theory that cystic worms were strayed, degenerated, dropsical worms, but he also came eventually to the view that with the exception of echinococci, all the cystic worms were derived from one species of tapeworm which he called T. serrata. Thus, von Siebold claimed that w hen he fed C. pisiformis of rabbits, C. tenuicollis of cattle, C. cellulosae of pigs and C. cerebralis of sheep to dogs, he always found T. serrata in the gut. He concluded that the nature of the cyst is determined by the species of host in which the T. serrata larvae find themselves. These false observations reinforced his incorrect belief that cystic worms were a pathological st ate rather than being a physiological necessity for continuation of the life cycle 109. The only feasible explanation for this amazing error on von Siebold's part is that his dogs were coincidentally infected with T. serrata and that the dog was not a favourable host for the development of some cysticerci such as C. cellulosae. In passing, it should be noted that the idea that all of these cysts were derived from T. serrata was one of the points which Pouchet and Verrier used a fe w years later (1862) to attack the whole concept of cystic migrations o f tapeworms. They also criticized the experiments of Küchenmeister, van Beneden, von Siebold and others on other grounds, including their belief that the experiments were "too successful". In th eir own experiments, Pouchet and Verrier recovered more tapeworms than the numb er of scolices that they had given,

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and claimed to obtain two distinct species of tapeworms after feeding a single coenurus to a dog. This induced van Bene den to return to the fray to refute their views, but Pouchet and Verrier remained recalcitrant saying: we cannot believe that a microscopic embryo of a taenia enclosed in the intestines of a sheep can make for itself a passage up into the brain of the ruminant, and then undergo transformation into a vesicle, which engenders numerous scolices. 93

Nevertheless, this was the last gasp of the sceptics and the views of Küchenmeister and others became generally accepted.

EXPERIMENTAL GENERATION OF E. GRANULOSUS ADULT WORMS By 1852, enough was known to stimulate feeding experiments with echino cocci. It was von Siebold who first achieved success. He began his invest igations in the summer of 1852 and re ported his results in the following year 108. He obtained hydatid cysts from sheep, then saturated milk with echinococcal larvae and poured it down the throat of a number of dogs. In a dog which was killed 12 days later, no worms were found in the stomach, but the entire small intestine was lined with innumerable small echinococcal worms, all wit h extended heads which were placed deep between the villi. They looked littl e different from the original larvae within the echinococcal cysts except that they were longer and more slender. When another dog was killed 22 days afte r infection, the worms were found to have d eveloped further, consisting of a head and two or three posterior segments. Finally, 27 days after infection, vo n Siebold discovered mature worms several millimetres long, which had a head and three posterior segments containing reproductive organs and eggs. These, von Siebold called Taenia echinococcus, and summarized his findings thus: Proof that the brood of the E. veterinorum must adapt well in the duodenum of the dog is the elongated state in which the Echinococcus larvae are seen there after feedings, the growth of the same which follows soon thereafter, and finally the production of eggs and embryos in those body segments having reached sexual maturity....that species of adult tapeworm to which the larval Echinococcus brood belongs seems to have escaped the eyes of the helminthologists until now. I suspect that this might be due in part to the small size of this species of tapeworm and in part to the short time span which is required for its sexual maturation. 108

These adult worms had in fact been noted earlier by a number of observers. Hartmann may have seen them as early as 1694, but he did not realize wha t they were53. In 1808, Rudolphi discovered them in the intestine of a young dog and regarded them as the immature heads of T. cucumerina (= cateniformis = Dipylidium caninum) formed by spontaneous generation from the intestina l villi101. They were seen again in 1850 by van Beneden who, thinking that they were a new species, described them in 1852 as T. nana 15. Von Siebold's experiments were soon repeated and his results confirmed by Küchenmeister (1853), Wagner (1854), van Beneden (1857), Leuckart an d

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Nettleship (1866). These investigators showed that echinococci from sheep , pigs and cattle transformed in the intestines of dogs, but incubation periods of up to 11 weeks were required. Not only did this discovery clarify much of the life cycle of this parasite, but it paved the way for resolving the longstanding battle over the identities of echinococci occurring in various hosts. Initially, all attempts by Küchen meister, Zenker, Ercolani, Vella and Levison to rear adult echinococcal tapeworms in the intestines of dogs from cyst s obtained from humans failed. Success finally attended the efforts of Bernar d Naunyn working in Berlin, Germany. On 17 February 1863, a large hepati c cyst was punctured and the fluid drained. Shortly thereafter, the patient die d from what was said to be typhus and autopsy confirmed the presence of a large hepatic hydatid cyst with well-preserved daughter cysts; this was thought to be E. altricipariens. Liquid containing a few hundred scolices was taken from this cyst and administered to two dogs. One dog, which had received a smalle r number of worms, was killed 28 days later, but no worms were found. Th e other dog was killed five weeks after infection; mature, small tapeworm s identical with the known Taenia echinococcus were found in the small intestine. Thus, Naunyn not only confirmed that echinococcal cysts of human origin undergo the same process of development as do hydatid cysts of animal origin, but in demonstrating that the adult worms obtained from the two sources were similar, also showed that there was but a single species, T. echinococcus 87. As a result of his experiments, Naunyn reached the following conclusions: since these taeniae in all known characteristics correspond to the Taenia echinococcus von Siebold, they must be considered identical....this Taenia originates from the scolices of the human Echinococcus....and....therefore, the Echinococcus of man is the bladder-worm stage of T. echinococcus living in the intestine of the dog.87

These results were confirmed soon afterwards by Krabbe and Finsen working in Iceland (1866) 64, then a few years later by JD Thomas in Adelaide, Australia (1883) 114, all of whom used hydatid cysts obtained from humans.

EXPERIMENTAL GENERATION OF HYDATID CYSTS To prove beyond all doubt that cystic worms were necessary steps in th e development of taenia, it was also requisite to show their development fro m tapeworm eggs. Such an experiment was first undertaken by Küchenmeiste r with the parasite he knew as Coenurus cerebralis (= T. multiceps). First he procured coenuri from a sheep then administered them to a dog in order t o obtain mature proglottids of the tapeworm. These were in turn given to a healthy sheep on 25 July 1853. Sixteen days later, the sheep became affected with vertigo (dizziness and loss of balance - coenurosis causes "staggers" i n sheep). When the animal was killed three days later, 15 small coenuri wer e

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found on the surface and in the substance of the brain. The experiment was then repeated in collaboration with Prof. Haubner of the Veterinary School i n Dresden, and at the expense of the government of Saxony. Similar results were obtained with Coenurus cerebralis, Cysticercus pisiformis , Cysticercus tenuicollis and Cysticercus cellulosae by these investigators 68. At around the same time, Leuckart was similarly able to produce Cysticercus fasciolaris in the livers of mice after feeding these animals with eggs from T. crassicollis from a cat. Although a number of investigators in the middle 1850's were able to produce a variety of cysticerci and coenuri by feeding eggs to appropriate animals, initial attempts to replicate these results with echinococci were unsatisfactory. Haubner came close to success when he fed a pig with eggs of T. echinococcus and found immense numbers of small vesicles resembling cystic worms in the various organs on dissecting the animal a f ew months later. Unfortunately, none of them were sufficiently developed for him to be sure that they wer e echinococcal cysts 55. Success finally crowned the efforts of Leuckart in 1867 75. He infected four suckling pigs with ova of T. echinococcus and was able to make careful naked eye examinations of the resulting cysts at intervals afte r infection. In one pig four weeks after feeding, he noted that the liver wa s studded with small, tubercular-like nodules 0.35 mm in diameter. Thes e nodules had a thick, homogenous capsule enclosing semisolid, granula r contents, and were most frequent in the interlobular spaces and beneath th e peritoneal coat of the liver. By eight weeks after infection, the parasites were 1 mm in diameter, showed slight lamination of the outer layer, possessed a well-marked inner germinal layer and contained fluid which escaped from it on puncture. After 19 weeks, the echinococcal cysts were 10-12 mm in diameter. Subsequently, Krabbe and Finsen successfully infected sheep wit h echinocococcal eggs, then Dévé and Dew r outinely infected many experimental animals.

STUDIES OF THE MIGRATION AND DEVELOPMENT OF LARVAE Two major series of investigations which did much to clarify the details of the migration of larvae and the deve lopment of cysts were undertaken in Paris then Rouen in France by Felix Dévé 34,35, and in Melbourne, Australia by Harol d Dew38 . It was observed that eggs hatched in the stomach then the liberate d larvae bored through the walls of that viscus or the small intestine and entered the radicles of the portal vein and were carried to the liver. Indeed, De w observed larvae in the portal vein within eight hours of feeding ova to pigs 37. Some larvae penetrated the hepatic filter and passed to the lungs. A few of the larvae managed to escape through this second net and enter the systemi c circulation and lodged finally in the peripheral tissues. This sequence of events

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fitted with the observed distribution of cysts in the human body. As early a s 1860, Davaine25 analysed reported cases and noted that in 373 cases, nearl y 50% of cysts were found in the liver, 10% in the lungs, and the rest wer e scattered throughout the rest of the body. Subsequent surveys such as those of Thomas114, Dévé34 and the "Australasian Hydatid Register "23 largely confirmed this distribution, except that a larger proportion of cysts were found in the liver, at the expense of non-pulmonary hydatids. T hese series also showed that a third or more of patients had multiple cysts. Goeze had observed a granular coat lining the interior of echinococcal cysts, but the germinal membrane was first properly described by Goodsir 51. Many observations were made on the mode of development of scolices and broo d capsules from this membrane by Huxley (1852), Naunyn (1862), Rasmmussen (1869) and Leuckart (1885), but considerable differences of opinion existe d until the position was clarified by Dew who carried out a series of invest igations in the 1920's. He studied the microsc opical appearances of echinococci in the livers of suckling pigs from as early as 12 hours after infection to as late as 150 days37. Even at the earliest time period, an accumulation of mononuclear cells was observed around the lar vae, together with lysis of adjacent liver cells; this was followed by a marked infiltration of eosinophils into the follicle . Vesiculation commenced in the second week and the follicle wall becam e marked more clearly into layers by four weeks; the elastic laminated cuticular membrane was developed and the nuclear material which comprised th e germinal layers of the cyst was scattered irregularly on its inner surface. These features were more apparent a t three months and the young cyst was beginning to be surrounded by a fibrous adventitia derived from the host. Scolices an d brood capsules did not appear until at least six months after infection. Th e brood capsules began as small masses on the germinal layer which vacuolated and formed scolices on their inner surfaces 36. Observations over many years in both humans and experimental animals showed that the rate of growth of these cysts was extremely variable, even within the same organ in the same subject. They undoubtedly grew faster in soft tissues but usually took between two and many years to grow large enough to produce symptoms. Occasionally, daughter cysts were found within hydatid cysts, i.e. they were replicas of the original cyst, bein g composed of an outer laminated layer and an inner nuclear layer usually containing brood capsules and scolices. It wa s Naunyn in 1862 who first showed that daughter cysts could arise directly from the germinal membrane or from brood capsules 86. He also claimed that th e daughter cysts could develop from sco lices, although this was denied by others. That he was correct, was proven subsequently by Dévé. Dévé and Dew both brought forward evidence that suggested that daughter cyst formation may be stimulated by environmental influences including trauma, entry of chemical s such as bile or urine into a cyst, and bacterial infection of cysts. In the late eighteenth century, the great English surgeon and anatomist, John

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Hunter, first formulated the idea that pelvic hydatid cysts were often secondary to rupture of a visceral cyst and were not the result of multiple infections 59. This view was criticized by Charcot and Davaine on theoretical grounds, but wa s revived by Bright in 1861 20 and by Petain and Volkmann (1877), all of whom warned surgeons about the risk of sowing hydatid elements by puncture of a fertile cyst. In 1889, Lebedev an d Andreev showed that if young daughter cysts were released into the peritoneal cavity, they continued to develop int o fully-fledged hydatid cysts 74. In 1898, Alexinsky in Russia injected hydati d "sand" (brood capsules and scolices) into the peritoneal cavity of seven rabbits and eventually recovered echinococcal cysts from four of the animals 1. Dévé then performed a series of experiments which put the matter beyond all doubt. On 21 September 1900, he injected brood capsules and scolices from a sheep hepatic cyst intraperitoneally into two rabbit s, remarking that echinococci never form daughter cysts in sheep. On dissection 16 weeks later, nine or ten small secondary echinococcal cysts were found in the peritoneal cavity of one rabbit and in the injection track in the subcutaneous tissues and in the omentum of the other rabbit26. Moreover, in the same series of experiments, Dévé demonstrated that, contrary to previous opinion, hydatid cysts do not die when they ar e punctured and the fluid drained 27. This still begged the question as to whether it was brood capsules, scolices, or both that produced secondary cysts. In a later study, Dévé produced hydatid cysts in many organs by intravenous o r intra-arterial injection of living scolices alone 29,30. This experience led Dévé to believe that daughter cysts probably arise most commonly from scolices. Dew repeated Dévé's experiments and concluded that secondary cysts may b e formed in all three ways, that is, from daugher cysts, brood capsules an d individual scolices 38.

RECOGNITION OF THE CLINICAL FEATURES One of the most striking features of echinococcosis is the fact that infectio n with large cysts may be completely asymptomatic. This has been known from time immemorial. Hydatid cysts (althoug h their true nature was unknown) were found frequently in slaughtered animals which had seemed perfectly health y while alive. Similarly, echinococcal cysts were encountered from time to time at post-mortem examination of humans who had not complained during life of symptoms that could be ascribed to the parasite. At the same time, it wa s appreciated gradually that most o f the clinical manifestations of echinococcosis were due to pressure effects on adjacent tissues, and were thus dependent upon the size, number and location of such cysts. The Icelandic physician, Joh n Hjaltelin, summed this up when he wrote in 1869: (The) symptoms are variable, according to the seat and the size of the parasite, and consist mainly in the functio laesa of the affected organ. This rule holds good,

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whether the hydatid exists in the brain, in the spine, in the organs of the chest, or in one of the abdominal organs.58

Since these cysts grew slowly, it was noted that the natural history of echinococcosis tended to have a slowly progressive, chronic nature. Perhaps the largest cyst or accumulation of cysts ever recorded was in th e case of a farmer from near Otago, New Zealand. When he was a child of si x years, he fell on a large stone and may well have caused a hydatid cyst to burst into the peritoneal cavity, for he became acutely ill for several weeks, the n gradually recovered. After two to three years, however, his abdomen gradually became more prominent and continued to increase in size slowly over the next 30 years. By the age of 39 years, his abdomen measured 57" (145 cm) in girth, and he weighed 17 stones (108 kg). His health deteriorated to the point where surgical advice was sought. Peritoneal flu id was aspirated and shreds of hydatid cyst were found. At operation in 1927, daughter cysts varying in size fro m cherries to coconuts were evacuated filling bucket after bucket and at least 11 gallons (50 litres) were removed. Ten weeks later, the patient, now weighing many stones less, returned to work as a shepherd. After three or four years, two cysts were observed growing in the abdomen, but the patient refused operation for another 13 years until 1943 when the two cysts, about the size of feta l heads, were excised 11. Perhaps the longest duration of infection on record is the case of an English boy aged 11 years who had an abdominal hydatid cyst removed in St. Bartholomew's Hospital, London in 1882. Two years later, he migrated to the United States of America. He was asymptomatic until 1926 when he developed recurrent bouts of abdominal and lumbar back pain. In 1939, at the age of 67, and 56 years after the initial operation, a mass was felt in the right upper quadrant of his abdomen. At operation, two masses of cysts were found in the liver and small, isolated lesions were scattered around the peritoneal cavity 72. The majority of patients have complications arising from echinococcal cysts of the liver44, while pulmonary echinococcosis has proved to be the secon d most frequent problem 12. Many patients have been recorded, however, wh o have suffered with echinococci in sites ranging from the heart (sudden death) to the bones (fracture). In addition to pressure effects, certain toxic reactions to echinococci began to be recognized. Among the more doubtful ones was the claim of Dévé tha t echinococcosis caused infantilism and that this condition could be improve d when the cysts were removed. Much more substantial was the appreciatio n around the turn of this century (at the same time that an understanding o f allergic reactions began to dawn) that anaphylactic reactions, often fatal, may occur in echinococcosis, particularly when echinococci ruptured either spontaneously or as a result of trauma such as diagnostic aspiration. Finally, major suppurative complications as a result of secondary bacterial infection wer e recognized.

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DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of echinococcosis has always been difficult, since not only does the parasite itself remain hidden in the tissues, but there are no embryoni c forms which issue forth into either the bloodstream or the excretions and which might be searched for. Rarely, a cyst has ruptured into the lungs or into th e biliary or intestinal tracts and the tell-tale grape-like daughter cysts have been coughed up or passed in the faeces. Similarly, a mass thought to be an abscess has been lanced and daughter cysts have extruded through the wound. Suc h observations have not always been reliable, however, for other lesions hav e sometimes been mistaken for echinoc occi, such as parts of a hydatidiform mole discharged from the uterus per vagina. Following the discovery by Goeze in the late eighteenth century of the pathognomonic scolices and hooklets, it became possible to be certain of the diagnosis. Nevertheless, this discovery was of only of limited value, particularl y when diagnostic aspiration of suspected echinococcal cysts fell out of favou r because of the risk of causing secondary echinococcosis or precipitating a n anaphylactic reaction. Some writers in the nineteenth century placed grea t reliance upon the sign of "hyda tid thrill"; this fremitus or vibration is produced by loosely-packed daughter cys ts shifting within the mother cyst. Nevertheless, it is so rare as to be of little practical value 10. For all of these reasons, attention turned during the early years of th e twentieth century to developing immunological tests to assist in the diagnosis of echinococcal infection. The first serological test was reported in 1906 b y Ghedini who described a complement fixation antibody assay using hydati d fluid from human cysts 48. This was followed in the next year by the demon stration by Fleig and Lisbonne of precipitating antibodies in the sera of persons with hydatid disease46. Weinberg then compared the two procedures, favoured the former, and did much to standardize the assay 120. The first skin test for echinococcosis was described in 1911 by Casoni who used carbolized, filtered antigens from the fluid in a sheep hydatid cyst; he noted the delaye d inflammatory reaction which developed some hours after immunization 21. Ten years later, Magath described an immediate reaction occurring within a fe w minutes of application of antigen 80 then this was confirmed as a more reliable diagnostic indicator by Dew and his colleagues 40. Much effort was made over the next few decades to improve these diagnostic tests, but they have remained only ancillary aids, for they are negative in up to a quarter of patients wit h proven infection, and are falsely positive in another small proportion o f patients. Nevertheless, they have proved useful adjuncts to diagnosis in th e right clinical setting. An alternative approach has to been to try to define the hydatid cyst b y radiological techniques, although until recently, these methods have had little chance of allowing the clinician to be completely confident about the nature of

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a space-occupying lesion. Chest radiography revolutionized the ease wit h which pulmonary echinococcal cysts could be discovered and observed. Contrast radiography was of limited value for hydatid cysts in the gastrointestinal tract and near the biliary tree. Hydatid cysts of the liver were particularl y difficult to characterize. Selective angiography began to offer possibilities i n the diagnosis of liver echinococci, but has largely given way to non-invasiv e techniques, first nuclear scanning of the liver, but now also ultrasound examination, whole body CT scanning and magnetic resonance imaging. Not only can these latter two techniques be used in any anatomical region, but in some cases, morphological delineation of daughter cysts may make the diagnosi s almost certain, despite the absence of histological confirmation of the presence of echinococcal tissue.

THE SEARCH FOR EFFECTIVE TREATMENT Despite many attempts to find anthelmintic drugs active against hydatid cysts, surgery has remained the mainstay of the therapy of echinococcosis. The first problem which all surgeons have had to face was to decide whether attempts at surgical intervention were more likely to do harm or good. This wa s particularly relevant prior to the advent of modern anaesthesia and surgica l techniques. John Hunter is quoted as saying, concerning hydatids of the liver, during one of his lectures on the principles of surgery: "When known to be a bag containing fluid it may be opened, but I would not be in a hurry to d o this"60. On the other hand, over a century later, another surgeon declared that although it is well-known that cysts occasionally die and atrophy resulting in "spontanteous cure", this happy outcome ought never be relied upon in place of surgery113. Throughout most of recorded history, surgery has consisted simply of puncture and drainage of a cyst. The experience of Aretaeus at the beginning of the Christian era8 has already been alluded to, and Bonetus in 1697 recorded the case of a patient with a liver cyst which discharged more than 200 vesicle s (daughter cysts) when it was opened 18. Another famous case from the sam e century is that of the Earl of Shaftesbury who was treated by his persona l physician, John Locke (cited in 88). Shaftesbury had a palpable abdomina l tumour for 12 years before it caused him any inconvenience. In May 1668, he experienced severe abdominal p ain and vomiting then suddenly a soft mass the size of an ostrich's egg appeared in his abdominal wall. On 12 June it wa s opened by cautery and a large quantity of purulent matter containing "man y bags and skins" was discharge d. Some of the most eminent surgeons and physicians in London were consulted and it was decided to keep the abscess open for drainage by insertion of a silver tube. This operation became commo n knowledge and Dryden penned the folllowing lines: The working ferment of his active mind

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in his weak body's cask confined would burst the rotten vessel where tis bent but that 'tis trapped to give the treason vent.

Shaftesbury's operation was successful for he survived another 15 years . Others, however, were not so fortunate. Some patients died from what is now recognized as an anaphylactic reaction precipitated by release of echinococcal products into the tissues. Other patients developed recurrent hydatid cysts , either in the course of the needle track or in the peritoneal cavity. As has been noted, there was considerable controversy among surgeons for many years as to whether this was due to se eding of the hydatid material released at operation or not. Some surgeons who were concerned about this possibility attempted to kill parasitic tissue by injection of noxious agents after drainage. One of th e earliest surgeons to do this was Dr Bobilli er of Dunkirk who in 1851 punctured a large swelling near the umbilicus of a 36 year old sailor, evacuated a larg e quantity of clear serum, then enuc leated a hydatid cyst of great size by grasping a shred which had presented at the aperture site. He then resorted to dail y injections of iodine for two months, with gradual resolution of the mass an d recovery of the patient 17. Other substances used for their supposed parasiticidal properties included alcohol and gall. The opposite viewpoint is exemplified by Hutchinson (1864) who claimed that injection of these compounds increased the risk to the patient, and that simple drainage was all that was required 61. This latter course became unt enable when Dévé and others at the turn of this century demonstrated experimentally in animals that secondary echinococcal cysts could be induced. Furthermore, Dévé investigated potentia l echinococcicides in rabbits and showed that injection of 1:100 solution o f mercury perchloride or a 1:200 solution of formol for two and half minute s destroyed the viability of germinal epithelium 28. This approach was taken u p immediately by Quénu (1903) who injected hydatid cysts with 1% formali n prior to drainage in three patients. He showed that not only did formalin no t inhibit prompt and complete recovery, but that the contents of the cyst wer e killed94. By 1910, the standard procedure was to isolate the cyst by carefully packing around it with pads, injection of formalin, aspiration of fluid contents , enucleation of the entire cyst wall (germinal epithelium and laminated mem brane) and swabbing of the adventitious layer with formalin 79. The subsequent course was controversial. Possi ble methods of dealing with the evacuated cysts included marsupialization (sewing of the adventitia to abdominal wall muscle to allow external drainage), drainage into the peritoneal cavity, filling wit h saline and sewing it up, or obliterating it with sutures. In his review in 1910, MacLaurin believed that the first course of action was the safest, but surgeons came eventually to treat each case on its merits in deciding which method t o choose. As surgical techniques improved, it became possible sometimes t o remove the cyst in its entirety, including the adventitial capsule 7. Even if an apparently solitary hydatid cyst is removed, only time will tell whether ther e

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will be a recurrence, either as a secondary cyst resulting from spillage a t operation, or as the delayed appearance of a more slowly-growing cyst acquired at the time of the original infection. Although the success rates of operation have continued to increase over the years, some cysts have remained inoperable. Cysts are sometimes placed i n locations that make it too danger ous to intervene, or the cysts are so massive or widespread as to militate against surgical assault. In these circumstances , therapy with drugs is the only potential alternative. No drug showed an y promise until it was found in 1 975 that the benzimidazole compound, mebendazole, retarded the growth of E. granulosus in white mice and killed th e germinal epithelium 56. This led to enthusiastic trials with this drug in humans suffering from echinococcal infection. Although initial reports were encour aging, hope was dampened by subsequent experience 6, and mebendazole has not proven to be the answer for the treatment of hydatid infections. Currently, the related compound, albendazole, is under investigation.

UNDERSTANDING THE EPIDEMIOLOGY The demonstration by von Siebold that dogs were the definitive host o f E. granulosus and the experimental generation by Leuckart of echinoccoca l cysts after feeding eggs to sheep clarified in a dramatic fashion ou r understanding of the mode of transmission of hydatid infection. The next steps were to define the incidence of infection in humans, the prevalence of infection in various intermediate hosts, and the frequency of infection in dogs, and t o analyse the factors influencing the transmission of the parasite. It had long been appreciated that hy datid infection was more common among people with particular occupations such as farmers and butchers and i n members of their families. The reasons for this were now plain. When suc h people killed domestic animals such as sheep and cattle, it was their common practice to feed the offal (which often contained cysts) to farm and house dogs. These became infected and the resultant adult worms produced multitudes of eggs which were passed in the faeces. Although infection may be acquired by children eating dirt or by the consumption of uncooked, contaminated fruit and vegetables or by drinking polluted water, it was realized that the most potent source of infection was the caressing of dogs, allowing them to lick the hands and face, or to feed from common plates and dishes. Just as the frequencies of hydatid infections in relation to occupation wer e analysed, so the distribution of echinococcosis in different countries wa s investigated. It became apparent by the middle of the ninteenth century tha t echinococcosis in Iceland had reached e pidemic proportions. The Physician-inchief of the country, Dr Thorensen, considered that about one in seven of the inhabitants were so infected, and one o f his successors, John Hjaltelin, believed from his own experience of numerous autopsies, that echinococcal cysts could

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be found in one or another of the internal organs of nearly every fifth adul t body58. This remarkable prevalence was attributed to the intimate relationship between the Icelanders and their sh eep, cattle and dogs. It was estimated at that time that in Iceland there were 20 dogs per 100 inhabitants 64. For the same reasons, high frequencies were noted in a number of other sheep-raisin g countries including Australia, New Zealand, Argentina, Uruguay and nations of North Africa and the Midd le East. Thus, a writer to the Melbourne Argus in Australia observed on 10 May 1874 that: Hydatid disease is endemic in this colony; and though not so constantly met with as in Iceland, we may probably claim the doubtful honour of holding the second place in the list of countries so affected....To meet with hydatids as a cause of deranged health is now a matter of daily expectation with every medical practitioner.

The common occurrence of hydatid infection in humans was found to be coexistent with a very high frequency of infection in certain stock animals. Thus, in Iceland in 1863, Krabbe found echinococcal cysts in 12.5% of sheep 64. Similarly, in a survey in Victoria, Australia in 1929, 16.5% of 11,257 sheep, 23.9% of 4922 cattle and 0.5% of 2497 pigs were found to be infected 45. Despite the higher frequency of infection in cattle, sheep were of mor e importance in the maintenance of the life cycle of the parasite since the cysts in cattle were commonly simple, unilocular and sterile. Similarly, Dévé in 1923 found that in Tunisia, nearly all of the cattle, 20-60% of sheep and 30% o f camels examined were infected, while infec tions were insignificant in goats and pigs31. Occurring pari passu with a high prevalence of infection in cattle and sheep, was a high frequency of infection in dogs. For example, in Iceland in 1863 , 28% of dogs were infected 64, while in New Zealand in 1937, about one third of the estimated 120,000 rural dogs harboured adult E. granulosus 9. It was thus clear that echinococcosis was a zoonosis with the cycle being maintaine d between dogs and farm animals, particularly sheep, with human infectio n occurring incidentally and playing no part in the continued transmission o f infection. While the sheep-dog cycle thus described is the most important epidemio logical scenario, a number of other life cycles which may be of local importance have been discovered. These include transmission between kangaroos an d dingoes in Australia (with the potential for infecting aborigines) and between deer and wolves in Canada. On the basis of these different intermediate hos t specificities and/or on morphological characteristics, E. granulosus has been separated into a number of subspecies including E. granulosus granulosus , E. g. borealis, E. g. canadensis and E. g. equinus. Although these subdivisions may be somewhat controversial, all of these data have provided an ample base on which to evolve effective methods of prevention and control.

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THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Just two years after von Siebold's epochal discovery, Küchenmeister in hi s textbook laid down one of the cardinal principles on which the control o f echinococcosis is founded69. He argued that people who slaughtered domesticated animals should not be allowed to throw offal containing bladders (cystic worms) to dogs as food. Further, water should not be drunk unboiled, no r should raw fruit or vegetables be eaten where there was a chance that the y could have been contaminated with eggs. These suggestions were not widely taken up, however, perhaps because: his sentiments were expressed in a tedious and diffuse style, so characteristic of his writings, they did not, perhaps, receive the consideration to which they were undoubtedly otherwise entitled.77

In 1862, an English physician, Arthur Leared, visited Iceland and drew the attention of the country's doctors to the recent German discoveries on the life cycle of echinococci. Since dogs were indispensable to the farmers, Leare d conceived the idea of dealing with the problem by dosing simultaneously all of the dogs in the country with an efficient a nthelmintic. He concluded that kamala was the most efficient taeniacide available, and drew up a paper detailing his proposal for submission to Dr Hjaltelin, the chief physician, who was also a member of the Legislative Assembly. Leared's paper was translated int o Icelandic by Hjaltelin and published in two newspapers, then Hjalteli n undertook to have the plan enacted by parliament. In order to effect this , however, it was necessary to communicate with the College of Health i n Copenhagen, Denmark (Iceland then being a territory of that country). Leared forwarded his paper to Baron Eschricht, the head of the College. However, as Leared has recorded: The result was an amusingly intemperate letter, inveighing against foreign interference in the affairs of Denmark, and stating that he would himself undertake to send a competent person to Iceland to investigate the subject. 73

In a footnote to the document, Leared indicated the effectiveness of kamala in a dog of his own that he brought back to England from Iceland. Hjalteli n believed that the plan was "both original and practical" 58 but it came to nought. Eschricht's nominee, Dr. Krabbe was despatched from Denmark "for a very short time, the greater part of which was spent in making some feeding experiments on dogs" 58. All Krabbe could suggest as a preventive was to kill a great number of the shepherds' dogs. This proposa l was placed before the Diet where it was rejected as unsatisfactory. In 1890, however, a law was passe d controlling dogs by taxation and ensuring their treatment with anthelmintics and enforcing the burial of material potentially contaminated with echinococci. The keeping of dogs within the boundaries of Reykjavik, the capital city (with a quarter of the country's population), was forbidden, and an educational cam paign was conducted throughout the country explaining how the disease was produced and how it might be averted. P erhaps the most important factor of all,

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however, was a fortuitous change in farming practice; male lambs were killed at a younger age (4-5 months), thus giving cysts insufficient time to reac h maturity43. The consequences of all these measures were that by 1927, th e number of dogs had fallen to one for every 15 people from the one per fou r persons obtaining in 1890, and only 1 in 1500 of the human population ha d hydatid infection 83. Campaigns of increasing sophistication were mounted in a number of more developed countries such as Australia and New Zealand. Educational pro grammes alone often had no great effect. Since the infection had no noticeably detrimental effects on wool and mutton, farmers had no particular incentive to keep their sheep clean of parasites. They objected especially to the extra labour involved in boiling offal prior to feeding their dogs. One despairing Ne w Zealander lamented that "It has been re ported to us that our leaflets are not only left unread, but are sometimes condemned to ignoble use" 9. The control of echinococcosis suffered from two major disadvantages compared with campaigns against that other common wormy zoonosis, trichinosis. In the latter case, epidemics of fatal infection so alarmed the populace that the legislature was prodded into action. This was reinforced by the sever e economic consequences of trichinous infe ction. In contrast, echinococcosis was an infection of low-grade endemicity and did little to penetrate the nationa l consciousness. Perhaps more importantly, infection of the viscera had n o deleterious effects on the flesh for food purposes and so did not interfere with the export of frozen meat which was a staple article of the sheep and cattl e trade of many countries 3. Ultimately, however, legislation was enacted in some countries embodying the control of dogs, the compulsory intermittent administration of anthelmintics (first arecoline, the active constituent of areca nut, and later of bunamidin e hydrochloride), prohibition of feeding raw offa l to dogs, educational campaigns, and the monitoring of the results of these efforts. In many places, thes e programmes have been eminently successful, but in other countries lackin g sufficient finanacial and technical resources, echinococcosis continues it s ravages unchecked. Perhaps immunization of animals may eventually become a practical proposition, but no-one has yet improved on the unsuccessfu l attempts of Dévé in 1927 to immunize rabbits challenged with echinococci 32.

OTHER SPECIES OF ECHINOCOCCUS E. MULTILOCULARIS During the first half of the nineteenth century, a number of European pathologists, including Ruysch, Buhr and Luschka, described a peculiar and rar e tumour of the liver which they called "alveolar colloid" or "colloid carcinoma". In 1855, Rudolf Virchow recognized the characteristic hooklets of Echino-

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coccus in such a tumour and showed that the lesion was not a malignant proliferation but was helminthic in nature. Believing that it was a variation of the larval form of the common Taenia echinococcus (as E. granulosus was then known), Virchow termed the lesion "ulcerative multilocular hydatid" 117. He suggested that growth took place exogenously (instead of endogenously within a cyst wall) in the lymphatic spaces, the size and shape of which determined the nature of the growth. Initially, helminthologists followed Virchow's line that there was only on e adult echinococcal parasite. It was then realized, however, that this form o f hydatid infection was restricted in dis tribution to Germany, Switzerland, Russia and adjacent regions. In 1875, Morin 85 first propounded the view that ther e were two distinct species, one causing the usual hydatid infection, and the other producing the lesion described by Virchow. Considerable controversy was to follow. Klemm in 1883 fed the Virchow- type hydatid to dogs and could discern no significant differences between the resultant adult worms and th e well-known T. echinococcus. Thus, he upheld Virchow's statement as to th e unity of the two forms 63. On the other hand, Mangold in 1892 infected a suckling pig with eggs of an adult echinococcal tapeworm derived previously from a human alveolar hydatid. Autopsy four months later revealed two small alveolar hydatid cysts in the lungs of the pig and Mangold believed that thes e results supported the dualist conception 82. Posselt in Austria repeated thi s experiment in 1904 and obtained tapeworms from a dog fed with an alveolar echinococcal cyst. These worms had minor variations in the size and number of hooklets and the ova were arranged in a different manner. Posselt regarded these differences as sufficient to justify the creation of a distinct species which he named T. alveolaris 91. He also believed (erroneously) that this type o f hydatid disease was frequent in oxen and its limited geographical distribution was attributable to close association of humans with these animals. Further more, Posselt did not think that the dog was the normal definitive host, although he did not know the exact means by which man was infected. Other authorities took up these points to evolve the "double or dualist theory" that postulated the existence of two species whose larvae had different pathological effects an d whose adults may be differentiated morphologically. The major point in favour of this theory was the peculiar geographical distribution of the parasite 92. Nevertheless, some parasitologists, in particular Dévé, still held to th e original single form or "unicyst theory" which held that there was one species of parasite, E. granulosus, which under certain conditions gave rise to th e alveolar form of hydatid cyst. The main argument in favour of this hypothesis was that the alveolar hydatids were believed to be confined to humans. Th e corollary to this was that since dogs do not have access to human livers, th e variety should have become extinct if they were a separate species. In 1931 , Dew reported the first apparent case of alveolar hydatid infection in Australia; the parasite showed characteristics of both an alveolar hydatid and the multilocular form of E. granulosus. He used this observation to support the notion

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that the two lesions were morphological variants of the larval form of the same adult parasite39. Dévé then obtained, from the Pathological Museum in Vienna, portions of a tumour which Posselt in 1906 had described as an ordinar y hydatid and an alveolar hydatid lying side by side in the heart of a human , separate and distinct and with no connection or intermediate morphologica l stages. On re-examination, Dévé fo und all intermediate stages between the two supposedly distinct forms and decided that the loculative change in the hydatid must be ascribed to some special environ mental effect 33. A commentator in The Lancet in 1933 felt that at last the matter had been probably settled and stated that: The reasonable conclusion from these facts is that there is one species o f hydatid which occasionally grows in an abnormal fashion as the result o f abnormal, presumably extrinsic stimuli; and that the health officer is no t faced with the attempt to devise special preventive measures in the effort to combat infection from unknown strobiles inhabiting an unidentified hos t species.5 But the dualist theory was not yet laid to rest. In 1951, Rausch and Schiller discovered alveolar hydatid in fections in the tundra vole ( Microtus oeconomus inuitus) on St. Lawrence Island, Alaska 97. Alveolar echinococcosis was als o found to be prevalent in the Eskimo population on the island and Rausc h speculated that this form was probably identical with that causing alveola r hydatid infections in Europe and in the USSR. Natural infections were the n found in other mammals, including ground squirrels and shrews. In 1955 , Vogel showed by feeding experiments that the Alaskan and European hydatids were identical118. Moreover, he found that foxes (Vulpes vulpes) in the Serbian Alps were infected naturally with adult Echinococcus. He took the proglottids of these worms and fed them to voles and rats, and alveolar echinococcosi s resulted. Conversely, when a cyst from an infected field vole was fed to a dog, adult worms were obtained which differed morphologically from E. granulosus in a number of respects. Ironically, when Vogel re-examined some of Posselt's material, held in the Innsbruck Pathological Institute, he found simila r tapeworms in the small intestine of a dog that Posselt had fed with huma n alveolar material in 1901. Vogel also determined that, unlike E. granulosus, this parasite also developed in cats and foxes as well as in dogs. Further, h e could find no major morpholo gical differences between Alaskan and European collections, and concluded that they were geographical races of the one species. Finally, Vogel pointed out 119 that on the basis of priority, the valid name for this species was not E. alveolaris but E. multilocularis Leuckart 1863. This designation stands today, although it is rather unfortunate as it sometimes lead to confusion with the multilocular form of echinococcosis commonly seen i n cattle and which has also been given the name "multilocularis" but is in fact a form of E. granulosus. Thus, it became generally agreed that there were two species of Echino-

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coccus responsible for human hydatid diseases; E. granulosus matured in dogs but not in foxes while ungulates were the usual intermediate hosts, whereas E. multilocularis matured in cats and foxes as well as in dogs while microtin e rodents were utilized as interme diate hosts. The problems of speciation may be even more complex, however, with E. granulosus and E. multilocularis perhaps being at each end of a hypothetical scale encompassing a number o f "races", strains or subspecies that incorporate a number of features of eithe r species111. It was found that these parasites occurred most commonly in the liver , although primary lesions were disc overed occasionally in other sites. Pathological examination of these echinococci revealed that the cysts were often of only microscopic size. The limits of the parasite were uncertain, there being no true peripheral encysting layer; when laminated material was laid down, it was often imperfect, irregular and lacking in rigidity. The cells of the germinal laye r tended to spread out in long outrunners a long tissue planes into the surrounding tissues, thus simulating a malignant neoplasm. Scolex formation wa s uncommon and occurred only in a few tru e, small, spherical cysts. The adjacent liver cells were necrotic, a chronic inflammatory reaction of lymphocytes , epithelioid cells, giant cells, and eosinophils usually developed as did a n obliterative endarteritis, thus producing central caseation not unlike that seen in tuberculosis. Again like an infiltrating neoplasm, the parasite tended t o invade blood vessels and spread by metastasis to other organs, particularly the lungs, lymph nodes and brain, where the parasites replicated and reproduced the original lesion. It was observed that many patients complained of vague abdominal discomfort succeeded by jaundice. Clinical examination revealed that the liver wa s enlarged simulating a hepatoma or secondary malignant deposit. The diagnosis was made by liver biopsy. Although a few patients have been recorded where partial hepatectomy with complet e removal of the parasite has been successful, most patients run a downhill course and die within several years. The quest for an effective anthelmintic has so far not met with success.

E. VOGELI The discovery in a Los Angeles zoo of an unusual proglottid in the faeces of a bush dog (Speothos venaticus) which had been captured recently in Ecuador, led ultimately to the description of a new species, E. vogeli, by Rausch and Bernstein in 1972 95. The larval stage of this parasite was first identified in 1979 in two patients in Colombia by D'Alessandro and colleagues; they did this by feeding parts of the cysts to dogs and recovering adult worms subsequently 24. Since that time, more cases have been reported from other parts of Central and South America. Subsequent studies have indicated that the natural cycle o f infection is between the bush dog and the paca ( Cuniculus paca), but that

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domestic dogs could also be infected and are probably the usual source o f infection for humans96. In the paca (a rodent), the larva forms a polycysti c hydatid with endogenous proliferation, but in humans, the parasite is invasive and spreads by exogenous budding similar to E. multilocularis. Experience of this infection is limited. Like ot her echinococcal infections, definitive diagnosis is made by recovery of all or part of the parasite. Treatment is by surgica l resection where possible, but longterm mebendazole therapy is being evaluated currently. The prognosis is frequently poor, and prevention is difficult.

REFERENCES 1. ALEXINSKY JP. Ueber ein neues Operationsverfahren zur Entfernung von Echinococcus in der Leber und anderen parenchymatösen Bauchorganen. Archiv für klinische Chirurgie 56: 819-826, 1898 2. ANONYMOUS. London Medical Society: Living hydatids. Lancet i: 719-720, 1833 3. ANONYMOUS. Hydatid disease and public health. British Medical Journal ii: 970, 1929 4. ANONYMOUS. Some problems of hydatid disease. British Medical Journal i: 146, 1931 5. ANONYMOUS. The alveolar hydatid. Lancet ii: 304, 1933 6. ANONYMOUS. Medical treatment for hydatiddisease? British Medical Journal ii: 563, 1979 7. ARCE J. Hydatid disease (hydatidosis). Pathology and treatment. Archives of Surgery 42: 1-17, 1941 8. ARETAEUS CAPPADOX. De causis et notis etc. In, The extant works of Aretaeus the Cappadocian, translated by F. Adams, The Sydenham Society, London, pp 510, 1856 9. BARNETT L. Hydatid disease. Prevalence and prevention. New Zealand Medical Journal 36: 105-117, 1937 10. BARNETT L. Hydatid disease: errors in teaching and practice. British Medical Journal ii: 593-599, 1939 11. BARNETT L. Colossal hydatids associated with choloperitoneum. Medical Journal of Australia ii: 511-514, 1944 12. BARRETT NR, THOMAS D. Pulmonary hydatid disease. British Journal of Tuberculosis 38: 39-95, 1944 13. BATSCH AJ. Naturgeschichte der Bandwurmgattung überhaupt und ihrer Arten insbesondere nach den neueren Beobachtungen in einem systematischen Auszuge, Halle, pp 298, 1786 14. van BENEDEN PJ. Les vers cestoides ou acolytes, considérés sous le rapport de leur classification, de leur anatomie et de leur développement. Extracted from Mémoires de l'Académie Royale de Belgique de Bruxelles, volume 25, pp 190, 1850. Abstracted in British and Foreign Medico-Chirurgical Review 10: 322-335, 1852 15. van BENEDEN PJ. Mémoires sur les vers intestinaux. Supplement to Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences, tome 2, Paris, pp 376, 1858 (written 1852, couronné par l'Institut, 1853) 16. BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1691, 1895-1890 17. BOBILLIER. Extraction of a large hydatid growth from the abdomen; iodine injections; recovery. Lancet ii: 583, 1851 (Abstract) 18. BONETUS T. Sepulchretum sive anatomica practica ex cadaveribus morbo denatis, L Chonet, Genevae, four volumes, pp 1706, 1697-1700 19. BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst einem Anhage über Pseudo-Helminthem, Carl Schaumburg und Comp., Wien, pp 284, 1819 20. BRIGHT R. Clinical memoirs on abdominal tumours and intumescence, London, pp 55, 1861 21. CASONI T. La diagnosa biologica dell'echinococcosi umana mediante l'intradermoreazione. Folia Clinica Chemica e Microscopica 4: 5-16, 1911

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22. COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference more particularly to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 23. COLE G. The Australasian hydatidregistry. Health Bulletin No. 83/84, Melbourne, pp 22552261, 1945. Abstracted in Tropical Diseases Bulletin 44: 602, 1947 24. D'ALESSANDRO A, RAUSCH RL, CUELLO C, ARISTIZABAL N. Echinococcus vogeli in man, with a review on polycystic hydatid disease in Colombia and neighboring countries. American Journal of Tropical Medicine and Hygiene 28: 303-317, 1979 25. DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, J-B Baillière et fils, Paris, pp 838, 1860 26. DÉVÉ F. Des greffes échinococciques. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 53: 115-116, 1901 27. DÉVÉ F. Du siège sous-séreux des greffes échinococciques péritonéales. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 53: 117-118, 1901 28. DÉVÉ F. De la greffe hydatique obtenue par l'inoculation de scolex. Bulletin et Mémoires de la Société de Chirurgie de Paris 28: 905-910, 1902 29. DÉVÉ F. Echinococcose secondaire emboliquepériphérique. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 75: 100-102, 1913 30. DÉVÉ F. Secondary echinococcosis. Lancet ii: 835-838, 1919 31. DÉVÉ F. Enquête étiologique sur l'échinococcose en Tunisie. Archives de l'Institut Pasteur de Tunis 12: 353-356, 1923 32. DÉVÉ F. Essai de vaccination anti-échinococcique par le sable hydatique tyndallisé. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 97: 1130-1131, 1927 33. DÉVÉ F. De l'existence de formes de transition entre l'échinococcosehydatique et l'échinococcose alvéolaire chez l'homme. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 113: 223-224, 1933 34. DÉVÉ F. L'échinococcose secondaire, Massen et Co., Paris, pp 228, 1946 35. DÉVÉ F. L'échinococcose primitive (Maladie hydatique), Librairie de l'Académie de Médecine, Paris, pp 362, 1949 36. DEW HR. Observations on the mode of development of brood capsules and scolices in the encysted stage of Taenia echinococcus. Medical Journal of Australia ii: 381-384, 1922 37. DEW HR. The histogenesis of the hydatid parasite (Taenia echinococcus) in the pig. The development of the Taenia echinococcus from embryo to hydatid cyst. Medical Journal of Australia i: 101-110, 1925 38. DEW HR. Hydatid disease. Its pathology, diagnosis and treatment, Australasian Medical Publishing Company, Sydney, pp 419, 1928 39. DEW HR. Echinococcus alveolaris, with report of an Australian case. Australian and New Zealand Journal of Surgery 1: 115-141, 1931 40. DEW HR, KELLAWAY CH, WILLIAMS FE. The intradermal reaction in hydatid disease and its clinical value. Medical Journal of Australia i: 471-478, 1925 41. DIESING CM. Systema helminthum, Wilhelmum Braumüller, Vindobonae, 2 volumes, pp 1267, 1849-1851 42. DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairie Encyclopédique de Roret, Paris, pp 654, 1845 43. DUNGAL N. Eradication of hydatid disease in Iceland. New Zealand MedicalJournal 56: 213-222, 1957 44. FAIRLEY KD. Hydatid disease of the liver. Medical Journal of Australia i: 177-186, 1924 45. FAIRLEY NH, WRIGHT-SMITH RJ. Hydatid infestation (Echinococcus granulosus) in sheep, oxen and pigs, with special reference to daughter cyst formation. Journal of Pathology and Bacteriology 32: 309-335, 1929 46. FLEIG C, LISBONNE M. Recherches sur un sérodiagnostic du kyste hydatique par al méthode des precipitins. Comptes Rendus Hebdomadaires des Séances et Mémoires de al Société de Biologie 62: 1198-1201, 1907 47. GALENUS CC. In, Medicorum graecorum opera quae extant, edited by KG Kühn (Greek text with Latin translation), 20 volumes, Leipzig, 1821-1833 48. GHEDINI G. Ricerche sul siero di sangue di individuo affetto da cisti da echinococco e sul

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liquido in essa contenuto. Gazzetta degli Ospedali et delle Cliniche 27: 1616-1617, 1906 49. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, PA Pape, Blankenburg, pp 471, 1782. Partly translated in 62. 50. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweiderwürmer thierischer Körper, PA Pape, Blankenberg, pp 471, 1782. Partly translated in 69. 51. GOODSIR. Cited in 16 52. HARTMANNUS PJ. Vermes vesiculares sive hydatoides in caprearum omentis et in pulmonibus arterius furfuracea. Miscellanea Curiosa Sive Ephemeridum Medico-Physicarum Germanicarum Academiae Naturae Curiosorum. Decuriae II. Annus Quarti Anni MDCLXXXV (1685). Observatio LXXIII, Johannis Ernesti Adelbulneri, Nuremberg, pp 152157, 1705. Translated in 62. 53. HARTMANNUS PJ. De anatome canis hydropici. Miscellanea Curiosa Sive Ephemeridum Medico-Physicarum Germanicarum Academiae Naturae Curiosorum. Decuriae II, Annus II, Anni 1694, Leipzig and Frankfurt, p 299, 1695 54. HARTMANNUS PJ. De vesicularibus vermibus in mure. Miscellanea Curiosa Sive Ephemeridum Medico-Physicarum Germanicarum Academiae Naturae Curiosorum. Decuriae III, Annus II, Anni 1694. Observatio CXCIII, Leipzig and Frankfurt, pp 304-305, 1695 55. HAUBNER. Cited in 69 56. HEATH DD, CHRISTIE MJ, CHEVIS RA. The lethal effect of mebendazole on secondary Echinococcus granulosus, cysticerci of Taenia pisiformis and tetrathyridia of Mesocestoides corti. Parasitology 70: 273-285, 1975 57. HIPPOCRATES. Works of, translated by WH Jones and ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953 58. HJALTELIN J. The hydatid disease in Iceland: a few remarks on district-physician John Finsen's contribution to our knowledge of the disease. Lancet ii: 178-180, 1869 59. HUNTER J. Medical and Surgical Transactions 1: 35, 1793. Cited in 34 60. HUNTER J. Cited in 4 61. HUTCHINSON J. The surgical treatment ofhydatid tumours in the abdomen. British Medical Journal i: 197-201, 1864 62. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, 2 volumes, pp 677, 1978 63. KLEMM H. Zur Kenntnis des alveolären Echinococcus. Münchener Dissertation, pp 1-27, 1883 64. KRABBE. Recherches helminthologiques en Danemark et en Islande, GEC Gad, Copenhagen, pp 68, 1866 65. KÜCHENMEISTER F. Vorläufige Mittheilung(Über Cysticercus pisiformis der Kaninchen). Zeitschrift für klinische Medicin 2: 240, 1851 66. KÜCHENMEISTER F. Einiges über den Übergang der Finnen in Taenien und über das Digitalin. Zeitschrift für klinische Medicin 2: 295-299, 1851 67 KÜCHENMEISTER F. Ueber die Umwandlung der Finnen (Cysticerci) in Bandwuermer (Taenien). Prager Vierteljahrsschrift für die Praktische Heilkunde 33: 106-158, 1852 68. KÜCHENMEISTER F. Experimente über die Entstehung der Cestoden Zweiter Stufe zunachst des Coenurus cerebralis. Under Mitwirkung des Herrn Professor Haubner auf Befehl und Kosten des hohen königliche sachsischen Staatsministerii des Innern. Zeitschrift für klinische Medicin 4: 448-451, 1853 69. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, Teubner, Leipzig, 2 volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 70. KÜCHENMEISTER F. Cited in 76 71. LAENNEC RT. Mémoire sur les vers vésiculaires, principalement ceux qui se trouvent dans le corps humain, pp 176, 1804 72. LAWSON TC. Echinococcus cysts of the liver of fifty six years' duration. Journal of the American Medical Association 112: 1331-1333, 1939

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73. LEARED A. The cystic plague of Iceland. Lancet i: 337, 1867 74. LEBEDEV AI, ANDREEV NI. (Transplantation of Echinococcus cysts of man into rabbits). Vrach, St. Petersburgh 10: 633-635, 1889. In Russian. Translated in Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 118: 552-556, 1889 75. LEUCKART R. Die menschlichen Parasiten unddie von ihnen herrührenden Krankheiten. Ein hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876. (pp 1-256, 1867) 76. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 1, pp 1009, 1879-1886. The parasites of man and the diseases which proceed from them. A textbook for students and practitioners, translated by WE Hoyle, YoungJ Pentland, Edinburgh, pp 771, 1886 77. LEUCKART R. Cited in 22 78. LIVOIS E. Recherches sur les échinocoques chez l'homme et chez les animaux. Thèse de Paris, p 123, 1843 79. MacLAURIN C. The clinical manifestations, diagnosis and treatment of hydatid disease of the liver. British Medical Journal ii: 957-961, 1910 80. MAGATH TB. Echinococcus disease: etiology and laboratory aids to diagnosis. Medical Clinics of North America 5: 549-571, 1921 81. MALPIGHI M. Opera posthuma. Quibus praefixa est vita, a seipso scripta, A et J Churchill, Londini, pp 187, 1697 82. MANGOLD C. Ueber den multiloculären Echinococcus und seine Taenie. Berliner klinische Wochenschrift 29: 50-55, 1892 83. MATTHIASON S. Hydatid disease in Iceland. World's Health 8: 408-411, 1927 84. MORGAGNI JB. De sedibus et causus morborum per anatomen indagatis libri quinque etc., Remondini-ana, Venetiis, two volumes, 1760-1761 85. MORIN A. Deux cas de tumeur à échinocoques multiloculaires. Thèse de Berne, 1875 86. NAUNYN B. Entwickelung des Echinococcus. Archiv für Anatomie, Physiologie und wissen schaftliche Medicin, pp 612-638, 1862 87. NAUNYN B. Ueber die zu Echinococcus hominis gehörige tänie. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin, pp 412-416, 1863. Translated in 62 88. OSLER W. An Alabaman student and other biographical essays, Oxford University Press, Oxford, pp 334, 1908 89. PALLAS PS. Miscellanea zoologica: quibus novae imprimis atque obscurae animalium species describuntur et observationibus iconibusque illustrantur, Petrum van Cleff, Hagae Comitum, pp 219, 1766. Partly translated in 62 90. PECQUET. Extrait d'une lettre de M. P. a M. .... sur le sujet des vers qui se trouvent dans le foie de quelques animaux. Journal des Sçavants 2: 382-385, 1688 91. POSSELT A. Zur Stellung des Alveolarechinokokkus. Münchener medizinische Wochenschrift 53: 537-541, 600-609, 1906 92. POSSELT A. Ueber die Natur des Echinococcus alveolaris und seine Beziehung zum Echinococcus hidatidosis. Proceedings of the Third International Congress of Comparative Pathology, Athens, Reports of the Section of Human Medicine, pp 27-55, 1936 93. POUCHET, VERRIER. Expériences sur les migrations des entozoaires. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 54: 958-963, 1862. Translated ni Quarterly Journal of Microscopical Science 2: 171-175, 1853 94. QUÉNU E. Kystes hydatiques du foie. Technique opératoire contre l'échinococcose secondaire. Bulletin et Mémoires de la Société de Chirurgie de Paris 29: 719-729, 1903 95. RAUSCH R, BERNSTEIN JJ. Echinococcus vogeli sp. n. (Cestoda: Taeniidae) from the bush dog, Speothos venaticus (Lund). Zeitschrift für Tropenmedizin und Parasitologie 23: 25-34, 1972 96. RAUSCH R, D'ALESSANDRO A, RAUSCH VR. Characteristics of the larvalEchinococcus vogeli Rausch and Bernstein, 1972 in the natural intermediate host, the paca,Cuniculus paca L. (Rodentia: Dasyproctidae). American Journal of Tropical Medicine and Hygiene 30: 1043-1052, 1981 97. RAUSCH R, SCHILLER EL. Hydatid disease (echinococcosis) in Alaska and the

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importance of rodent intermediate hosts. Science 113: 57-58, 1951 98. REDI F. Osservazioni intorno agli animali viventi che si trovano negli animali viventi, Piero Matini, Firenze, pp 253, 1684. Partly translated in 62 99. RUDOLPHI CA. Beobachtungen über die Eingeweidewürmer. Archiv für Zoologie und Zootomie 2: 1-65, 1801 100. RUDOLPHI CA. Bemerkungen aus dem Gebiet der Naturgeschichte, Medicin und Thierarzneykunde, auf einer Reise durch einem Theil von Deutschland, Holland und Frankreich, Realschulbuch, Berolini, two volumes, pp 518, 1804-1805 101. RUDOLPHI CA. Entozoorum sive vermium intestinalium historia naturalis, Treuttel et Wurtz, Paris, 2 volumes, pp 1370, 1808-1810 102. von SIEBOLD CT. Parasiten. In, Handwörterbuch der Physiologie mit Rücksicht auf physiologische Pathologie, R Wagner (Editor), Braun Schweig 2; 650-676, 1844. Partly translated in 69 103. von SIEBOLD CT. Ibidem. Partly translated in 76 104. von SIEBOLD CT. Lehrbuch der vergleichenden Anatomie, volume 1, Wirbellose Thiere, Berlin, pp 679, 1848. Partly translated in 69 105. von SIEBOLD CT. Ueber den Generationswechser der Cestoden nebst einer Revision der Gattung Tetrarhynchus. Zeitschrift für wissenschaftliche Zoologie 2: 198-230, 1850. Abstracted in British and Foreign Medico-Chirurgical Review 10: 322-335, 1852 106. von SIEBOLD CT. Experiénce sur la transformation des vers vésiculaires ou cysticerques in taenias. Annales des Sciences Naturelles, series 3, 17: 377-381, 1852 107. von SIEBOLD CT. Ueber die Verwandlung des Cysticercus pisiformis in Taenia serrata. Zeitschrift für wissenschaftliche Zoologie 4: 400-408, 1853. Translated in Quarterly Journal of Microscopical Science 2: 255-263, 1854 108. von SIEBOLD CT. Ueber die Verwandlung der Echinococcus-brut in Taenien. Zeitschrift für wissenschaftliche Zoologie 4: 409-425, 1853. Partly translated in 62 109. von SIEBOLD CT. Über die Band- und Blasenwürmer nebst einer Einleitung über die Entstehung der Eingeweidewürmer, W Engelmann, Leipzig, pp 115, 1854. On tape and cystic worms with an introduction on the origin of intestinal worms, translated by T H Huxley, pp 88; bound with volume 2 of F Küchenmeister's Manual of Parasites, The Sydenham Society, London, 1857. 110. von SIEBOLD CT. Cited in 76 111. SMYTH JD. The biology of the hydatid organism. Advances in Parasitology 2: 169-219, 1964 112. STEENSTRUP JJ. Om Fortplantning og Udvikling gjennem vexlende Generations Raekker, en saeregen Form for Opfostringen i de lavere Dyreklasser, CA Reitzel, Kjøbenhavn, pp 76, 1842. On the alternation of generations, or, the propogation and development of animals through alternate generations: a peculiar form of fostering the young in the lower classes of animals, translated by G Busk from the German translation of CH Lorenzen, Ray Society, London, pp 132, 1845 113. STEVENS WM. The spontaneous cure of hydatid cysts. British Medical Journal i: 11391140, 1901 114. THOMAS JD. Hydatid disease with special reference to its prevalence in Australia, E Spiller, Adelaide, pp 219, 1884 115. TYSON E. Journal Book of the Royal Society, London, volume 7, pp 88 and 90, 1687 116. TYSON E. Lumbricus hydropicus; or An essay to prove that hydatides often met with in morbid animal bodies, are a species of Worms, or Imperfect Animals. Philosophical Transactions of the Royal Society 17: 506-510, 1691 117. VIRCHOW R. Die multiloculäre ulceriende Echinokokkengeschwulst der Leber Verhandlungen. Sitzungsberichte der physikalisch-medicinischen Gesellschaft zu Würzburg 6: 84-95, 1856. (Sitzungen 10 March-12 May 1855) 118. VOGEL H. Über den Entwicklungszyklus die Artzugehörigkeit des europaïschen Alveolarechinococcus. Deutsche medizinische Wochenschrift 80: 931-932, 1955 119. VOGEL H. Über den Echinococcus multilocularis Süddeutschlands. I. Das Bandwurmestadium von Stämmen menschlischer und tierischer Herkunft. Zeitschrift für Tropenmedizin und Parasitologie 8: 404-454, 1957

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120. WEINBERG M. Valeur comparée de deux procédésde laboratoire (déviation du complement et précipito-diagnostic) de l'échinococcose. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 66: 133-135, 1909 121. WEPFER JJ. Ventriculi tumor verminosus cum folliculo. Miscellanea Curiosa Sive Ephemeridum Medico-Physicarum Academiae Imperator Leopold Naturae Curiosorum. Decuriae II, Annus VII, Anni 1688, Observatio XVI, pp 26-35, 1689 122. ZEDER JGH. Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer von JAE Goeze mit Zusätzen und Anmerkungen herausgegeben von Zeder, Siegfried Lebrecht Crusius, Leipzig, pp 320, 1800 123. ZEDER JGH. Anleitung zur Naturgeschichte der Eingeweidewürmer, Bamberg, pp 432, 1803

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Table 12.1. Landmarks in echinococcosis ___________________________________________________________________ c.400 BC

Hippocrates alluded to lesions that were undoubtedly hydatid cysts in the abdomen of humans 1766 Pallas hypothesized that human hydatid cysts arose from tapeworms 1782 Goeze described the scolices within hydatid cysts and indicated their similarity with the heads of tapeworms 1851 Bobillier injected iodine into an hydatid cyst 1853 von Siebold discovered the adult tapeworms in the small intestine of dogs after feeding them with larvae from echinococcal cysts obtained from sheep 1855 Küchenmeister argued that offal of slaughtered domestic animals should not be fed to dogs 1855 Virchow discovered characteristic echinococcal hooklets in so-called "colloid carcinoma", now named E. multilocularis 1863 Naunyn recovered adult tapeworms from the small intestine of a dog fed with the contents of an hydatid cyst obtained from a human 1867 Leuckart generated hydatid cysts in pigs by feeding them with eggs obtained from adult tapeworms 1867 Leared reported that kamala eradicated tapeworms from the intestines of dogs 1889 Lebedev and Andreev showed that daughter cysts released into the peritoneal cavity of rabbits developed into fully-fledged cysts 1898 Alexinsky demonstrated that cysts developed from "hydatid sand" (brood capsules + scolices) injected intraperitoneally in rabbits 1906 Ghedini described a complement fixation test for serodiagnosis 1911 Casoni described a skin test for immunodiagnosis 1913 Dévé produced cysts by injection of scolices alone 1922-5 Dew described in detail the development of larvae in the tissues 1975 Heath and colleagues showed that mebendazole had some parasiticidal activity in experimental echinococcosis ___________________________________________________________________

Chapter 13

Taenia solium AND TAENIASIS SOLIUM AND CYSTICERCOSIS

SYNOPSIS Common name: tapeworm Distribution: cosmopolitan but absent from Australia and some parts of Oceania Life cycle: the adult tapeworms, usually 2-7 metres in length, live in the small intestine with the head attached to the mucosa. Eggs and gravid proglottids are passed in the faeces. When ingested by pigs, eggs hatch in the small intestine and each released larva (oncosphere) penetrates the mucosa and passes via the bloodstream to the tissues, especially the muscles, subcutaneous tissues and central nervous system, where it vesiculates to form a bladder worm (Cysticercus cellulosae); these usually reach 5-10 mm in size and contain an invaginated head. When ingested by a human, the head evaginates in the small intestine and develops into an adult tapeworm which produces eggs after approximately 3 months. Should humans ingest eggs, the larvae hatch and pass to the tissues in the same manner as they do in pigs Definitive host: humans Intermediate host: pigs Major clinical features: 1. intestinal taeniasis: abdominal discomfort, spontaneous passage of proglottids 2. cysticercosis: epilepsy, visual disturbances may occur Diagnosis: 1. intestinal taeniasis: finding of eggs (any Taenia) or proglottids (T. solium) in the faeces 2. cysticercosis: suggested by radiography and other imaging techniques, serology; proven by excision biopsy Treatment: 1. intestinal taeniasis: niclosamide, praziquantel 2. cysticercosis: praziquantel, surgery if necessary and possible

AWARENESS OF THE ADULT WORM AND DETERMINATION OF ITS NATURE Tapeworms have been known for generations. Individual proglottids o r segments of worms are so obvious that pr ehistoric man must have noticed them and wondered about their origin. They were alluded to by a number of writers at the beginnings of recorded history. Tapeworms were prevalent in ancien t Egypt and were probably mentioned in the Papyrus Ebers, dating around 1550 355

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BC32,85; the parasites may, in fact, have been Taenia saginata since, according to Herodotus, the ancient Egyptians did not eat pork. Tapeworms wer e described by the Greeks including Hippocrates (460-375 BC) 51, Aristotle (384-c.322 BC)8 and Threophrastus (c.372-286 BC) who called them eithe r µ (HELMINS PLATEIA) meaning "flatworm" or (TAINIA, TAENIA) meaning "band" or "ribbon" worm. Thus, Threophrastus remarked: This worm (flatworm) naturally infects certain races. Speaking generally, the following are liable to it - the Egyptians, the Arabians, the Armenians....The Thracians have it not, nor the Phrygians. Among the Hellenes, those Thebans who frequent wrestling schools and the Boeotians generally are liable to it: but not the Athenians. 105

Romans such as Celsus (c.20 AD) 24, Pliny the Elder (23-79 AD) 20 and Galen (129-c.200 AD)41 recognized tapeworms and named them "lumbricus latus". "Lumbricus" was a group term meaning "worm" and "latus" meant "broad" or "wide". Thus, Galen wrote concerning intestinal worms: Again, worms also occasionally take possession of the bowel, and these are discharged at one time from the lower bowels, at another more nastily from the mouth; and we observe them sometimes to be flattened, which are the worst, at times to be rounded.41

Similarly, these worms were apparent to peoples in many other parts of th e world, including India and China and mention is made of them in the Asia n ancient literature 52. Early writers had various ideas about the nat ure of these worms. Hippocrates, Aristotle and Galen regarded the tapeworm as an animal, but Aetius 2 (c.550 AD) and Paulus Aegineta 1 (c.640 AD) thought that a tapeworm represented a transformed strip of intestinal lining. In the latter part of the first milleniu m after Christ, some Arab authors such as Serapion (c.800 AD) regarded th e individual tapeworm proglottids as distinct worms 99. These were named cucurbitini, not only because of their resembl ance to pumpkin seeds ( Cucurbita species), but also because pumpkin seeds were one of the earliest remedies for tapeworm infection. Many Arab writers did not consider the whole tapeworm as a worm at all, but believed that it was a membrane formed by the intestine to hold these cucurbitini, whereas others, including Ibn Sina (Avicenna , 981-1037 AD) thought that cucurbitini (pumpkin seed worms) and taeni a (gigantic worms) were completely different creatures 10. The name taenia "solium" was apparently first used in relation to tapeworms in a publication by Arnaldo Villanovani (Arnault de Villeneuve, c.1300 A D) who wrote: quidam dicunt quod isti cucurbitini generantur in ventre cujusdam maximi lumbrici qui aliquando emittitur longior uno vel duobus brachiis, qui solium sive cingulum dicitur.111

According to Nicholas Andry , this expression was already in verbal use before Villanovani's time and reflected the erroneous belief that a person could only be host to a single tapeworm. He wrote that the worm was "called solium from its being the only one of its species in the body" 4. This view was disputed by

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Leuckart, however, on the grounds that the Latin word for "single" or "alone" is "solus" whereas "solium" means "seat" or "throne" 66. Leuckart therefore solicited the views of Dr Krehl, professor of oriental languages at th e University of Leipzig, who reported: "It is impossible to derive the word solium from the classic languages" 61. Krehl then went on to say that there were n o appropriate words in either Arabic or Hebrew, but that: "I should like to offer as an explanation the certainly somewhat Syriac word for tapeworm, namel y Schuschl-e (properly 'chains')"61. Krehl postulated that schuschl-e had become transformed into solium via Arabic then French or Spanish authors of th e Middle Ages: "Among the Arabians it would be changed into susl or sosl, and among the romance authors it would lose the second s" 61. This explanation seems a bit far-fetched. Simpler ones could be invoked equally well; perhaps the worm has been called "solium" because segments of the worm issue from the "solium" (meaning "seat" or "ru mp") while sitting on the "solium" (meaning the "throne", i.e. toilet)! As will be discussed in the next two chapters, Taenia solium was confused with Taenia saginata and Diphyllobothrium latum for two thousand years or more. Although Platter was ab le to discern differences between the strobiles of Taenia and Diphyllobothrium (see chapter 15), the key to the definitiv e separation of the various tapeworm species, as well as to a proper under standing of the nature of these parasites, was the discovery that tapeworms had a head. It fell to the Englishman, Edward Tyson, to make this fundamenta l discovery in 1683107, then, in the following year, the Italian, Francesco Redi , independently published small-scale and rather crude illustrations of the heads of dog and cat tapeworms 90. Many earlier anatomists had noticed a difference in the size of each end of a tapeworm segment. Some, including Spigelius104 and Amatus Lusitanius, did not take the setting of the worm segmen t in relation to the intestine into account and were misled into describing the more slender end as the tail. Others , despite their most diligent enquiries, could not come to any certain conclusion as to the orientation of the worm within the body. Others again, such as Tulp 106 and Fehr37, even described and illustrated heads that were not heads at all . Tyson, near the end of the seventeenth century, eloquently summed up th e current state of knowledge: The head of the Nile does not seem to be more plerplex't, and obscure to the Ancients, than that of this Worm, which has created as many controversies among Anatomists of late, as that has with the Geographers of old. 107

Tyson was fortunate in not only having a number of patients who suffered from tapeworm infections, but in encountering such worms in a variety of animals. It was the finding of tapeworms in the intestines of dissected dogs that allowed him to orientate the worm in the bowel correctly and gave him access to th e whole worm, thus permitting him to find the head: And it was in a Dog I opened at our private meeting, at the Anatomical Theater of the College of Physicians, where I observed this worm alive in the Ilion; not lying streight,

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but in many places winding and doubling. Having taken notice how the Joynts were, I traced it up, by carefully opening the intestine to the smallest Extream; where I expected the head to be; and which did lye towards the Duodenum; whereas the broader end was free, and did nothing adhere; whereas that small extream did do firmly stick, and has fasten'd itself to the inward coat of the Intestine, that it was not without some trouble, by gently raising it with my Nail, that I freed it from its adhesion.107

Tyson put the worm in spirit of wine then took it home to examine it at leisure with a microscope. Thereupon, he found that the head: very plainly appeared....beset with two orders of Spikes, or Hooks, whereof the larger did arise from the Center or Middle spreading themselves over the edges of the circumference; the other which were issuing out about the middle from the Center and were shorter....I could not upon my strictest Enquiry and with extraordinary Glasses too, inform myself of any orifice here, which we may suppose to be the mouth....This end was not perfectly flat, but a little globous and I could perceive....the neck....For some little space here, I could not observe with the glasses any Joynts at all, but after, very thick set, and small, and gradually increasing in length, as they descended towards the Tail.107

Subsequently, Tyson found similar hea ds in other tapeworms and was left in no doubt as to the correctness of his observations. He was troubled by his failure to observe a mouth in the head of the worm, and solved this dilemm a incorrectly by mistaking the genital aperture in each proglottid for a mouth . Tyson was, however, on the right track in his assessment of the hooks: Upon the whole, what seems most agreeable to me, and to be the true use of this part we call the head is this; by means of these hooks, or Spikes it might fasten itself, and so prevent, its too easy ejection out of the body. For it being so very long, and large too, and its body in many places winding, and convoluted, the descent of the faeces upon all occasions would be apt to carry it out with them; had it not this hold, which is so fast, that rather than loosen itself, parts of the body are sooner broken off, which we frequently see in the stool....hence it is that this Worm is of so difficult a cure. 107

Tyson also addressed two other questions. Firstly, it had been asserted by a number of authorities, both ancient and moder n, that tapeworms were not living creatures. This opinion seemed to Tyson to be wide of the mark, for he, as well as as many other physicians, had "observed it to move, and therefore to be an Animal and alive" 107. Secondly, other authors admitted a tapeworm to be alive, but maintained that it was not a single worm but many worms linked together and enveloped by a lining derived from the intestine. This sac was deemed not to be animated itself but received its motion from the proglottids (cucurbitini) enclosed within it. Thus, Gabucinus in 1547 wrote: I think the Broad worm to be nothing else, as Hippocrates says, than the white scourings of the Guts within which living creatures like Gourd-seed are bred....It comes away very frequently in pieces.39

Tyson disputed this view, for while examining a tapeworm recovered from a dissected dog, a couple of joints fell off intact, and yet there was no evidence of any membrane attached to the remainder of the worm. Further, he wa s unable to find such a structure in any tapeworm he examined, whether o f

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human or animal origin. The discovery of a head, together with the conclusion that a tapeworm was not a sac containing many cucur bitini, raised more questions as to the nature of the organism. Tyson himself was perplexed, and did not venture to give an y definitive answer, observing instead that it had not been his design to raise a new hypothesis, but to enquire into the truth of those of others, it being much easier to spy others' faults than to avoid them oneself! A few years later (1700), Nicholas Andry published his observations on the anatomy of tapeworms 4. He was the first to illustrate the head of a huma n tapeworm (which happened to be T. saginata). He did not follow Tyson's view that the genital pores were mouths, but regarded them as pulmonary openings through which the tapeworms took air: "the nipples must be looked upon as so many lungs"4. He was also familiar with the uterus and its ramifications, bu t mistook them for a tracheal system analogous to the tracheal system i n silkworms described previously by Malpighi. These errors were perpetuated by other authors and new ones were made . Thus, van Doeveren (1764) 30, Rosenstein (1778) 93 and Linnaeus, like Tyson, mistook the genital openings for mouths. Van Doeveren also considered that tapeworms had no real head but a sort of mouth at one end, and thought that the hooks on the scolex were teeth 30. The latter mistake had also been made some years earlier (1697) by Malpighi 75. Malpighi also considered that the suckers were eyes, as did Andry, although the latter author quoted Merry (1654-1722) of the Académie des Sciences as regarding them as nasal openings. Bloc h (1782), on the other hand, believed that these suckers were mouths; indeed, he thought that this was a good example of anatomical adaptation to physiological requirements, there being four mouths to enabl e sufficient food to be swallowed to sustain the very long body of the tapeworms 17. In contrast to the many staunch proponents of the theory of the spontaneous generation of worms, Andry was a firm upholder of the view that worms must develop from eggs. He believed that he had descried such structures: We cut up half an Ell (an English ell is 113 cm and a Flemish ell was 68 cm) of it, and examined it very narrowly....We only perceived all over it heaps of small Globular Bodies resembling corns of millet, but very round....M. Bellestre....examined these Globular Bodies, along with me, and is of Opinion, that these are Eggs....These Eggs are so numerous in the worm, that if you touch them with the Point of a Pin, that which sticks to the Pin, though no bigger than a grain of Dust, would appear to be an incredible Pile of small eggs.4

Some later commentators have believed that Andry may have mistaken th e round, calcareous bodies in proglottids for eggs. The next significant advance in the understanding of tapeworms was made by the German, Johann Goeze. He reported in 1782 that he was able t o demonstrate that the marginal opening at the side of each proglottid which had been mistaken for a mouth or for an airway was in fact connected with th e reproductive system:

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On the mature lower segments the marginal openings in part project so far that the protrusion and the indented osculum can be seen with the naked eye. I inserted a horse hair, and afterwards I pulled off the surface with fine instruments until I saw with pleasure under the magnifying glass that the hair was in the transverse canal that led to the ovary.43

Goeze observed eggs in the ovaries and drew rudimentary figures depictin g them. He was particularly puzzled by the fact that he had never seen an y tapeworm, whether of human or animal origin, which did not have eggs, and wondered how fertilization took place. Although Goeze did not know th e answer, he postulated a number of mechanisms, amongst which was the idea that these worms may be hermaphroditic: Are there, therefore, two sexes amongst them? Or is every tapeworm sufficient to itself and does it fertilize its own eggs? How are the organs for this purpose constituted and where are they?43

Over the next few decades, many of the details of the anatomy of tapeworms were elucidated. The absence of a digestive sys tem was confirmed and the presence of a vascular system was defined. Goeze himself had noticed two smal l openings on each side of every proglottid, each of which traversed the length of the proglottid. It was then shown that these vessels were interconnected at the head and descended throughout the length of the tapeworm, communicating with each other from proglottid to proglottid at their lateral margins. In 1841, Eschricht published the first detailed anatomy of a tapeworm ( D. latum) 34. In 1847, Emile Blanchard discovered the nervous system of tapeworms 16. Finally, the anatomy of the sexual apparatus w as gradually pieced together by a number of investigators, particularly the Germans, Mehlis, Platner and von Siebold. In 1835, von Siebold had observed that Taenia eggs contained an embryo wit h small hooks100, then in the following year he had discovered Taenia spermatozoa101. Leuckart provided a major analysis of the reproductive system in 1862, then Sommer a few years later provided further details of thi s system103. There still remained the problem o f defining the nature of the organization or individuality of a tapeworm. As mentioned earlier, many of the ancient Greek and Roman investigators were of the opinion that a tapeworm originate d through the union of separate proglottids. Some writers believed that th e cucurbitini were held together by an enclosing membrane derived from intestinal mucus, others thought that they were glued together, while yet other s believed that they held each other by mouth openings. This view that tape worms were formed by the union of previously free cucurbitini held sway until the end of the 17th century when the heads of tapeworms were discovered . Although this concept was now disposed of, a new question arose. Was a tapeworm a simple animal with a head and jointed body, or was it a compoun d animal? Most authors considered the tapeworm as a single animal that maintained its hold in the gut by means of the head and fed itself through it; th e longitudinal canals that had been recognized as running through the entir e

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length of the worm were thought to arise in the suckers and were regarde d erroneously as an intestine. Thus, a tapeworm was viewed as a single animal with numerous proglottids which were cast off at the posterior end. A n alternative proposition, championed by P J van Beneden (1850), suggested that the tapeworm was a compound animal of separate individuals. This concep t grew out of Steenstrup's theory of the "Alternation of Generations" . Accordingly, a tapeworm was believed to be a combination of two generations: the scolex which was single and had arisen by asexual multiplication, and the proglottids or sexual individuals which were usually present in large numbers. In essence, the scolex was considered to be the "nurse" to the strobila . According to van Beneden: the head (scolex) remains like a true nurse, asexual....By continued budding there arises from an originally isolated nurse a whole community of individuals - a colony in which one has to distinguish not only animals at various stages of maturity, but also one asexual and aberrant member, the so-called 'head'. 12

This view was attractive to Moquin-Tandon who wrote that the Taenia is a perfect animal which is composed of a scolex and a number of proglottid s which: constitute special organisms placed end to end and enjoying a community of life, but each of which at the same time is provided with all the elements essential to its individuality.78

Just as there was confusion over t he nature of tapeworms, so have there been differences of opinion over terminology. Felix Dujardin introduced the ter m "proglottis" to describe the isolated joint or cucurbitinus. This word wa s derived from the Greek word (GLOTTIS) meaning "tongue". Strictly speaking, since the plural of this word is "proglottides", "proglottis" should be used for a single joint and "proglottides" for more than one. These classica l niceties have been corrupted in many textbooks, however. I have followed the practice of the major text on medical parasitology 11 in using the terms "proglottid" and "proglottids" to describe one or more joints, respectively. The term "segment" is also vague, but is commonly used to indicate a number o f proglottids joined together. Similar etymological difficulties confront the user of the word "scolex". This term was introduced by van Beneden 12 to describe the head of a tapeworm. It is derived from the Greek word (SKOLEX, SCOLEX) for a worm. The use of "scolices" as the plural form of this word is firmly entrenched in the literatu re, presumably by analogy with the Latin words "index" and "indices". According to the Oxfor d English Dictionary, and as more recently discussed by Arme 9, such usage is erroneous and the rules of Gree k declension dictate that it should be "scoleces". Since it is hallowed by custom, I have continued to use "scolices" in this book. Similar difficulties apply to the term "strobila", also introduced by van Beneden, to indicate the connecte d series of proglottids. This word could be derived either from the Greek word (STROBILOS) meaning "anything twisted" or a "pine-cone" o r from (STROBILE) meaning "plug of lint twisted into the shape of

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a pine-cone" and which became "strobila" in modern Latin. Again, there ar e problems with the plural form of this word. It should not be "strobilae" (which would imply falsely a Latin origin). An Anglicized plural form of "strobilas " could be used; alternatively, Arme has suggested that "strobila" could be used for both the singular and plural forms of the word9. Perhaps even simpler would be to Anglicize the word completely and use the terms strobile and strobiles for the singular and plural forms of the parasite. Finally, it needs to be said that the worm was given its modern zoologica l nomen Taenia solium when Linnaeus placed it in the tenth edition of hi s Systema Naturae 67.

DISCOVERY OF CYSTICERCI The ancient Greeks were well-acquainted with measly pork although they did not comprehend its nature. By the time of Aristophanes of Athens (c.448-386 BC), the condition was so well known that he could use it in his play, "Th e Knights", with the slave Demosthenes suggesting that Cleon (one of the main characters) should be treated in the same way that pigs were examined: Let us force a stake into his mouth as do the cooks, and then, by pulling out his tongue, we will examine boldly and at our ease his wide-opened mouth to see if he is measled."

Similarly, Aristotle knew the chief localizations of cysts in pigs and compared them to hailstones 8, while others remarked upon their resemblance to pearls. Aristotle considered that infected pigs could not remain standing on their hind legs, and that if the bristles, especially those of the back, were pulled out they usually had drops of blood on their roots. J Rumler in 1558 may have been the first person to describe cysticerci i n humans when he found tumours on the surface of the dura mater in an epileptic person96. Some authorities also cite Conrad Gesner as having described th e parasite in 1558, but I have not been able to find a specific reference to such a passage. Panarolus in 1652 found similar cysts in the corpus callosum of the brain of an epileptic priest83. In 1656, the Englishman Thomas Wharton found large numbers of cysts, which he took to be glands, in the adipose tissue and muscles of a soldier 116. As discussed in chapter 12, none of these observers was aware of the animal nature of these lesions, and recognition of this fac t developed pari passu with similar observations made with other cysti c parasitic worms. In 1688, three years after he had described the motion of cysticerc i (Cysticercus tenuicollis) in the omentum of a goat, Philip Hartmann also found cysts in the heart of a pig. Within each cyst, and attached to its inner surface by bands which he termed the "frustulum", Hartmann found a worm, although he did not realize that he was looking at a head with its suckers and circlet o f hooks:

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In the heart of a pig I noticed that there were very many cysts....when the capsules were cut open a peculiar skin of thin membrane could be removed. This covered both a clear liquid and a white filament coiled like a white thread - itself a small worm. 48

Marcus Malpighi, at the end of the seventeenth century, discovered independently the animal nature of these cysticerci, and was the first person to speak of the head of a worm within each cysticercus. He investigated the structure o f cysts found in measly pork and saw within each vesicle, a whitish body which looked like a spiral staircase. At its extremity, he recognized a small head and wrote: "in apice atollitur capitulum" 75 meaning that at the apex of this body, a small head was erected. Around this period, Otto Fabricius also recognized the animal nature of measly pork. Nevertheless, these descriptions were eithe r vague or remained unnoticed for many years. In 1784, and apparently ignoran t of these earlier reports, Goeze re-examined the cysts found in pork, recognized that they were helminthic in nature, an d described clearly their morphology. In addition, he pointed out the similarities between the head of the worm with in the cyst and that of an adult Taenia found in the intestinal tract of humans 44. He included these wormy cysts among hi s "Taenia viscerales hydatigenae". Nevertheless, Goeze still believed in th e zoological independence of these parasites from tapeworms. In 1786, Werner rediscovered these cysticerci in humans. While dissecting the body of a soldier who had been in good health but who had drowne d accidentally, he found two small cysts, each of which contained a worm, under the pectoralis major muscle. These he named "Finna" since they resemble d measly pork which was called "fi nnen" in Germany 115. Over the next few years, a number of pathologists including Fischer, Treutler, Brera, Stenbech, Loschge and Laennec found similar lesions in humans, mostly in the muscles an d choroid plexus. When Gmelin came to publish his revision of Linnaeus's Systema Naturae in 1790, he accepted the verminous nature of these cysts, as well as thei r resemblances to tapeworms, and called them Taenia cellulosae 42. In 1803, Zeder created a new genus, Cysticercus, to house these parasites 123. This name was derived from a combination of the Greek words (KUSTIS, (KERKOS, CERCOS) meaning "bladder" and "tail" , CYSTIS) and respectively. A few years later, Rudolphi adopted this generic classification and applied the specific name "cellulosae" of Gmelin, the parasite thus becoming known as Cysticercus cellulosae 95. This name persisted until the genus wa s abolished when cysticerci were shown to be larval stages of Taenia, but the term "cysticercus cellulosae" continues to be used to describe the organisms of this type found in pigs and humans.

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ELUCIDATION OF THE MODE OF TRANSMISSION EXPERIMENTAL GENERATION OF ADULT T. SOLIUM The origins of intestinal tapeworms were a mystery for most of recorde d history. Indeed, as late as the early part of the nineteenth century, som e learned authorities still held that they were the products of spontaneou s generation (see chapter 2). The origin of tapeworms was uppermost in the mind of Edward Tyson in 1683 when he wrote the paper in which he described the head of a tapeworm, for he began his discourse in the following manner: The consideration of Insects, and their manner of generation, as it is a subject of curious speculation; so of late hath been much illustrated by the laborious researches of many inquisitive persons: whose travels therin, tho' they have much advanced the doctrine of univocal generation [i.e. sexual reproduction]; and bid very fair for the exploding of that, too easily received, and common error, of their production for putrefaction, yet one great difficulty still remains with me, how to account for several of those that are bred in Animal bodies not such as we may supposed to be hatched from eggs of like kind, that are received with the food or other ways, but of whom we cannot meet with a parallel, or of the same Species, out of the body. 107

Tyson was completely mystified as to h ow tapeworms could have arrived in the intestines by seeds introduced from the external environment for there were no free-living worms which resembled these creatures and could have provide d spawn: And what I have laid down I think I have made out, how different this sort of Worm, bred in animal bodys, is from all others hitherto observed out of it; from whence any Seminal matter of it, it may be supposed to be propogated. 107

This seemed to him to give some credence to the idea of spontaneous generation and he concluded the title of his manuscript with: "And the whole urged as a difficulty against the doctrine of univocal generation" 107. Tyson believed that the genital pores were mouths and considered that the proglottids became turgid after absorbing "chylous" intestinal contents through these openings . When he placed proglottids in spirit of wine, they spewed out what he took to be chylous juice into the receptacle. If he had examined this material under his rudimentary microscope, he may well have found the eggs and this could have given him a clue to the origin of the worms. Following the discovery of tapeworm eggs by Andry at the beginning of the eighteenth century, some commentators were induced to believe that the ov a must be involved in the generation of adult worms. A natural experiment was that reported by Peter Pallas in 1760. He introduced the small red eggs of the dog tapeworm, T. cucumerina (= Dipylidium caninum), through a small wound into the abdominal cavity of a pup. One month later, Pallas claimed to fin d there small tapeworms, less than an inch long and with very short segments 82. No-one was ever able to repeat this experiment and Küchenmeister in hi s

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textbook of 1855 summed up the general view succinctly: "This is ver y improbable, and, I think a complete mistake" 62. It is very difficult to known how this error occurred, for Pallas was a very talented and sagacious observer . Another obvious experiment, suggested by Pallas, Goeze and others, was t o feed eggs to animals in order to see if adult worms developed in the intestines; such experiments were entirely ne gative. This inability to produce adult worms from eggs administered either orally or parenterally, appeared to so confound the doctrine of "omne vivum ex ova" (all life comes from eggs), that bot h Rudolphi (1810) and Bremser (1819) actually believed that tapeworm s constituted the strongest argument known in favour of the doctrine o f spontaneous generation (see chapter 2). All this was to change with the demonstration that many cystic worms metamorphosed into adult worms in the intestines when ingested by suitable hosts (see chapter 12). By 1854, the conversion of Cysticercus fasciolaris , C. pisiformis, C. tenuicollis, Coenurus cerebralis and Echinococcus granulosus into their respective mature forms had already been prove n experimentally. Studies with a number of cysticercus/tapeworm systems ha d shown that following ingestion of cysticerci, each scolex attached itself to the intestinal mucosa by hooks and/or suckers, assumed a flattened form, the n produced, by budding, proglottids which became progressively more distinctly jointed and sexually mature; these were then cast off at the posterior end. The morphological similarities between the head of a mature T. solium from humans and the scolex of C. cellulosae, first pointed out by Goeze in 1784 then re-emphasized by Dujardin in 1845 31, suggested that a similar connection might exist between these two forms. In view of the difficulties of experimentatio n with humans, a number of German investigators including von Siebold i n Breslau, (now Wroclaw, Poland) , May in Weishenstephen, and Küchenmeister in Zittau, administered Cysticercus cellulosae to dogs. Both von Siebold and May claimed to rear mature tapeworms (which the former called Taenia serrata and the latter believed to be Taenia solium) in the intestines of thes e animals. In his experiment, May had kept his cysticerci preserved in water at 9oC for ten days before feeding. Küchenmeister regarded these results a s erroneous. He himself never succeeded in obtaining mature tapeworms afte r feeding C. cellulosae to dogs. Secondly, he demonstrated that the incubation of C. pisiformis (which metamorphoses easily in dog small bowel) in water for ten days made them incapable of further development. Finally, Küchenmeister thought that von Siebold's tapeworm was probably Taenia ex cysticerco tenuicollo (i.e. Taenia hydatigena) 62. At the beginning of 1853, however, Küchenmeister determined to examine the effects of administering C. cellulosae to humans. He obtained permission to administer bladder worms to a murderess under sentence of death, but was unable to proceed with the experiment. A year of so later, an opportunit y presented itself when a convict was scheduled to be executed several mile s

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from Küchenmeister's home, although the short time at his disposal gav e Küchenmeister scant hope for success. The investigation was undertaken i n collaboration with two medical colleagues, Dr D and Dr Z, whose names h e was not allowed to publish 63. Since C. cellulosae was not available at the time, one of these colleagues gave fresh C. pisiformis from a rabbit and C. tenuicollis from a pig intermingled with noodles in a soup cooled to blood temperature to the convict, so that he received the bladder worms without knowing it. Three and a half days before the convict's death, ho wever, Küchenmeister's wife found some C. cellulosae in their evening meal, which consisted of warm roast pork obtained from a nearby restaurant. Küchenmeister rushed around to th e restaurant, and after much pleading, obtained one pound of pork from the pig, which had been slaughtered 60 hours previously. Next morning, the priso n doctor gave the convict some blood sausage, from which a few of the fatt y pieces had been removed and a dozen bladder worms inserted, for breakfast. Over the next two and a half da ys, the condemned man ingested a further 61 C. cellulosae in sausage or soup. Forty eight hours after execution, the intestines were examined by Küchenmeister and his medic al collaborators in the presence of several professors. Not only did he find young larvae with hooklets, bu t Küchenmeister found a young tapeworm: I was successful in finding a small Taenia which was tightly attached with its projected proboscis to a piece of duodenal mucosa which I had softened in water for a few minutes.63

This was examined under the microscope and: we saw a young Taenia with a projected proboscis to which four hooklets pointing forward were loosely attached; these, when compared with other preparations of T. solium, T. serrata vera, and Taenia cystic. tenuicolli, proved clearly to be hooklets of the T. solium.63

Subsequently, they found another nine specimens, one of which had the complete classical crown of T. solium with 22 hooklets in two rows. Küchenmeister was left in no doubt that all these specimens harboured hooklets of the typ e seen in T. solium and C. cellulosae and not in the other cysticerci. Most of the worms were 3-4 mm long, but one was 6-8 mm in length and had an appendage. No traces of the last feedings were found in the intestines, and Küchen meister believed that those cy sticerci were probably already dead at the time of administration. In reviewing his r esults, he summarized them by saying that the experiment had established: (1) that the C. cellulosae is the scolex of the T. solium hominis (2) that the mode of infection with T. solium is exactly the same as with all others originating from bladder worms and probably like that of most of the Taeniae (3) that we, therefore, infect ourselves with T. solium since cysticercus is transmitted by those foods which we eat raw.63

Küchenmeister recognized, however, that th e experiment needed to be repeated with a longer time being allowed for comp lete development of adult tapeworms to occur. In an attempt to head off any adverse criticis m of the ethics of the experiment,

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he concluded his paper by pleading: that the surely harmless experiment of bladder-worm feeding be allowed to be repeated on criminals under probable death sentence; so that the whole developmental cycle of T. solium could be observed....In the case of the subsequent pardon of a convict, the tapeworms can be easily expelled; this will calm anxious souls and serve science at the same time.63

Nevertheless, criticism followed inevitably. The Lancet merely abstracted Küchenmeister's paper including his final point, and made no comment for or against the investigation, but the anonymous reviewer of his textbook in th e British and Foreign Medico-Chirurgical Review was scathing in his comments: What does our English reader think of the moral side of this experiment? The reviewer is aware that much may be said of using these and similar opportunities for the promotion of science. But he protests against a living fellow-creature being regarded in the light of a mere subject of experiments of this kind, even though he be a murderer whose hours are numbered. And he ventures to think that few would controvert the conclusion of one of the most eminent physiologists of the day, who indignantly alluded to this experiment at being 'debasing to our common nature'. 5

In the same year (1855) that Küchenmeister reported these observations , Aloys Humbert produced a patent infection in himself. In the middle o f December 1854, he swallowed 13 C. cellulosae. During the first few days of March, he began to pass segments of T. solium; however, notification of this experience was not published until 1856 when it was mentioned by Bertolus in his thesis54. In 1856, Rudolf Leuckart confirmed these observations. He gave four cysticerci to a 30 year old man who, after two and a half months, began to pass proglottids in his faeces; one month later, he was treated with kousso and two T. solium were expelled, although one was without a head 65. Leuckart repeated the experiment twice more that year, but on both occasions failed to produce a patent infection. In 1859, Hollenbach also infected himself with C. cellulosae; five months later, he passed a segment of Taenia five feet long, but lacking in a head 53. In late 1859, Küchenmeister had the opportunity to repeat his origina l experiment, but on this occasion, he was able to infect the subject muc h earlier64. In this instance, Küchenmeister collaborated with Dr. Liebenhaar. The prisoner was induced to swallow C. cellulosae on 24 November 1859 an d again on 18 January 1860, totalling 40 bladder worms in all. He was decap itated on 31 March 1860 and , at autopsy, half of the swallowed cysticerci were found to have developed into T. solium, eleven of them possessing sexuall y mature proglottids and the largest reaching five feet in length. Küchenmeister believed that the sheer numbe r of tapeworms produced ought to convince even the most sceptical that they were derived from the cysticerci that had bee n ingested. Again, the morality of the experiment was questioned. The British Medical Journal, after recounting these findings and Küchenmeister's assertion that the prisoner could have been treated if pardoned, went on to compare this method

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of experiment with the ancient way of thinking of the Rationalists, a s enunciated by Celsus, who thought that criminals might fairly be made use of for the purpose of extending medica l knowledge. The anonymous commentator then went on to cloud irrelevantly and emotively the specific issue in question by referring to: certain rather go-a-head proceedings in this way done by our Yankee medical brethren and recorded in Dr. Brown-Séquard's Journal. These gentlemen calmly investigated the movements of a palpitating human heart rapidly ripped from, the chest of a criminal, who after execution was cut down with a pulse still beating - we suppose we may say alive - for the satisfaction, it would appear, of the curiosity of the doctors. 6

and then went on to quote Wordsworth: Physician art thou, thing of eyes, Philosopher, a prying knave, A man who'd peep and botanise Upon his mother's grave"

These criticisms did not harm Küchenmei ster's ultimate reputation, for he came to be acclaimed as one of the most eminent parasitologists of his day, and the person who, above all others, established expe rimental scientific methods in the study of helminth infections. Similar results were obtained y et again when Heller gave 22 C. cellulosae to a patient suffering from phthisis. The person died 18 days later and autops y revealed twelve heads of T. solium, all small and without any segmentation visible50. Attempts were then made to infect rabbits, cats, dogs, pigs, sheep and cynomolgous monkeys with this parasite, but all were in vain, and it becam e accepted generally that humans were the sole definitive host of T. solium. EXPERIMENTAL PRODUCTION OF CYSTICERCUS CELLULOSAE A complete understanding of the life cycle of T. solium required not only that mature tapeworms be produced in humans after ingestion of C. cellulosae in measly pork, but that these cy sts should also be generated in pigs following the consumption of T. solium eggs obtained from proglottids passed by infecte d humans. This latter course was pursued contemporaneously with the former . It will be remembered that from the time of Pallas, various experimenters had fed eggs to animals, but they had sought adult worms in the intestines rather than cysticerci in the tissues. The first person to demonstrate the generation of C. cellulosae was the Belgian, P J van Beneden. In 1853, he gave T. solium eggs to a pig, then when it was slaughtered at the abattoirs four and a hal f months later, found a large number of C. cellulosae in the muscles. Van Beneden controlled the investigation by keeping another pig under the sam e conditions, except that it was not given any eggs; it had no cysticerci a t autopsy13. Similar results were then reported by Prof. Haubner in collaboration wit h Küchenmeister49. In view of the economic importance of the subject, Küchen-

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meister and Haubner had been commissioned by the Royal Saxon Ministry of State to investigate the metamorphosis of cystic worms. Three pigs were given T. solium proglottids on 7, 24 and 26 J une and on 2 and 13 July 1855. The first animal was killed on 26 July and small cysticerci with incompletely developed heads were found. The second pig was slaughtered on 9 August and a thousand cysticerci were disseminated in the viscera. The third hog, sacrificed on 2 3 August, was massively infected; Haubner and Küchenmeister counted 133 C. cellulosae in 4.5 drachms of meat which was the equivalent of 80,00 0 cysticerci per stone (approximately 6.4 kg) of pork. In a similar series o f experiments, they failed to generate C. cellulosae in dogs and sheep fed with T. solium proglottids. These observations were confirmed in the following year (1856) by Leuckart who infected successfully a number of pigs and observed them for up to si x months after infection 65. Similar experiences were then reported by Mosle r (1865) and Gerlach (1870). Occasionally, humans, like the pig, were found to be infected with C. cellulosae although this represented a dead end for the parasite, in civilize d communities, at least. The obvious conclusion (which, naturally, has neve r been put to the test), was that such infections in humans were acquired b y ingestion of T. solium eggs. The ova could either be ingested in contaminated food or water, or could be transferred directly from the anus to the mouth via fingers. An alternative possibility, suggested by Leuckart 66, was that reversed peristalsis might sometimes occur with retrograde movement in the intestines of mature proglottids which in turn then ruptured to release infective eggs. Attention then turned to study of the proce sses by which migration and development of larvae occurred in animal intermediate hosts. Early workers found that when eggs were swallowed by a pig, they hatched and the released larvae, furnished with hooks, bored their way through the intestinal mucosa an d migrated to the tissues where they lodged and developed into cysticerci , producing a scolex by a process which was ter med "asexual gemmation". These events were then described in great detail by Yoshino 119,120.

RECOGNITION OF THE CLINICAL FEATURES TAENIASIS SOLIUM The sign of tapeworm infection, par excellence, has always been the passage of proglottids through the anus. Sometimes, huge segments of worm wer e passed, particularly when anthelmintics were taken, thus engendering considerable terror in the patient. Tyson records the instance of a 20 year old patient of his, who, upon the use of an emulsion of cold seeds, dragged a tapewor m from himself "not without some frightful Apprehensions that the Guts and all were coming out" 107. This parasite measured 24 feet in length and numbere d

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507 proglottids. The total length of worm passed could sometimes b e extraordinary. Borrichius is said to have seen a patient who voided more than 800 feet of tapeworm during the co urse of a year, although whether this was all from one worm is questionable 18. In more recent times, a healthy woman who was treated with extract of male fern and castor oil passed four portions o f tapeworm (species not identified) into a bucket. When laid out and measured, the total length attained 79'4" (24.2 metres) and in places the proglottids had a breadth of 1" (2.5 cm). No heads were recovered, but as far as the autho r could ascertain, all the portions belonged to the same strobile 70. While many patients are infected wi th only one T. solium, multiple infections are possible, perhaps the record being the patient who was reported as having 25 mature tapeworms 86. In order to determine how many proglottids are produced and passed by a tapeworm, Yoshino (1934) infected hims elf with 3 C. cellulosae then observed himself for the next two years. Either two or three tapeworms grew and th e number of gravid proglottids passed were 334 in the first month, 174 in th e sixth and 126 in the twelfth month of patent infection; this approximates to 1-5 proglottids per worm per day 121,122. Goeze (1782) quotes the unusual case of a patient of his friend, Dr. Wagler; he was a young scholar who felt little distress except when he heard music: Then he had to run away or of fear had to ask that one would stop the music. Otherwise he was healthy and had great strength. I have seen anxiety and unpleasant sensation from music in several cases of taeniasis.112

Wagler's observation that the young scholar was otherwise healthy was the usual finding. The majority of patients were asymptomatic or had vague , indefinite abdominal discomfort. Nevertheless, a multitude of symptoms were ascribed to tapeworm infection, many of them being considered "sympathetic phenomena" and so-called "proof" of the aetiological relationship bein g provided by their cessation after removal of the offending parasite. These were anecdotal accounts, of course, and were not subjected to rigorous, scientifi c analysis. Thus, according to Davaine (1860), tapeworms might cause general indisposition, anxiousness, giddiness, noises in the ears, impaired vision, a n itchy nose or anus, salivation, palpitations, anorexia, indigestion, colic , syncope, weariness, emaciation, an insatiable appetite and convulsions 29. To these might be added chorea 40, insanity117, and diabetes 57. Küchenmeister was more circumspect than this, noting: All these symptoms are very deceptive if we should ascribe them to the presence of the tapeworm. Very often, they do not disappear when the worm is expelled, a proof that the latter is not their first cause. The stronger an individual is, the less does he complain of his symptoms when he suffers from tapeworm. 62

Time has supported Küchenmeister's cautions. The life span of T. solium is uncertain, but these tapeworms probably live for many years. The fact that humans usually suffer infection with only a singl e tapeworm was often interpreted as evidence of immunity to reinfection, but is was realized that this could also indicate non-immunological resistance which

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was dependent upon the continuing presen ce of an adult tapeworm 28. Definitive studies in which the recurrence of infection in a treated subpopulation in a n endemic area is assessed are still awaited. CYSTICERCOSIS Cysticercosis in humans was recognized much less frequently than was taeniasis solium. Occasionally the two conditions occurred together in the sam e patient. Thus, von Graefe (1866) found intestinal tapeworms in five of 8 0 patients with ocular cysticercosis 46. In many cases, patients were asymptomatic, as instanced by the incidental discoveries by Wharton and Werner of th e organisms in previously healthy individuals. Some persons had smaller o r larger numbers of subcutaneous nodules. One of the more dramatic examples of a patient with disseminated cysticercosis was described thus: He was pale and the face appeared puffy, but two outstanding features were the chain of nodules visible on the forehead and the greatly enlarged, apparently well developed and powerful muscles....The nodules....are found in the subcutaneous tissues of the forehead, scalp, beneath the left eye, in the neck and in the tissues of the cheek. They occur singly or in groups of two or three of varying size. When single, they are ovoid, flattened ovoid, or spherical according to the amount of pressure exerted by the surrounding tissues. In size, they range downwards from half an inch in longest diameter. They are found in the aponeuroses of the abdomen, elbow-joints, thighs and legs. In the muscles, they can be felt singly, in groups and in chains. One cyst is present in the left eye. . They have never been painful. They are movable and not at all adherent to the skin. Nearly all the muscles are enlarged, especially those of the shoulder girdle, and on contraction the muscles present a nodular appearance. He gives the appearance of being a powerful man....but the muscle power is in fact very feeble. Enlargement is due to the presence of the cysticerci and to the concomitant myositis.88

Such infections frequently left no serious musculo-skeletal sequelae, however, as evidenced by the man with hundreds of calcified cysts in his muscles, who after three days in hospital following an epileptic fit, attended the Scottis h Highland Games and took second place in the long jump 35. By the time Cobbold wrote his textbook on helminthology in 1864, it wa s well-recognized that cerebral cysticer cosis might cause convulsions and mental disturbances as well as various cranial nerve and long tract signs 26. In 1934, interest in this subject was re-awakened when a large number of Britis h soldiers returning from various outposts of Empire with "idiopathic epilepsy" were found to be suffering from cerebral cysticercosis 71,72. An unexpected feature of this study was that parasite s were often present for many years before the onset of cerebral symptoms; these appeared to be associated with death of the worms. In explanation of this, MacArthur (1935) hypothesized that th e biological objective of cysticerci while in the tissues of the intermediate host is to remain quiescent and he likened them to: "thieves who have entered some premises where they stay hidden so long as concealment is helpful to thei r purpose"73 and suggested that death of the parasite may have liberated toxins

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which increased the irritation which they caused. The recognition that humans might develop c ysticercosis by ingestion of eggs after contamination of their fingers with faeces or by peri-anal scratching lent urgency to the diagnosis and effective treatment of T. solium infections. At the same time, it became obvious that the outlook for patients with cysticercosi s was dependent upon both the number of cysticerc i and their location in the host. Whereas parasites in most tissues were usually of minor significance and were generally limited to less than one centimetre in size by the host inflammatory and fibrotic reaction, those situated in the ventricles of the brain o r subarachnoid spaces could grow much larger and endanger life. Similarly, a cysticercus in a strategic organ such as the eye could seriously impair vision. Whereas little could be done for such patients in the past, advances i n ophthalmology and neurosurgery and the recent advent of effective anthelm intics have improved the outlook considerably for many of these persons.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of tapeworm infection was obvious when a patient passed proglottids, but identification of the species of worm was not possible from these specimens for many years. After Küchenmeister described in 1852 the appearances of the reproductive organs, parti cularly the number of lateral branches on the gravid uterus in T. solium and T. saginata (which he called T. mediocanellata; see chapter 14), identification of the proglottids became possible on a routine basis. Alternatively, a specific diagnosis could also be made afte r treatment of a patient and recovery of the tapeworm head, but this was ofte n less feasible. At about the same period, it was also found that a diagnosis of tapeworm infection could be made by demonstration of taeniid eggs in the faeces. The first person to describe such eggs (which he took to be indicative of a new species of tapeworm) in faeces was Ransom in 1856 89. He was followed soon afterwards by Davaine who, in his textbook, emphasized the value of faeca l examination29. Despite occasional claims to the contrary, subsequent exper ience indicated that this technique did not permit differentiation of T. solium and T. saginata infections. With the introduction of the perianal swab tech nique for the diagnosis of enterobiasis (see chapter 17), it was found that this method also enhanced the ability to diagnose tapeworm infections, particularly those due to T. saginata 87. On the other hand, the diagnosis of cysticercosis was an altogether different proposition. The only certain method of diagnosis was by specific identification of the parasite following surgical removal of a cyst. This was particularl y difficult in patients with cerebral cysticercosis, although diagnosis was helped when eosinophils were found in t he cerebrospinal fluid 113. Despite the manifest advantages of a reliable immunodiagnostic assay for cysticercosis, repeate d

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attempts to develop such tests have not led to significant improvements . Serodiagnosis of cysticercosis began with the studies in animals of Weinberg 114 and with the demonstration by Fairley that complement fixing antibodies were present in the serum of only two thi rds of selected patients 36. These assays have not yet found a routine place in the diagnosis of cysticercosis 38. Radiology has had more to offer. Calcification of dead cysticerci appears to have been demonstrated radiologically first by Roth in 1926 94. New radiological techniques such as CT scanning and magnetic resonance imaging ma y facilitate greatly the diagnosis, particularly in patients with cerebra l cysticercosis.

THE SEARCH FOR EFFECTIVE TREATMENT Remedies effective against tapeworms have been sought and their virtue s expounded from the earliest time s23. So many agents had been declared to have anthelmintic properties, that in the middle of the nineteenth century, Küchenmeister was induced to declare: if the multitude of remedies recommended for any disease is an evidence of their want of power against it, we must say that the therapeutics of the tapeworm is extremely defective.62

Yet this was not entirely fair, for many of these preparations did possess some antitapeworm activity. Anecdotal clinical experiences over centuries hav e provided fairly convincing evidence of the efficacies of many of these drugs . They were often given concurrently with powerful purgatives which increased peristalsis and assisted in evacuation of the tapeworm. Küchenmeiste r attempted to produce some order out of the chaos by a series of in vitro experiments in which he mixed Taenia ova in egg white with various com pounds and determined the time that the ova took to die 62. It is only in the last 100 years that various putative anthelmintics have been submitted to carefu l clinical trial and rigorous scientific analysis. Perhaps the best known and most commonly used anthelmintic in the treatment of tapeworm infection over the centuries has been oleoresin of Aspidium, otherwise called filix mas or extract of male fern. This drug, which is prepared from rhizomes of the plant now known as Dryoptera filix mas, dates from the time of early Greek medicine. These plants are widespread in the norther n hemisphere. The rhizomes were collected in the autumn, freed from roots and dead parts, then dried carefully. An extract was obtained by soaking th e powdered, dry rhizomes in ether for 48 hours, then the ethereal phase wa s filtered and concentrated. This elixir, or its principal anthelmintic constituent, filicic acid or filicin, maintai ned the premier place in the array of antitapeworm anthelmintics until the middle of the present century 23. Filix mas, in fact, was the major component of the famous but secret tapeworm remedy of Madame Nouffer in Morat, Switzerland, which w as purchased for 18,000 francs in 1776

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by the French government. A less toxic drug is kamala which had been known since the late Middl e Ages. It is found in the glands and hairs covering the fruits of Mallotus philippinensis, a plant which is widespread in the Orient 23. Another anthelmintic which caught the imagination of European doctors during the last century was kousso, prepared from the blood red flowers of Hagenia abyssinica (= Brayera anthelmintica), a plant which is common in Ethiopia. The firs t recorded use of the drug in that country was around 1550 AD and it became an important article of trade 84. Pumpkins seeds (especially Cucurbita pepo) ground into a paste is another traditional remedy which has been shown i n recent years to have considerable antitapeworm activity 77. Betel nut, the seed of the palm, Areca catechu, cultivated in Asia, has been employed in th e treatment of tapeworm infections in C hina for 1400 years 69; its active principle, arecoline, has been used in more recent times. The anthelmintic activity of the pomegranate, Punica granatum, was recognized during the Middle Empire of ancient Egypt; this has been shown in recent decades to be due to its alkaloid, pelleteriene23. Likewise, anthelmintic activity has been claimed for Chrysanthemum for many centuries, and pyret hrin powder prepared from the flowers of C. cinerariifolium has been used recently as an anthelmintic 23. Metallic tin has been given for tapeworm infections for some centuries, while preparations based upon the combination of metallic tin with oxide and salts are more recent origin23. By the middle of the nineteenth century, male fern and kousso were the most commonly used drugs, although kamala had its advocates and turpentine was popular7,19,56,80. Although this last drug was often effective, Jenner (1856 ) believed that: its horribly nauseous flavour and unpleasant effects on the head and occasionally on the kidneys (made it) a remedy which should only be used as a last resort. 56

The more enlightened practitioners realized that proof of the effectiveness of a drug was either recovery of the head of the parasite or failure to pas s proglottids over the next several months. Nevertheless, finding the head wa s not a simple task, and some practitioners were not convinced of the necessity, as evidenced by the following conversation among various learned professors of Edinburgh University in 1852: Physiologus (Prof. Bennet). Did you find the heads of the creatures - i.e. taenia? Medicus (Prof. Christison). No. That is no easy matter; I have been looking for a tapeworm head all my life but have not yet found one. Editor (Dr. Robertson). Nor I. Physiologus (Prof. Bennet). Nor I. Did you ever know any one who has found one? Chirugus (Prof. Syme). Yes, I knew Rudolphi. Physiologus (Prof. Bennet). But if you say you did not find the head in your cases, you can scarcely say the patients were cured. Medicus (Prof. Christison). So it is pretended, but I doubt the authority. 56

The complexity of the various therapeutic regimens is illustrated by th e method recommended by Magath and Brown in 1927 in a paper entitled :

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"Standardized method of treating tapeworm infections in Man to recover th e head".74. On the day preceding specific treatment, the patient was prohibite d from taking either the midday or evening meal, but was permitted black coffee or water freely. At 6.00 p.m., 15-30 g of magnesium sulphate were admin istered then this was repeated next morning at 6.00 a.m. After the bowels had moved, and without having had any breakfast, the patient was given 30 ml of an emulsion of oleoresin of aspidium together with powdered acacia in 60 ml of water. One hour later, a further 30 ml were taken. This was followed after another two hours by 30 g of magnesium sulphate, then finally, two hours after this, a large enema of soapsuds was given. Since the margin between therapeutic and toxic doses of these drugs wa s slight, many physicians during the last few years of their popularity preferred to administer them through a d uodenal tube, after Schneider (1924) had shown that small doses could be used just as effectively but with less sideeffects when this technique was adopted 98. A number of synthetic compounds with antitapeworm activity have bee n introduced in the twentieth century, including thymol 3, carbon tetrachloride 22, 79 hexylresorcinol 76, quinine102, betanaphthol, mepacrine , chloroquine, 55 118 97 dichlorophen , bithionol , paromomycin and mebendazole 81. Of these, mepacrine secured the most favoured place for a while, but it was the n superseded by the introduction of the salicylamide derivative, niclosamide . Gönnert and Schraufstätter screened a g reat number of salicylamide derivatives and reported in 1960 that this particular compound was extremely activ e against Hymenolepis diminuta in rats45. World-wide clinical trials followed and showed that the drug was highly active against practically all the tapeworm s infecting man, with cure rates ranging between 80% and 100% 27,60. Niclosamide caused lysis of tapeworms in the intestines, so concurrent administration of a laxative was deemed advisable because of the theoretical risk of causing cysticercosis in T. solium infections, although this view has been dispute d recently91. In 1972, an heterocyclic pyrazino-isoquinoline derivative, praziquantel, was found to have unusually broad anthelmintic activity. Five years later, it wa s reported that this drug had cure rates of nearly 100% in patients infected with T. solium (adult worms), T. saginata and D. latum, and, in addition, was effective against Hymenolepis species21,33. Furthermore, it was noted to b e active against C. cellulosae, including cysticerci in the brain, but sinc e administration of this drug may precipitate severe side-effects, concurrent use of corticosteroids may be needed to suppress the inflammatory reaction 47,92. The treatment of cysticercosis has been surgical with removal or parasite s whenever possible, together with symptomatic treatment of complications such as epilepsy. It is possible that praziquantel may revolutionize the management of cysticercosis in many patie nts and obviate the need for surgical intervention.

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UNDERSTANDING THE EPIDEMIOLOGY The elucidation of the life cycle of T. solium by experimental infection o f humans with C. cellulosae and the production of these cysts in pigs by feeding them with gravid proglottids obtained from infected humans clarified th e epidemiology of taeniasis solium. It became obvious that this infection was a zoonosis and that humans were not only the definitive host of the adul t tapeworms, but could also be a potential intermediate host with the acquisition of cysticercosis, although this was, of course, a dead end for the parasite i n most human societies. Further studies confirmed that humans alone were the definitive host of the worm and pigs were the only significant vector o f infection. Thus, the reasons for the previously well-recognized paucity o f infection in certain religious groups such as Muslims and Jews, who wer e forbidden to eat pork, were now well-understood. Attention then turned to defining the prevalence of infection in pigs and i n humans in various parts of the world110. During the first half of the last century, approximately 2% of post-mortem examination s of humans conducted in Berlin revealed cysticercosis. Although the insti tution of control measures has reduced greatly the prevalence of infection in Europe, similar frequencies are still seen in many countries of Africa, Asia and Central and South America, wit h cysticercosis in slaughtered pigs ranging betgween 0.5% and 20% in thes e regions. This high frequency of infection was explained by the demonstration that enormous numbers of eggs were released by each proglottid; for example, Yoshino calculated that each proglottid discharged about 40,000 eggs whil e creeping about121. Thus, each infected person might release 100,000 eggs or more into the environment each day.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Comprehension of the life cycle of T. solium provided a rational basis for the institution of effective control measures. In his paper of 1855 detailing th e experimental infection of a human with T. solium, Küchenmeister was quick to point out the implications for a population that was in the habit of eating raw pork and recommended that the best method of preventing infection with adult tapeworms would be by "public instruction and warning to be careful wit h infected pork"63. By public instruction, Küchenmeister meant the necessity for the thorough cooking of all por k. Further studies on his part revealed that these cysts could remain viable for up to a week after slaughtering a pig 64. The value of proper cooking of pork was emphasized several years later when th e transmission of Trichinella spiralis in this medium was also demonstrated. The temperatures necessary to kill cysticerci were investigated by Perroncito in a series of experiments with T. saginata (see chapter 14). Further researche s indicated that pickled, salted or smoked pork was not necessarily safe 15 but that

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freezing at -10 oC for a week110 or at -20oC for at least 12 hours was an effective control measure 15. Recently, it has also been shown that infected carcasses can be sterilized by gamma irradiation without affecting the quality of the meat 109. Similarly, it became apparent that good sanitation, particularly with respect to disposal of human wastes, was essential for the prevention of both porcine and human cysticercosis, since Taenia eggs were extremely resistant t o destruction in the environment (see chapter 14). In this respect, vegetable s grown in gardens fertilized with human faeces were especially dangerous and needed to be avoided. By these means, it was hoped that the incidence o f human cysticercosis would be reduc ed and that the economic wastage resulting from the condemnation of pork would be curtailed. A mere recitation of th e facts was often insufficient to attain these ends, however, and intensive health education was often required to achieve a change of habits. Thus, Viljoe n (1937) recorded the instance of the South African farmer and his househol d who preferred to use the rear of a hedge close to the homestead rather than a stinking, fly-infested privy, to relieve themselves. This area could, moreover, be cleaned immediately by pigs trained to come at a whistle. Similarly, three farmers of high repute had the ir faith in the life cycle of T. solium shaken when their scrupulously-styed pigs developed cysticercosis; subsequent detectio n revealed that some black members of the staff were in the habit of easin g themselves in the sty and that one of them had tapeworm infection 110. Finally, the effectiveness of prompt diagnosis and treatment of T. solium infections in the reduction of human cysticercosis was appreciated. In developed countries, taeniasis and cysticercosis are both now kept at bay by a combination of treatment with effective anthelmintics, personal hygiene, efficient disposal of human wastes, rigid inspection and disposal of infecte d meat, and storage of pork in refrigerators.

REFERENCES 1. AEGINETA P. De re medica. The seven books of Paulus Aegineta, translated by F Adams, The Sydenham Society, London, three volumes, 1844-1847 2. AETIUS ANTIOCHENUS. De lumbrico lato. In, Medica Graeci contractae ex veteribus medicinae tetrabiblos etc., G et M Beringer, Lugduni, 1549 3. ALLAN W. Thymol for Taenia saginata. Journal of the American Medical Association 59: 197, 1912 4. ANDRY de BOISREGARD N. De la génération des vers dans le corps de l'homme. Avec trois lettres sur les sujets des vers, les deux premières....par M. Nicolas Hartsoeker et l'autre . . par M. Georges Baglivi, Laurent d'Houry, Paris, pp 468, 1700. An account of the breeding of worms in human bodies etc, translated by H Rhodes and A Bell, pp 266, 1701 5. ANONYMOUS. British and Foreign Medico-Chirurgical Review 19: 112-132, 1857 6. ANONYMOUS. British Medical Journal i: 46, 1861 7. ANONYMOUS. The treatment of tapeworm. Lancet i: 442, 1876 8. ARISTOTLE. Opera omnia, graece et latine, cum indice nominum et rerum absolutissimo, F Dübner, E Heitz and UC Bussemaker (Editors), Didot, Parisiis, five volumes, 1848-1874 9. ARME C. The terminology of parasitology: the need for uniformity. International Journal for Parasitology 14: 539-540, 1984

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10. AVICENNA (IBN SINA). "Al canon fi Al Tib", c. 1000 AD. In Arabic. Libri in re medica omnes, qui hactenus ad nos pervenere. Id est, libri canonis quinque, De virisbus cordis, De removendis nocumentis in regimine sanitas, De sirupo acetosa et cautica, translated by JP Mongio Hydruntino et J Costaeo Laudens, V Valgrisius, Venetiis, pp 966, 1564. Cited in 59 11. BEAVER PC, JUNG RC, CUPP EW. Clinical parasitology, Lea & Febiger, Philadelphia, pp 825, 1984 12. van BENEDEN PJ. Les vers cestoides ou acolytes, considérés sous le rapport de leur classification, de leur anatomie et de leur développement. Extracted from Mémoires de l'Académie Royale de Belgique, Bruxelles, pp 190, 1850. Abstracted in British and Foreign Medico-Chirurgical Review 10: 322-325, 1852 13. van BENEDEN PJ. Note sur des expériences relatives au développement des cysticerques. Annales des Sciences Naturelles 1: 104, 1854 14. BERTOLUS G. Dissertation sur les métamorphoses des Cestoides. Thèse de Montpellier, 1856 15. BIAGI F, VELEZ G, GUTIERREZ ML. Destrucción de los cisticercos en la carne de cerdo parasitada. Boletín de la Oficina Sanitaria Panamericana 58: 303-307, 1965 16. BLANCHARD E. Recherches sur l'organisation des vers. Annales des Sciences Naturelles, séries 3, Zoologie, 6: 271-341, 1847; 7: 87-127, 1847; 10: 321-364, 1848: 11: 106-202, 1849 17. BLOCH ME. Abhandlung von der Erzeugung-wuermer und den Mitteln wider dieselben, Sigismund Friedrich Hesse, Berlin, pp 54, 1782 18. BORRICHIUS. Cited in 107 19. BUDD. Report of cases treated by kousso. Lancet i: 773-774, 1850 20. CAIUS PLINIUS SECUNDUS. Historia naturalis, translated by J Bostock and HT Riley, Bohn's Classical Library, London, six volumes, 1855-1857 21. CANZONIERI CJ, RODR GUEZ RR, CASTILLO HE, IBAÑEZ de BALLELA C, LUCENA M. Ensayos terapéuticos con praziquantel en infecciones porTaenia saginata e Hymenolepis nana. Boletín Chileno de Parasitología 32; 41-42, 1977 22. CARMAN JA. A note on the clinical aspect of the treatment of taeniasis withcarbon tetrachloride. Transactions of the Royal Society of Tropical Medicine and Hygiene 25: 187-190, 1931 23. de CARNERI I, VITA G. Drugs used in cestode infections. In, International Encyclopedia of Pharmacology and Therapeutics, Section 64, volume 1, Chemotherapy of Helminthiasis, R Cavier and F Hawking (editors), Pergamon Press, Oxford, pp 145-213, 1973 24. CELSUS AC. De medicina, translated by WG Spencer, Loeb Classical Library Heinemann, London, three volumes, 1948-1953 25. CLERICUS (Le CLERC D). Historia naturalis etmedica latorum lumbricorum intra hominem et alia animalia, nascentium etc., Fratres de Tournes, Genevae, pp 449, 1715. A natural and medicinal history of worms bred in the bodies of man and other animals etc., translated by J Brown and J Wilcox at the Green-Dragon, Little Britain, pp 436, 1721 26. COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference more particularly to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 27. da CRUZ FERREIRA FA. Ensaios terapêuticos con o Bayer 2353 (Yomesan) na teniase (T. saginata). Anais do Instituto Medicina Tropical (Lisboa) 17: 1009-1015, 1960 28. CULBERTSON JT. Immunity against animal parasites, Columbia University Press, New York, pp 274, 1941 29. DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, J-B Baillière et fils, Paris, pp 838, 1860 30. van DOEVEREN W. Observations physico-médicales sur les vers, qui se forment dans les intestins; ou l'on traitement particulièrement du taenia, antrement dit, le ver solitaire, Lyon, pp 369, 1764 31. DUJARDIN F. Histoire naturelle des helminthes our vers intestinaux, Librarie Encyclopédique de Roret, Paris, pp 654, 1845 32. EBBELL B. Altägyptische Bezeichnungen für Krankheiten und Symptome. Skrifter Utgitt av Det Norske Videnskaps-Akademi i Oslo. II. Hist.-Filos. Klasse, No. 3, pp 65, 1938 33. ESPEJO H. Tratamiento de infecciones por Hymenolepis nana, Taenia saginata, Taenia solium y Diphyllobothrium pacificum con praziquantel. Boletín Chileno de Parasitología 32:

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39-40, 1977 34. ESCHRICHT DF. Anatomische-physiologische Untersuchungen ueber die Bothryocephalen. Nova Acta Leopoldino-Carolinae Academiae (Breslau) 19, Suppl. 2: 3-152, 1841 35. EVANS RA. Cysticercosis in an athlete. Transactions of the Royal Society of Tropical Medicine and Hygiene 32: 549-550, 1939 36. FAIRLEY NH. Cited in 72 37. FEHR JM. Hiera picra vel de Absynthio ad normam et formam Academiae Naturae Curiosorum selecta, 1664; J Tresner, Lipsiae, pp 176, 1667 38. FLISSER A, PEREZ-MONTFORT R, LARRALDE C. The immunology of human and animal cysticercosis: a review. Bulletin of the World Health Organization 57: 839-856, 1979 39. GABUCINUS H. De lumbricis alvum occupantibus etc., commentarius, H Scotus, Venetiis, pp 56, 1547. Partly translated in 25 40. GALBRAITH HT. Tapeworm as a cause of chorea. Lancet i: 1348, 1904 41. GALENUS CC. Works of, In, Medicorum graecorum opera quae extant, edited by KG Kühn (Greek text with Latin translation), Leipzig, 20 volumes, 1821-1833 42. GMELIN JF. Systema naturae per regna tria naturae, secundum classes, ordines, genera, species cum characteribus differentiis, synonymis, locis, thirteenth edition, GE Beer, Lipsiae, 8 volumes, pp 3021-3909, 1788-1793 43. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, P A Pape, Blankenburg, pp 471, 1782. Partly translated in 58 44. GOEZE JAE. Neueste Entdeckung dass di Finnen, im Schweinefleische keine Drüsenkrankheit sondern wahre Blasenwürmer sind, etc, Halle, pp 40, 1784 45. GÖNNERT R, SCHRAUFSTÄTTER E. Experimentelle Untersuchungen mit N-(2'-Chlor-4-nitrophenyl)-5-chlorsalicylamid, einem neuen Bandwurmmittel. I. Mitteilung: Chemotherapeutische Versuche Arzneimittel-Forsch 10: 881-884, 1960 46. von GRAEFE A. Nächtragliche Bemerkungen über die modificirte Linear-extraction. Archiv für Ophthalmologie 12: 150-223, 1866 47. GROLL E. Cisticercosis humana y praziquantel: una appreciacíon panorámica de las primeras experiencas clínicas. Boletín Chileno de Parasitología 36: 29-37, 1981 48. HARTMANNUS PJ. Anatomia glandiorum. Miscellanea Curiosa Sive Ephemeridum MedicoPhysicarum Germanicarum Academiae Imperialis Leopoldinae Naturae Curiosorum Decuriae II. Annus Septimus, Anni MDCLXXXVIII (1688) Observatio XXIV, Literis Joannis Ernesti Adelbulneri, Nuremberg, pp 58-59, 1716. Partly translated in 58 49. HAUBNER GC, KÜCHENMEISTER F. Weitere Mittheilungen über die Entwickelung der Band- und Blasenwürmer Nach den Versuchen von Dr. Küchenmeister und Dr. Haubner. Magazin für die gesellschaft Thierheilkunde 20: 366-368, 1854; 21: 100-118, 1855 50. HELLER A. In, Cyclopaedia of the practice of medicine (H von Ziemssen, editor), volume 3, Chronic infectious diseases, translated by AH Buck, The Sydenham Society, London, pp 595-613, 1875 51. HIPPOCRATES. Works of, De morbis, Book IV, section 5, translated by WH Jones and ET Whithington, Loeb Classical Library, four volumes, 1948-1953 52. HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 53. HOLLENBACH. Wochenschrift der Thierheilkunde und Viehzucht 2: 301, 353, 1859 54. HUMBERT A. Cited in 14 55. JACKSON FC. The treatment of tapeworm infestation with dichlorophen. South African Medical Journal 30: 853-854, 1956 56. JENNER W. On tapeworm and its treatment by the oil of male fern. Association Medical Journal 4: 718-721, 1856 57. JUDSON JE. Tapeworms as a possible cause of diabetes. Lancet ii: 1256, 1903 58. KEAN BH, MOTT JE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 59. KHALIL M. An early contribution to medical helminthology translated from the writings of the Arabian physician Ibn Sina (Avicenna) with a short biography. Journal of Tropical Medicine and Hygiene 25: 65-67, 1922 60. KNORR R. Bandwürmbehandlung mit Yomesan abei 36 Patienten. Medizinische Klinik (München) 55: 1937-1938, 1960

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61. KREHL. Cited in 66 62. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 63. KÜCHENMEISTER F. Offenes Sendschchreiben an die k.k. Gesellschaft der Aertze zu Wien. Experimenteller Nachweis, dass Cysticercus cellulosae innerhalb des menschlichen Darmkanales sich in Taenia solium umwandelt. Wiener medizinische Wochenschrift 5: 1-4, 1855. Translated in 58 64. KÜCHENMEISTER F. Erneuter Versuch der Umwandlung des Cysticercus cellulosae in Taenia solium hominis. Deutsche Klinik 12: 187-189, 1860. Abstracted in Medical Times and Gazette ii: 414, 1860 65. LEUCKART R. Die Blasenbandwürmer und ihre Entwickelung, Giessen, pp 162, 1856 66. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 1, pp 1009, 1879-1886. The parasites of man and the diseases which proceed from them. A textbook for students and practitioners, translated by WE Hoyle, YoungJ Pentland, Edinburgh, pp 771, 1886 67. LINNAEUS C. Systema naturae, per regna tria naturae, secundum, classes, ordines, genera, species, cum characteribus differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 68. von LINNÉ C (LINNAEUS). Vom Bandwurme. Auserlesene Abhandlungen aus der Naturgeschichte, Physik und Arzneiwissenschaft. Nach den Amoenitates. (Dissertatio de taenia. Amoenitates Academicae II 1762), übersetzt von E J T H. II., Theil 3, p 101, 1762 69. LIU HL. Betel nut as a useful taeniafuge. Chinese Medical Journal 50: 1273-1278, 1936 70. LUNN WE. Case of tapeworm. Journal of the Royal Army Medical Corps 19: 99, 1912 71. MacARTHUR WP. Cysticercosis as a cause of epilepsy in Man. Transactions of the Royal Society of Tropical Medicine and Hygiene 26: 525-528, 1933 72. MacARTHUR WP. Cysticercosis as seen in the British army, with special reference to the production of epilepsy. Transactions of the Royal Society of Tropical Medicine and Hygiene 27: 343-357, 1934 73. MacARTHUR WP. Cysticercosis of the brain. British Medical Journal ii: 1229, 1935 74. MAGATH TB, BROWN PW. Standardized method of treating tapeworm infestations in man to recover the head. Journal of the American Medical Association 88: 1548-1549, 1927 75. MALPIGHI M. Opera posthuma. Quibus praefixa est vita, a seipso scripta, A et J Churchill, Londini, pp 187, 1697 76. MAPLESTONE PA, MUKERJI AK. Hexylresorcinol as antihelminthic. Indian Medical Gazette 67: 610-612, 1932 77. MITTELMAN G. (Treatment of cestode infestation with pumpkin seeds). Meditsinskaya Parazitologiya i Parazitarn e Bolezni 2: 143-146, 1933. In Russian. Abstracted in Tropical Diseases Bulletin 31: 782, 1933 78. MOQUIN-TANDON A. Elements of medical zoology, translated by RT Hulme, Baillière, London pp 423, 1861 79. NEGHME A, FAIGENBAUM J. Nueva modalidad de tratamiento en las teniasis. Revista Médica de Chile 75: 54-57, 1947 80. OGLE JW. Observations of the treatment of taenia, especially by the use of oil of male-fern. British Medical Journal i: 264-266, 1863 81. OLIVEIRA-GOMES MD. The treatment of taeniasis with mebendazole. Folha Médica 66: 1043-1051, 1975 82. PALLAS PS. Einige Erinnerungen die Bandwürmer bettrefend; in Beziehung auf das zwölfte und vierzehnte stück des Naturforschers. Neue nordische Beyträge Physikalische und Geographische Erd- und Völkerbeschriften 2: 113-131, 1781 83. PANAROLUS D. Iatrologismorum, seu medicinalium observationum pentecostae quinque etc, F Moneta, Romae, pp 445, 1652 84. PANKHURST R. The traditional taenicides of Ethiopia. Journal of the History of Medicine

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24: 323-334, 1969 85. PAPYROS EBERS. Das hermetische Buch über die Arzneimittel der alten Aegypter ni hieratischer Schrift. Herausgegeben mit Inhaltsangabe und Einleitung versehen von Georg Ebers. Mit hieroglyphische-lateinischen Glossar von Ludwig Stern, two volumes, Leipzig, 1875. The Papyrus Ebers, translated from the German version by CP Bryan, Geoffrey Bles, London, pp 167, 1930 86. PINDEA A, BOTERO O, BRAVO C. Taeniasis. Presentación de 74 casos, 2 de ellos con infección múltiple. Antioquia Médica 22: 417-422, 1972 87. PODYAPOLSKAYA VP. (Diagnosis of helminthic infestations by the examination of scrapings from the perianal folds.). Meditsinskaya Parazitologiya i Parazitarn e Bolezni 12: 83-85, 1943. In Russian. Abstracted in Tropical Diseases Bulletin 41: 301, 1944 88. PRIEST R. A case of extensive somatic dissemination of cysticercus cellulosae in man. British Medical Journal ii: 471-472, 1926 89. RANSOM WH. On the diagnosis and treatment for roundworm; and on the occurrence of a new species of Taenia in the human body. Medical Times and Gazette, new series, 12: 598-601, 1856 90. REDI F. Osservazioni intorno agli animal viventi che si trouvano negli animali viventi, Piero Matini, Firenze, pp 244, 1684 91. RICHARDS F, SCHANTZ PM. Treatment of Taenia solium infections. Lancet i: 1264, 1985 92. RIM HJ, PARK CY, LEE JS, JOO KH, LYU KS. Studies on the human cysticercosis and its therapeutic trial with praziquantel. Korea University Medical Journal 17: 459-472, 1980 93. ROSEN de ROSENSTEIN N. Traité des maladies des enfants, translated by Febre de Villebrune, Paris, pp 484, 1793. Original Swedish edition 1788 94. ROTH EJ. Man as the intermediate host of the Taenia solium. British Medical Journal ii: 470-471, 1926 95. RUDOLPHI CA. Entozoorum, sive vermium intestinalium historia naturalis, Treuttel et Wurtz, Paris, three volumes, pp 1370, 1808-1810 96. RUMLER JU. Secto a me, in capite, pustulae supra duram meningen apparuerunt, erosa ipsa et cerebro per foramina eminente pluribus in locis. Observationes Medicae, 1558. Cited in 108 97. SALEM HH, al-ALLAF G. Paromomycin and Taenia saginata. Lancet ii: 1360, 1967 98. SCHNEIDER H. Eine Modifikationder üblichen Bandwürmkur mittels der Duodenalsonde. Wienerüklinische Wochenschrift 37: 338-339, 1924 99. SERAPION (YUHANNA IBN SARA-BIYUN). In, Practica etc, translated from the Arabic, Venetiis, 1497. Cited in 29 100. von SIEBOLD CT. Helminthologische Beiträge. Archiv für Naturgeschichte 1: 45-83, 1835 101. von SIEBOLD CT. Ueber die Spermatozoen der Crustacean, Insecten, Gasteropoden und einiger anderer wirbellosen Thiere. Archiv für Anatomie und Physiologie (Mueller) pp 13-53, 1836 102. SOKOLOWSKI W (Transduodenal expulsion of cestodes with quinine.) "Militaer Medicinische Zeitschrift, Leningrad" 4: 274-276, 1933. In Russian. Abstracted in Tropical Diseases Bulletin 31: 781-782, 1934 103. SOMMER F. Ueber den Bau und die Entwickelung der Geschlechtesorgane vonTaenia mediocanellata (Küchenmeister) und Taenia solium (Linné). Zeitschrift für wissenschaftliche Zoologie 24: 499-555, 1874 104. SPIGELIUS. De lumbrico lato liber (cum ejusdem lumbrici icone et notis), L Pasquati, Patavii, pp 88, 1618 105. THREOPHRASTUS. Enquiry into plants, translated by AF Hort, Loeb Classical Library, two volumes, 1948-1949 106. TULPIUS N. Observationes Medicae. Editio nova, L Elzevirium, Amsteloedami, pp 403, 1652 107. TYSON E. Lumbricus latus, or a discourse read before the Royal Society, of the joynted worm, wherein a great many mistakes of former writers concerning it, are remarked; its natural history from more exact observations is attempted; and the whole urged, as a difficulty against the doctrine of univocal generation. Philosophical Transactions of the Royal Society 13: 113-144, 1683

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108. VELSCHIUS GH. Sylloge curiatonum et observationum medicinalium, centurias v i complectens etc, Rumlerus J, pp 63, G Goebelii, Augustae Vindelicorum, pp 448, 1668 109. VERSIER H. The effect of gamma radiation on the cysticerci of Taenia solium. Onderstepoort Journal of Veterinary Research 43: 23-26, 1976 110. VILJOEN NF. Cysticercosis in swine and bovines, with special reference to South African conditions. Onderstepoort Journal of Veterinary Science and Animal Industry 9: 337-570, 1937 111. VILLANOVANI A. De lumbricus et ascaridibus. In, Opera omnia, Basileae, 1585. Original edition c.1300 AD 112. WAGLER. Cited in 43 113. WATERHOUSE R. Cysticercus cellulosae in the central nervous system: with an account of two cases. Quarterly Journal of Medicine 6: 469-485, 1913 114. WEINBERG. Recherches des anticorps spécifiques dans la distomatose etla cysticercose. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 66: 219-221, 1909 115. WERNER PC. Vermium intestinaliorum brevis expositionis continuato secunda. Edita et animadversionibus atque tabulis a aeneis aucta JL Fischer, Lipsiae, pp 96, 1786 116. WHARTON T. Adenographia: sive glandularum totius corporis descriptio, Londini, pp 287, 1656 117. WOOD W. On a case of insanity caused by tapeworm and cured by kousso. Lancet i: 9, 1851 118. YOKOGAWA M, YOSHIMURA H, OKURA T. The treatment of Taenia saginata with bithionol. Japanese Journal of Parasitology 11: 39-44, 1962 119. YOSHINO K. (Studies on the postembryonal development of Taenia solium. Part II. On the youngest form of Cysticercus cellulosae and on the migratory course of the oncosphere of Taenia solium within the intermediate host.) Taiwan Igakkai Zasshi 32: 1569-1586, 1933. In Japanese, with English summary. 120. YOSHINO K. (Studies on the postembryonal development of Taenia solium. Part III. On the development of Cysticercus cellulosae within the definitive intermediate host). Taiwan Igakkai Zasshi 32: 1717-1736, 1933. In Japanese, with English summary 121. YOSHINO K. (On the evacuation of eggsfrom detached gravid proglottids of Taenia solium and on the structure of its eggs.) Taiwan Igakkai Zasshi 33: 47-58, 1934. In Japanese, with English summary 122. YOSHINO K. (On the subjective symptoms caused by the parasitism ofTaenia solium and its development in Man.) Taiwan Igakkai Zasshi 33: 183-194, 1934. In Japanese 123. ZEDER JG. Anleitung zur Naturgeschichte der Eingeweidewürmer, Bamberg, pp 432, 1803

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Table 13.1. Landmarks in taeniasis solium and cysticercosis ___________________________________________________________________ BC

Tapeworms in humans and cysticerci in animals were known but their true nature was not appreciated. Multiple remedies, including extract of male fern (filix mas), were described for intestinal taeniasis c.1550 Kamala and kousso were introduced as antitapeworm agents 1558 Rumler probably described cysticerci in a human 1683 Tyson discovered the head of a tapeworm 1688 Hartmann discovered the verminous nature of C. cellulosae in pigs 1784 Goeze pointed out the similarities between the heads of tapeworms found in the human intestinal tract and the invaginated heads in C. cellulosae in pigs 1854 van Beneden reported that he had generated C. cellulosae in the muscles of a pig fed with T. solium ova 1855 Küchenmeister fed C. cellulosae in pork to a condemned murderer and recovered small tapeworms several days later 1855 Humbert infected himself with C. cellulosae then began passing segments of T. solium three months later 1856 Ransom described the diagnosis of intestinal taeniasis by finding eggs on microscopical examination of the faeces 1860 Küchenmeister fed C. cellulosae in pork to a condemned murderer 4 and 2.5 months prior to execution, then recovered a large number of adult T. solium, one being five feet in length 1926 Roth demonstrated calcified cysticerci by radiography 1934 Fairley showed that antibodies were present in the sera of patients with cysticercosis 1960 Niclosamide was introduced for the treatment of intestinal taeniasis 1977 Praziquantel was introduced for the treatment of intestinal taeniasis 1980 Praziquantel was shown to be effective in cysticercosis __________________________________________________________________

Chapter 14

Taenia saginata and TAENIASIS SAGINATA

SYNOPSIS Common name: tapeworm Major synonym: T. mediocanellata Distribution: worldwide Life cycle: The adult tapeworms, usually about 5 metres in length, live in the small intestine with the head attached to the mucosa. Eggs and gravid proglottids are passed in the faeces. When ingested by cattle, the eggs hatch in the small intestine and each released larva (oncosphere) penetrates the mucosa and passes via the bloodstream to the tissues, especially the muscles, subcutaneous tissues and central nervous system, where it vesiculates to form a bladderworm (Cysticercus bovis); these usually reach 10 mm in size and contain an invaginated head. When a cysticercus in insufficiently cooked beef is ingested by a human, the head evaginates in the small intestine and develops into an adult tapeworm which produces proglottids after approximately two months Definitive host: humans Intermediate host: cattle Major clinical features: abdominal discomfort, spontaneous passage of proglottids Diagnosis: finding of eggs (any Taenia) or proglottids (T. saginata) in the faeces Treatment: niclosamide, praziquantel

DIFFERENTIATION OF THE SPECIES FROM TAENIA SOLIUM Tapeworms have been known for generations (see chapter 13), but conceptions about the three species of large tapeworms that commonly infect man, Taenia solium, T. saginata and Diphyllobothrium latum , were hopelessly confuse d and intermingled for many centuries. As discussed in Chapter 15, D. latum began to be recognized as a separate entity in the seventeenth century, leaving the other two species lumped together under the name, amongst many others, of T. solium. Distinction between D. latum and the species of Taenia was relatively easy, even when a head was not available for examination, because the shape of the proglottids and the position of the genital pore were quit e different. It was another matter with the worms we now know as T. solium and T. saginata, however, for the distinguishing fe atures in the proglottids are much more subtle and their classification required a knowledge of their interna l anatomy, particularly the branches of the uterus. It required the discovery o f tapeworm heads before definite distinction between these two species wa s 385

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achieved. Remarkably though, 170 years were to pass after Tyson's discovery of the head of a tapeworm (see chapter 13), before general agreement on the two species was obtained. In 1700, Nicolas Andry de Boisregard described, under the name T. solium or Taenia sans épine (Taenia without thorns), a cestode which was none other than T. saginata 2. Andry not only provided illustrations of the proglottids, but also, for the first time, gave drawings of the head of a tapeworm obtained from a human. The scolex had no hooks and there is no doubt that this worm was T. saginata, but he was completely unaware of the existence of two species o f Taenia. Vallisneri in 1714 again made the same mistake, describing an d figuring T. saginata under the name of T. solium 39. As discussed in chapter 15, Charles Bonnet then drew a hybrid tapeworm in 1750, with the head of T. saginata and the body of D. latum; he did, however, correct this error in 1777. Again, in his Systema Naturae (1758), Linnaeus, under the designation T. solium, described what was in fact a T. saginata as the typical form of the Taenia infecting Man, although he did note that the worm had some variations in its appearance 27. Peter Pallas was also confused by this variability. He wrote that T. solium (which he called T. cucurbitina, and to which he ascribed a crown of thorns) was sometimes delicate, thin and narrow, and at other times, stout, thick and fat 31. Although he did not realize it, he was in fact describing T. solium and T. saginata, respectively. Johannes Goeze, recognizing both the morphological differences and th e variations in the geographical distribution of the two forms, in 1782, separated the human taeniid tapeworms into two categories: I know and possess two species of intestinal tapeworm; the first is well known - long, with thick, fattened segments which I shall call Taenia cucurbitina, grandis, saginata. The second seems to be a variety of the first, which under all circumstances remains the same and is found in my part of the country more frequently than the former; I call it Taenia cucurbitina, plana, pellucida.12

Like Pallas, Goeze called these worms T. cucurbitina. His name of Taenia cucurbitina, grandis, saginata indicated that one parasite was large and fat , while the Taenia cucurbitina, plana, pellucida reflected the flat and transparent nature of the other tapeworm. Goeze possessed nine specimens of T. saginata, seven without heads and two complete examples. He wrote that: It is truly amazing to compare the pieces of this flattened tapeworm with others. The most mature lower segments are not as long as in the flat, transparent variety, but are much thicker. Some have the thickness of half a line [1mm] and are all marked with little lines lengthwise on the surface. In a section of worm more than one ell [an English ell is 1.13 metres and a Flemish ell is 68 cm] in length, the marginal openings are set in each segment, one on each segment, some right, some left....In the next ell of this specimen, the segments are much narrower and almost pushed one on top of the other and thereby give a considerable thickness. 12

Goeze was intrigued by variations in position of the marginal openings for he noted that "The order in the position of the marginal openings, which is hardly ever the same, still remains very puzzling and yet it cannot be withou t

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purpose"12. He did not dwell at length on the appearances of the two heads of the Taenia cucurbitina, grandis, saginata that he possessed, merely writing: In the first specimen the head is not flat and ribbonlike but round, ascarislike; in the latter, however, it is flatter. I am only adding that the head end of both of these specimens is completely different from the head end of the notched, segmented tapeworm from the cat, as mere observation shows. In the first, however, one cannot see, as in the cat's tapeworm, the suckers and the hooks with the naked eye, and the segments only start after a very narrow neck.12

Goeze then went on to contrast the appearance of the flat, transparent variety, Taenia cucurbitina, plana, pellucida (i.e. T. solium), after first proving that it was not simply an immature form of Taenia cucurbitina, grandis, saginata. Goeze had several specimens of Taenia cucurbitina, plana, pellucida which were complete with head. He noted that the dendritic ramifications of the uterus were far more defined and visible in this form of tapeworm than in Taenia cucurbitina, grandis, saginata, then he described definitively the head of the tapeworm now called T. solium: The head of the worm is like a small box and not round. At the four corners of the head there are four suckers and a superior rostellum which can be seen through the microscope.12

In addition, the accompanying figures indicate clearly the four suckers and the crown with two rows of hooks. Although Goeze's description of the head of T. solium was unequivocal, he did not stress (and perhaps was not aware of) the value of this feature i n distinguishing T. solium from T. saginata, the latter species not having a crown of hooks. Just before Goeze published his findings, M. Bloch, a physician in Berlin, contributed a discourse which won the gold medal given by th e Academy of Science at Copenhagen for its prize essay set in 1780. The title of this essay was "Concerning the seeds of intestinal worms: whether tapeworms etc. are inborn in animals or enter from outside". Amongst other things, Bloch proposed in this essay a classif ication of tapeworms in which, for the first time, the presence or absence of hooks on the head was used as a specific character. Although he divided the genus Taenia into the "inarmatae" containing 1 6 species and the "armatae" with four species, he did not use this feature t o differentiate between the human tapeworms, T. saginata and T. solium 7. Several years later, Batsch expresse d similar views to Goeze. As with Pallas, he preferred the name T. cucurbitina and distinguished two constant varieties within this species; these were recognizable by the features mentioned b y Goeze, as well as upon the ramifications of the uterine branches that he noted. In addition, Batsch was also aware of regional variations in the relativ e frequencies of the forms of tapeworms 3. Nevertheless, these judicious observations largely passed unnoticed or were ignored. T. saginata continued to be confounded with T. solium, or was simply considered as a variety of the latter. Thus in Berlin, Rudolphi saw onl y specimens of Taenia with hooks, while Bremser in Vienna, by contrast , encountered only Taenia without hooks. Indeed, Bremser 8 believed, along with

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FS Leuckart and Mehlis, that all young taeniae had hooks and lost them with advancing age, just as an ageing man loses his hair. In 1830, Nicolai agai n drew attention to the presence of hooks in on e form of tapeworm and named the parasite T. dentata 29, but his views were still not heeded. Further examples of regional variations in the type of tapeworm present were described. Thus , Wawruch noted that in the parts of Wurtemberg situated in the Danube basin, only unarmed taeniae were present, while in the region in the Necker basin , only armed Taenia occurred40. Similarly in Java, Schmidtmuller examined 148 taeniae in the space of 15 years, and finding them all to be unarmed, name d them Bothriocephalus tropicus. The situation became so confused that neither Dujardin (1845) nor Diesing (1849-1851) in their major textbooks admitted two distinct species of Taenia infecting humans. In 1852, Friedrich Küchenmeister declared that there were definitely tw o distinct species of Taenia, clearly distinguishable, not only by their genera l appearances, but particularly by the structures of their heads and thei r reproductive systems. He observed that the head of T. solium was armed with hooks, whereas the other species, which was also larger and fatter, was always bare of hooks. Again, there were 9-15 lateral uterine branches in the proglottids of T. solium whereas the other species had 15-20 such branches. To this latter species, Küchenmeister gave the name T. mediocanellata, the specific epithet denoting a main transverse channel running through the region between th e four sucking discs 19,20. When Leuckart reviewed this matter a few years later, he gave Küchenmeister little credit: In 1852, Küchenmeister again advanced the opinion that besides T. solium there was another large-jointed species to be distinguished in man....if Küchenmeister had been better acquainted with the literature of helminthology, and had consulted it more carefully, he would have learned that his discovery was not as new as he supposed, but was rather only a confirmation and extension of observations which would have long since been fully settled if the observers had a more rich and complete material to work upon.26

This comment was typical of Leuckart's penchant for unfair criticism o f Küchenmeister. The fact is that the distinction between T. saginata and T. solium was not generally recognized until Küchenmeister's publication, but was accepted thereafter. Not only was Küchenmeister's designation, T. mediocanellata, founded on an erroneous anatomical idea, but some of the purists objected to thi s nomenclature on the suspect ground that t he term "mediocanellata" was derived from a combination of Greek and Latin roots. Some authors consequentl y preferred the term T. inerme or T. inermis to describe T. saginata. This created a dilemma since such usage flew in the face of precedent, but the problem was solved when Leuckart in 1867 pointed out that Goeze had earlier used th e designation "saginata" to describ e this species and that the correct name should therefore be T. saginata 25,26. This name was then adopted generally, although first Leuckart then Blanchard 6 considered that it would be more in keeping with

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the rules of zoological nomenclature to accord the name T. solium to the unarmed tapeworm and call the tapeworm with hooks, T. pellucida Goeze. They conceded, however, that such a course was impractical and woul d augment the already consider able confusion which surrounded the terminology of tapeworms. Discussion has continued until the present day with som e taxonomists believing that the unnamed tapeworm of man acquired by th e consumption of beef should be called Taeniarhynchus saginata whereas other authorities believe Taenia saginata to be the correct designation. Furthermore, while most investigators believe there to be only one species of beef tapeworm infecting humans, some have considered that there are number of suc h species32.

ELUCIDATION OF THE MODE OF TRANSMISSION EXPERIMENTAL PRODUCTION OF C. BOVIS The successful demonstration in the 1850's of the complete life cycle o f T. solium naturally suggested that a similar process might occur wit h T. saginata. The difficulty was to know wh ich animal was the intermediate host containing cysticerci. A. Judas probably saw cysticerci of T. saginata in the lungs of cattle in the abattoirs at Orleansville, Algeria in 1854, although he did not recognise them as such 16. Blanchard6 has canvassed the possibility tha t Judas had in fact found C. tenuicollis, but thought this unlikely since thi s species is generally found in the liver and mesentery whereas C. bovis may be found in the lungs of cattle. The clue was to come from clinical and epidemiological observations. Physicians had noticed that sickly children, who had been ordered to eat raw beef in order to strengthen them, particularly those in St. Petersburg (no w Leningrad, USSR), not infrequently contracted infection with T. saginata 41. It was also realised that European Jews, who were proscribed from eating pork, were not afflicted with T. solium, but acquired infections with T. saginata. Finally, travellers to various parts of the globe reported that T. saginata infections were more common in cert ain countries. The most notorious of these was Abyssinia (Ethiopia) where almost everyone was infected and where the inhabitants ate mostly beef, and that raw, by preference. In 1860, Huber pu t forward the hypothesis that cysticerci would be found in the tissues of cattle 14. These pointers, together with the failure o f several previous attempts to infect pigs and sheep with T. saginata eggs and the observations of Knox, led Rudolf Leuckart to investigate the effects of feeding such eggs to cattle. Army surgeon Knox had witnessed a tapeworm epidemic among soldiers who had eate n "overdriven and unsound" oxen during the first Kaffir War in South Africa 18. Leuckart knew, moreover, that specimens of Taenia submitted to him from South Africa were T. saginata. On 13 November 1861, therefore, Leuckart fed

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a mature segment of T. saginata about four feet long to a four week old calf, then reinfected the animal one week later with smaller pieces of the sam e tapeworm. The animal appeared well but then died suddenly on 8 December. At post-mortem examination, all the muscles and some of the visceral organs as well as the lymphatics were permeated with: cysts which were 1.5-3 mm wide and 2-4 mm in length. They had a whitish appearance as though filled with a chalky or caseous mass, as I had never observed in any young cysts of the Cysticercus cellulosae in a similar way. Inside the exudative layer, which was surrounded by a firm connective tissue membrane, they contained a light, clear vesicle of 0.4-1.7 mm in diameter. On cutting into this cyst, this protruded and proved on closer examination to be a young cysticercus....At this stage of development, no suckers could be found. The inner parts of the head cone showed little enlargement of the end, and in the region of the smaller cysticerci it was a simple conical shape.24

Leuckart then repeated the experiment and infected another calf with 25-3 0 proglottids of T. saginata. The animal became quite sick during the third week after infection, but then recovered completely. Seven weeks after infection, a biopsy was taken from the sternomastoid muscles and about a dozen cysticerci were obtained. In contrast to the scolex of C. cellulosae: this head cone was without a bend and in spite of its small size (hardly 1 mm), also in spite of the small size of the vesicle (3-4 mm), was already provided with completely developed suckers. Instead of the protruding hooks, there was on the bottom of the invagination, between the suckers, a tight circle of small rudiments. 24

Leuckart believed that the larval stage of T. saginata may lag behind that of T. solium with respect to size, and that this might partly account for it having escaped the attention of helminthologists up to that time. He concluded that by these experiments he had established beyond any doubt the specifi c nature of T. saginata and, furthermore, that he had shown that infection with this parasite was acquired by humans from cattle and possibly othe r ruminants22,23. Leuckart's findings were confirmed twice in 1863 by Mosler 28, by Cobbold and Simonds in 1864 and again in 1865 38, then by Roll (1865), Gerlach (1870), Zurn (1872), Saint-Cyr (1873), Jolicoeur ( 1873), Masse and Pourquier (1876), Perroncito (1877) and others. Various investigators confirmed the earl y observations that pigs and sheep were insusceptible to this species of tape worm, and demonstrated that rabbits were likewise inhospitable hosts. Th e cysticercus was designated Cysticercus ex Taenia mediocanellatae by Davaine then as C. bovis by Cobbold 10; the latter name has stuck. One wonders why so many investigators felt it necessary to confirm these findings. Perhaps the y wanted a ready demonstration of the almost incredible phenomenon of th e migration of worms and the alternation of generations, and this provided a convenient excuse and a workable system. Perhaps they wanted to prove their mastery over these worms. Perhaps it simply gave them a feeling of achievement and satisfaction. In any event, it was c lear that cattle were the intermediate host of T. saginata, and that humans were likely to acquire infection with this

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parasite by eating raw or poorly-cooked beef.

EXPERIMENTAL GENERATION OF ADULT T. SAGINATA Following the experimental production of the cysticercus of T. saginata in cattle by Leuckart, there seemed little doubt that humans acquired T. saginata infection in just the same way as they contracted taeniasis solium. Under standably enough, no-one went to Küchenmeister's lengths and infected a criminal destined to be executed. Indeed, it was a number of years befor e anyone repeated the similar experiment first done with T. solium by Humbert. John Oliver, a British medical officer stationed with the Royal Artillery a t Jullundur, India, made some poorly controlled experiments during 1868-1869, not so much as to demonstrate completion of the life cycle, but in order t o examine the clinical effects of consumption of measly beef under differen t conditions. Cysticercosis bovis was endemic in the area and T. saginata infection was common in the local camel drivers. Oliver's results are recorded in the annual report for 1870 of the Sa nitary Commissioner for the Government of India: 1st - After explaining to them the possible consequences of eating it, a buttock of beef studded with cysticercus was given to three natives of low caste. They all declared that they were free of taenia. The meat they cook in their own way. These men were under my observation for some six months. Two of them had no symptoms of taenia, but the third, who was a low class Mahomedan syce, and had probably eaten the meat in a very raw state, developed a T. mediocanellata in about three months. 2nd - My own sweeper ate this cyst-infected beef regularly two or three times a week for some months. He cooked it well, generally as an ordinary stew, and has never shown a sign of having tape-worm. 3rd - In the case of a Hindoo boy of low caste, two scolices of cysticercus within three or four months produced a T. mediocanellata.30

This last patient cited is particularly surprising as it would be unheard of for a Hindu to eat beef - perhaps Oliver administered isolated scolices. A more precise study was undertaken by Ed uardo Perroncito in Italy in 1877. In that investigation, which was designed to determine the effects of heating of cysticerci on their infectivity, a control subject ingested an uncooked C. bovis on 4 March 1877; 54 days later, he began to pass proglottids. Treatment with kousso and oil of ricin on the 57th day yielded a T. saginata 4.27 m long and containing 866 proglottids. It was calculated that this tapeworm produce d between 13 and 14 proglottids per day 36. Thus, it was finally proven that T. saginata had a life cycle similar to that of T. solium, except that infection was acquired by ingestion of contaminated beef instead of pork.

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RECOGNITION OF THE CLINICAL FEATURES Although rare claims have been made for findin g C. bovis in humans11, the clinical manifestations of infection with this parasite, for all practical purposes , devolve from the presence of intestinal worms. Consequently, the symptom s and signs are much the same as have been described already for taeniasi s solium. Proglottids of T. saginata are said to break off more easily than those of T. solium and Küchenmeister has a particularly graphic description of their passage which he notes may occur either in the faeces or separately: The segments pass when the patient is standing quietly and falling into his trousers, he suddenly has a moist and cool feeling about the legs, and when he seeks to free himself from this unpleasant sensation, finds a single proglottis attached to or creeping about the leg. Women especially are afraid lest the proglottides should fall unperceived upon the ground when they are walking or standing. 21

Presumably they were grateful for the invention of elastic underwear! It ha s been concluded that 8-9 proglottids are produced per worm per day34. These tapeworms might also reach remarkable lengths. One patient treated wit h extract of kamala passed three yards of T. saginata, and then on being treated again almost immediately with oil of male fern, passed a further 11 yards , together with the head, making 14 yards of tapeworm in total 1. Despite their ability to reach huge sizes, these worms rarely cause intestinal obstruction , although several cases of this complication are on record 9. It has even been claimed that a complete T. saginata, ten feet long, has been removed from the gall bladder of an old man with acute cholecystitis 4. Infections may also be multiple. In 1893, Bérenger-Férand 5 reviewed 2686 cases and found that one worm was present in 87% of persons, two were present in 7.8% and 2.3% had three tapeworms. Cases with more t han 5 worms was exceptional although one patient was claimed to have 27 T. saginata and another, 59 tapeworms. More certain is the patient of Hodson who, when treated in the Khartoum Civi l Hospital with filix mas, produced 31 specimens of T. saginata 13. Observations over the centuries have sho wn that the prognosis is good in this infection since there is no likelihood of people developing cysticercosis.

DIAGNOSIS AND TREATMENT The diagnosis of taeniasis saginata is made in the same way as is taeniasi s solium. Although T. saginata was said to be slightly more resistant tha n T. solium to the older anthelmintics 21, these infections respond well to th e newer drugs described in chapter 13.

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UNDERSTANDING THE EPIDEMIOLOGY The experimental generation of C. bovis in cattle by feeding them with T. saginata eggs in mature proglottids obtained from infected humans, and the subsequent infections of humans by such cysticerci, clarified the epidemiology of taeniasis saginata and indicated that, like taeniasis solium, this infection was a zoonosis. Further researches confirmed that humans were the sole definitiv e host and cattle were the principal intermediate hosts. Efforts were made to define the life span of eggs and cysticerci. As wit h T. solium, enormous numbers of eggs were discharged into the environment, it being estimated that each proglottid released an average of 80,000 eggs . Thus, each infected patient might pass about half a million eggs daily 34. These eggs were remarkably resistant to destruction in the laboratory by a grea t variety of physical and chemical means 15 and were found to survive for several months in pastures 35. Studies of experimentally-infected cattle showed tha t cysticerci lived in the tissues for a variable period but that most were not viable within four months, and all were dead by nine months after infection 33. Epidemiological investigations then concentrated on defining the prevalence of taeniasis in humans and cysticercosis in cattle in various parts of the world. The organism was found to be spread wide ly but sporadically around the globe.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The discovery that taeniasis saginata was acquired by ingesting contaminated beef suggested that infection should be preventable by proper cooking of beef. The observations of Oliver 30 indicated that this was likely then it was confirmed by the experimental studies of Perroncito 36. The latter investigator expose d cysticerci to various tempera tures, then administered them to his collaborators. Dr. Ragni consumed a cysticercus which had been heated to 47 oC; it had no sign of life and failed to develop. S imilar outcomes awaited the medical student Gemelli who ingested a cysticercus heated to 45 oC and his colleague Martini whose cysticercus had been exposed to 44 oC. In contrast, a patent infectio n developed in a fourth person who ate an unheated C. bovis. Perroncito further showed that even without heating, cysticerci die between two and three weeks after slaughter of the cattle. A few years later, Ranso m found that they could also be killed by refrigeration at -10 oC for six days. 37 In addition to these measures, improved methods for the disposal of human faeces helped reduce the incidence of infection in many places, as did th e introduction of compulsory inspection of cattle and condemnation of measl y beef.

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REFERENCES 1. ANONYMOUS. A case in which fourteen yards of Taenia mediocanellata were voided with the head. (Under the care of Dr. Murchison). British Medical Journal ii: 86, 1867 2. ANDRY de BOISREGARD N. De la génération des vers dans le corps de l'homme. Avec trois lettres sur les sujets des vers, les deux premières....par M. Nicolas Hartsoeker et l'autre ....par M. Georges Baglivi, Laurent d'Houry, Paris, pp 468, 1700. An account of the breeding of worms in human bodies etc., translated by H Rhodes and A Bell, pp 266, 1701 3. BATSCH AJ. Naturgeschichte der Bandwurmgattung überhaupt und ihrer Arten insbesondere, Halle, pp 298, 1786 4. BENEDICT EB. Taenia saginata in the gall bladder. Journal of the American Medical Association 87: 1917, 1926 5. BÉRENGER-FÉRAND. Du nombre et de la longueur des taenias que l'on rencontré chez l'homme. Bulletin de l'Académie de Médecine 29: 12-15, 1893 6. BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1689, 1885-1890 7. BLOCH M. Abhandlung von der Erzeugang der Eingeweidewürmer und den Mitteln wider dieselben. Eine von der königlich dänischen Societät der Wissenschaften zu Copenhagen gekrönte Preisschrift, Sigismund Friedrich Hesse, Berlin, pp 54, 1782 8. BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst einem Anhange über Pseudo-helminthen, Carl Schaumburg und Comp., Wien, pp 284, 1819 9. CHRISTOPHERSON JB, IZZEDIN M. Acute intestinal obstruction by tapeworms (T. saginata): mechanical blocking of the ileo-caecal valves, necessitating laparotomy. British Medical Journal i: 697-698, 1918 10. COBBOLD TS. Parasites: a treatise on the entozoa of man and animals including some account of the ectozoa, J&A Churchill, London, pp 500, 1878 11. FONTAN C. Cysticercus bovis chez l'homme localisé à la région mammaire. Taenia inerme de l'intestin. Parasitism adulte et larvaire chez le meme sujet. Gazette des Hôpitaux 92: 183-185, 1919 12. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, P A Pape, Blankenburg, pp 471, 1782. Partly translated in 17 13. HODSON VS. Tapeworm hospitality. Lancet ii: 728, 1921 14. HUBER. Notizen über das Vorkommen pflanzicher und thierischer Parasiten in unserm Bezirk. 13 Bericht die Naturhistorische Vereins in Augsburg, pp 121-129, 1860 15. ISOBE M. (On the resistance of the egg of Taenia saginata.) Taiwan Igakkai Zasshi No. 222, pp 29-75, 1922. In Japanese, with English summary 16. JUDAS A. Nouveau documents sur la fréquence du Taenia en Algérie. Receuil de Mémoires de Médecine, de Chirugie et de Pharmacie Militaires 13: 230, 1860 17. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 18. KNOX R. Observations on the Taenia solium; and on its removal from the human intestinal canal by spirits of turpentine. Edinburgh Medical and Surgical Journal 17: 384-393, 1821 19. KÜCHENMEISTER F. Ueber eine neue Taenia des Menschen, Taenia mediocanellata hominis, seu Zittauensis (mihi). Deutsche Klinik 4: 101-103, 1852 20. KÜCHENMEISTER F. Ueber Cestoden im Allgemeinen und die des Menschen insbesondere etc., Zittau, pp 148, 1853 21. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. 1. Animal parasites belonging to the group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 22. LEUCKART R. Ueber Taenia solium und T. mediocanellata (Helminthologische Experimentaluntersuchungen 2). Nachrichten von der königlich Gesellschaft der Wissenschaften und der GeorgAugusts Universität, Göttingen, pp 15-21, 1862.

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23. LEUCKART R. Ueber den Finnenzustand der Taenia mediocanellata. Nachrichten von der königlich Gesellschaft der Wissenschaften und der Georg-Augusts Universität, Göttingen, pp 195-206, 1862 24. LEUCKART R. Die menschlichen Parasiten unddie von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sche Verlagshandlung, Leipzig, volume 1, pp 776, 1863. Partly translated in 17 25. LEUCKART R. Bericht über die wissenschaftlichen Leistungen in der Naturgeschichte der niederen Thiere während der Jahre 1866 und 1867. Archiv für Naturgeschichte 33J, 2: 163-304, 1867 26. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 1, pp 1009, 1879-1886. The parasites of man and the diseases which proceed from them. A textbook for students and practitioners, translated by WE Hoyle, YoungJ Pentland, Edinburgh, pp 771, 1886 27. LINNAEUS C. Systema naturae per regna tria naturae, secundum classes,ordines, genera, species, cum characteribus, differentiis, synonymis locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 28. MOSLER KF. Helminthologische Studien und Beobachtungen, A Hirschwald, Berlin, pp 89, 1864 29. NICOLAI KF. Zur Geschichte der Bandwürmer. Neuer Zeitschrift für Natur- und Heilkund 1: 464-471, 1830 30. OLIVER JH. Cited in Seventh Annual Report of the Sanitary Commissioner (1870) of the Government of India, Calcutta, pp 82-83, 1871 31. PALLAS PS. Bemerkungen über die Bandwürmer in Menschen und Thieren. Neue nordische Beyträge Physikalische und Geographische Erd- und Völkerbeschriften 1: 39-112, 1781 32. PAWLOWSKI Z, SCHULTZ MG. Taeniasis and cysticercosis (Taenia saginata). Advances in Parasitology 10: 269-343, 1972 33. PENFOLD HB. The life history of Cysticercus bovis in the tissues of the ox. Medical Journal of Australia i: 579-583, 1937 34. PENFOLD WJ, PENFOLD HB, PHILLIPSM. Taenia saginata: its growth and propagation. Journal of Helminthology 15; 41-48, 1937 35. PENFOLD WJ, PENFOLD HB, PHILLIPS M. Ridding pasture ofTaenia saginata ova by grazing cattle or sheep. Journal of Helminthology 14: 135-140, 1936 36. PERRONCITO E. On the tenacity of life of the cysticercus in the flesh of oxen and on the rapid development of the corresponding Taenia mediocanellata in the human body. The Veterinarian 50: 817-818, 1877 37. RANSOM BH. The destruction of the vitality of Cysticercus bovis by freezing. Journal of Parasitology 1: 5-9, 1914 38. SIMONDS JB, COBBOLD TS. On the production of the so-called "acute cestode tuberculosis" by the administration of proglottides of Taenia mediocanellata. Proceedings of the Royal Society 14: 214-220, 1865 39. VALLISNERI A. Opera fisico-mediche stampate e manoscritte, raccolte da Antonio suo figliuolo, S Coleti, Venezia, three volumes, pp 469, 1733 40. WAWRUCH AI. Practische Monographie der Bandwürmkrankheit etc., C Gerold, Wien, pp 212, 1844 41. WEISSE JF. Wieder einmal über das rohe Fleisch. Journal für Kinderkrankheiten 16: 384-385, 1851

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Table 14.1. Landmarks in taeniasis saginata __________________________________________________________________ BC

Tapeworm infections in humans were known but the various species were not distinguished. Various anthelmintics were used 1700 Andry drew an illustration of Taenia saginata although he called it T. solium 1782 Goeze recognized two forms of Taenia but little notice was taken of this observation 1852 Küchenmeister clearly distinguished T. saginata from T. solium on the basis of the morphology of the head and the number of lateral branches of the uterus 1861 Leuckart generated Cysticercus bovis in a calf fed with T. saginata proglottids 1868-9 Oliver, in a poorly-controlled study, observed T. saginata infection in persons who ate measly beef 1877 Perroncito infected a person with a single C. bovis and the subject began to pass T. saginata proglottids 54 days later 1960 Niclosamide was introduced for treatment 1977 Praziquantel was introduced for treatment ___________________________________________________________________

Chapter 15

Diphyllobothrium BOTHRIASIS

latum

AND

DIPHYLLO-

SYNOPSIS Common name: broad tapeworm Major synonyms: Bothriocephalus latus, Dibothriocephalus latus, Dibothrium latum, Taenia lata Distribution: foci in Europe (especially Scandinavia and the Baltic countries), northern USSR, Japan, North America, Chile, Uganda Life cycle: The adult tapeworm, up to 10 metres in length, lives in the small intestine with the head attached to the mucosa. Eggs and gravid segments are passed in the faeces. When deposited in moist environments, each egg hatches and the larva (coracidium) swims about until it is ingested by certain species of small crustaceans (copepods). The larva develops over 2-3 weeks into a procercoid in the body cavity of the copepod. When an infected copepod is ingested by certain species of freshwater fishes, the procercoid is liberated in the fish's gut and migrates to the muscles where it develops into a plerocercoid (or sparganum) up to 2 cm in length. When a plerocercoid in raw or insufficiently cooked fish is ingested by a human, the plerocoercoid develops into an adult worm and begins to pass eggs 4-6 weeks later Definitive host: humans First intermediate host: certain copepods (Cyclops, Diaptomus species) Second intermediate host: certain freshwater fish, including species of burbot, eel, lawyer, perch, pike, ruff, salmon and trout Major clinical features: abdominal discomfort, spontaneous passage of proglottids Diagnosis: finding of eggs or proglottids in the faeces Treatment: niclosamide, praziquantel

DIFFERENTIATION OF THE SPECIES FROM TAENIA SOLIUM Although tapeworms have been known since ancient times (see chapter 13), it was not until around the beginning of the seventeenth century that it was realized that more than one species of tapeworm infected humans. According to Davaine 24, it is now apparent in retrospect that two Swiss observers, first Thaddeus Dunus in Lucarno in 1592, then Gaspard Wolphius in Zurich, described in a recognizable fashion, the worm now known as Diphyllobothrium latum. Dunus wrote: "De lumbrico lato (mirae longitudinis): squamosus instar serpentis, nisi rectius geniculatus dicatur, fotus sui simillimus" 26 meaning that the broadworm of remarkable length had the scaly appearance of a snake 397

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except that the leading joints were attached and supported each other. Nevertheless, these observers did not allude to the differences between this worm and either of the two species of Taenia now known to infect humans. The first person to do this, although his description is somewhat vague, was Felix Platter (Platerus) in Basel (Switzerland) in 1602. Whereas his predecessors and contemporaries called all tapeworms "Lumbricus latus", Platter discerned two forms of tapeworms passed by humans. He called the first of these, Taenia intestinorum, and this became known to later authors as Taenia prima plateri (the first Taenia of Platter): One is characterized by a kind of membranous skin, similar to the fabric of the small intestine, equal to it in length but not at all empty inside as it, and about a finger's breadth wide. This they call the Latum lumbricorum (the broad intestinal worm), but more correctly it should be called the Taenia intestinorum (the taenia of the intestines) since it has no likeness to the lumbricus; it is not alive, as is the lumbricus; nor is it stirred from its place, but remains fixed for a long time until it is passed....On this fascia there are generally transverse lines about a finger's breadth apart. They appear along its whole length and resemble vertebrae, swelling out in the intervals between them.63

The second form he called Taenia longissima, and this became known as Taenia secunda plateri (the second Taenia of Platter) to later authors. It probably refers to T. solium, but may possibly have been T. saginata: On another occasion, very long taenia of the same type were observed. However, they were shaped differently and appeared to be composed of many attached segments which could be separated from one another. These segments, since gourds sometimes bear square seeds, are called the vermis cucurbitinus. The worm is rarely passed whole, but generally in many pieces. Previously, each of these individual pieces was believed to have been an individual worm, called a cucurbitinus; however, they are only pieces broken off from the fascia.63

Thus, the hallmark upon which Platter based his distinction between the two species of worms was the shape of the proglottids. His descriptions were incomplete and to some degree erroneous. He was unaware that tapeworms had a head and does not appear to have realized that tapeworms were living organisms. In 1618, the Dutchman, Adrien van der Spiegel (Spigelius), probably without being aware of the previous account, again reported the existence of two distinct species of tapeworms in humans80. Nicholas Andry in 1700 also recognized two types of tapeworms: One has....a long Thorn full of knots running along the middle of its body upon the upper side....The other wants this Thorn, but at every Joint upon the sides, has a sort of small Nipple open at the Point.3

The first of these he labelled as Taenia à épine (Taenia with a spine) and the second he called Taenia sans épine (Taenia without a spine). Perusal of his illustrations of Taenia à épine leaves no doubt that the spine which he described as running down the middle of the entire length of the worm is in fact the medially-placed genital openings of the worm now called D. latum.

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Similarly, examination of his figures of Taenia sans épine clearly indicates that the small nodules that he described at the margin of each proglottid are the laterally-placed genital pores of T. solium or T. saginata. Thus, the key distinguishing feature for Andry was the position of the genital apertures (although he did not recognize them as such, considering them to be pulmonary openings). It is not certain who first saw the head of D. latum following the first description of a tapeworm head by Edward Tyson in 1683. In 1750, in Geneva, Charles Bonnet published his study of human tapeworms. In this work, he emphasized the "stigmata umbilicialia" of the broad tapeworm and the "stigmata lateralia" of Taenia, but he included a figure showing what Blanchard11 later called "un être fanstastique" (a fantastic being) with the head of a T. saginata and the body of Diphyllobothrium 12. In 1777, however, Bonnet corrected his earlier publication and described the head of the broad tapeworm in detail for the first time, noting its attenuated shape and the two suctorial grooves, then went on to outline the appearance of the proglottids ("rings", as he called them)13. Shortly thereafter (1779), von GleichenRusworm likewise described the scolex of the worm31. Bremser in 1819 again described the worm and created a new genus, renaming the worm Bothriocephalus latus, to indicate that it was the broad worm with the grooved head18. In 1841, Eschricht published the first detailed description of the anatomy of the adult worm28. Nine years later, Diesing renamed the parasite Dibothrium latum 25, then this was changed to Dibothriocephalus latus by Lühe in 189949. Finally, the parasite was transferred by Lühe50 in 1910 to the genus Diphyllobothrium erected by Cobbold in 185720. The generic name was derived from a combination of the Greek words (DIS), (PHYLLOS) and (BOTHROS) meaning "two", "leaf" and "groove" or "sucker", respectively.

ELUCIDATION OF THE MODE OF TRANSMISSION The origins and mode of transmission of this parasite remained obscure for many years. Several epidemiological observations, however, pointed towards the direction in which the solution would be found. As observers became more confident in their ability to differentiate D. latum from other tapeworms, it became apparent that this infection had a restricted geographical distribution. These infections were at first unknown outside Europe and were thought to be most common in Switzerland and adjacent areas of France, Scandinavia and the Baltic regions. For example, in the early parts of the nineteenth century, one quarter of the inhabitants of Geneva were said to be infected21. This indicated to many commentators that there was something unusual about the mode of transmission of this infection, but its nature was by no means clear.

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Nevertheless, ideas abounded. As early as 1747, the Finn, Herman Spöring, made the very perspicacious observation that people who lived on the banks of rivers, rapids, and lakes where there was plenty of fish, suffered from the tapeworm more commonly than did populaces living in other areas81. This idea that consumption of fish might be important in the acquisition of tapeworm infection received a boost with a discovery of Peter Abildgaard in Copenhagen in 1819. Abildgaard became interested in a cestode worm that lived in the abdominal cavity of the little fish known as the stickleback. He perceived certain resemblances between this worm, which had no reproductive organs, and the tapeworms that he had seen in mergansers and other fish-eating birds. He wondered whether the worms in the fish could be an immature form of the bird parasite so he fed some of them to domestic ducks. Abildgaard was delighted to find later, in the ducks' intestines, tapeworms, filled with mature eggs, which looked just like those occurring in mergansers 2. The time was not ripe for a proper appreciation of such revolutionary discoveries, however, nor did the confirmatory observations of Creplin22 with Schistocephalus and Ligula receive the acceptance they deserve. More than fifty years were to pass after Abildgaard's pioneering experiment before Steenstrup published his theory of the "Alternation of Generations" (see chapters 2 and 4), and thus opened up new vistas for understanding the manner of transmission of diphyllobothriasis. Initially, attention was paid to the ova of D. latum. These had been mentioned by Andry in 1718 and primitive drawings had been made by Goeze in 178232. Schubart of Utrecht hatched ova of D. latum in water and observed the liberated embryo with its mantle of cilia. He died before he could publish the observations in detail but notice of the finding was given, first by Kölliker in 185176, then by Schubart's friend, Verloren in 185577. Küchenmeister in 1855 described the egg as having a brittle shell with an opercular opening and containing a limpid vesicle with six hooklets. Probably unaware of Schubart's findings, Knoch in St. Petersburg (Leningrad), Russia (1862) 43, R Leuckart in Germany (1863) 48 and Bertolus in France (1863) 8 all observed independently the hatching of ova. They agreed that hatching took several weeks or months to occur, depending upon the temperature. Nevertheless, these observations did little to help answer the fundamental question of the mode of transmission. Following dissemination of Steenstrup's ideas on the alternation of generations, concepts about the transmission of D. latum generally fell into one of two categories. Some scholars, such as Vogt91 held that transmission was direct with a human to human cycle in which humans ingested eggs in food contaminated with sewage. Knoch, for example, believed that he had proved this mode of infection and adduced two pieces of evidence to support his view. First, he attempted to infect a number of potential intermediate hosts by introducing embryos to various aquatic animals but met with no success. Secondly, in 1862, he administered embryonated eggs and non-embryonated eggs to two dogs. Four months later, he found

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diphyllobothria in various stages of development in one dog, then after another six weeks, found two worms, 45 and 53 cm long, in the other animal43. In retrospect, it is clear that these dogs had acquired natural infections, for when similar experiments were repeated by other investigators in non-endemic areas, particularly Leuckart in Giessen and Grassi in Italy, no worms matured. The alternate view was that ova developed into larvae in an intermediate host before ingestion by humans. This hypothesis was strengthened by the discovery in the 1850's that the taeniid cestodes underwent migration and metamorphosis in mammalian intermediate hosts. In the case of Diphyllobothrium, however, the known association of the infection with lakes and rivers, together with the precedents established with various trematodes (see chapter 4) suggested to many that the intermediate hosts were likely to be aquatic animals. This notion was amplified when Stein in 1882 drew attention to the fact that many orthodox Jews were carriers of D. latum although they never ate raw meat and were not infected with T. solium 82 Despite earlier suggestions that fish may be related to the acquisition of infection, Küchenmeister writing in 1855 thought that this was unlikely, for he was under the misapprehension that infection could only be caught by eating fish intestines, and this was not the habit of the populace45. This idea flowed from the Abildgaard's demonstration, referred to earlier, that some cestodes found in the intestinal tract of fish only matured after ingestion by some predaceous bird. Küchenmeister thought it more likely that the larvae might live in snails which could be ingested accidentally with fruit and vegetables. Others, however, kept returning to fishes as potential intermediate hosts. Bertolus postulated that Ligula nodosa in salmon was the intermediate form of D. latum 9, and Leuckart attempted, without success, to infect trout in a stream near his home by contaminating the water with large quantities of eggs and hatched D. latum larvae48.

DISCOVERY OF THE PLEROCERCOIDS AND THE FISH SECOND INTERMEDIATE HOST Since attempts to infect potential hosts with larvae derived from eggs were unsuccessful, attention turned to the other end of the life cycle. As it was known that other species of bothriocephali could be found in animals or birds which either primarily or exclusively ate fish, Max Braun in Dorpat (Tartu), Estonia (present-day Estonskaya SSR, USSR), decided to look for the intermediate host of D. latum among the fish eaten ordinarily by the people living in his region. He therefore examined fish brought to the market in Dorpat from Lake Peipus and surrounding regions, and soon found young bothriocephali in pike (Esox lucius) and burbot (Lota vulgaris). More than 90% of the fish in the market were so infected, with variable numbers of unencapsulated worms being found in the muscles and viscera. Such worms had been seen previously by Knoch in St. Petersburg but he had not realized what they were. In fact, plerocercoids of

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Diphyllobothrium may have been seen in fish as early as 1688 by PJ Hartmann, although, of course, he did not relate them to the broad tapeworm infecting humans36. The worms found by Braun were between 8 and 30 mm in length and appeared to be analogous to cysticerci and echinococci as they were sexually immature; he called them plerocercoids 16. At first glance, they did not look much like Diphyllobothrium for the head was usually withdrawn but Braun wrote that if the worm: "is placed in warm water or egg white, the head unfolds and one recognizes the suction grooves on it"16. Subsequent investigations showed that a number of other species of fish, including perch (Perca fluviatilis) and ruff (Acerina cernua), were also infected sometimes. Since diphyllobothriasis was rare in dogs and was never seen in cats in Dorpat, Braun began, in 1881, a series of feeding experiments to prove that these plerocercoids could develop into adult D. latum. Initially, he gave plerocercoids to three dogs then sacrificed them four, eight and eleven days later. In their intestines, he found worms which resembled the original plerocercoids but which grew progressively in size. After treatment with a variety of anthelmintics, Braun infected a number of dogs and cats, sometimes with positive results, but on other occasions he failed to find any diphyllobothria. In order to be absolutely sure that the infections were not acquired naturally in some other manner, Braun, at the suggestion of Professor E Rosenberg, infected a dog which up to that time had only been fed with its mother's milk: I was able to give a three-week-old dog 17 pike bothriocephali in one day by forced feeding....The dog, which ingested only boiled cow's milk, thrived; but because of its continued howling, had to be killed ten days after infection. In the intestine . . I found sexually immature bothriocephali 14-15 cm long which matched, although not completely, corresponding initial parts of B. latus; they can only be attributed to the infection which took place.16

Finally, Braun investigated the effects of giving plercocercoids to humans. On 15 October 1882, he gave three or four worms obtained from pike to each of three medical students who were not carriers of D. latum. After about three weeks, they began to feel ill and complained of abdominal pain. On examining the faeces on 18 November, a large number of D. latum eggs were found in the stools of each student. A few days later, they were treated with ethereal extract of male fern; one student expelled two specimens of mature D. latum, another produced three parasites, while the third subject passed only fragments of tapeworm16,17. These results were confirmed several years later by Grassi and Ferrara34 then by Zschokke. DISCOVERY OF THE PROCERCOIDS AND THE CRUSTACEAN FIRST INTERMEDIATE HOST

The question still remained as to the manner in which the precursors of the plerocercoids reached these fish. In 1883, Braun found five round holes in the

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stomach of a burbot. Two of them still contained a plerocercoid of D. latum with the head of each worm pointing away from the lumen of the stomach towards the submucosa. The other three holes were empty but Braun found the worms not far away in the stomach wall between the glandular and muscular layers. This observation led him to propose that ciliated embryos of D. latum develop into cysticerci in an as yet unknown intermediate host, then together with this intermediate host, they reach the gut of a fish where they are freed during the process of digestion, then penetrate the intestinal wall of the fish and migrate into its body wall16. Although this idea was later abandoned by Braun in favour of a direct infection of fish, the concept was seized upon by the Pole, Constantin (Konstanty) Janicki who, while working in Lausanne, Switzerland in the summer of 1916, made a similar observation. Janicki had first tried to infect fish directly but had failed. Thereupon, he invited a fellow Pole named Felix Rosen who was working in Neuchatel, Switzerland to collaborate with him40. Since Janicki had used unstained, formalin-fixed material, Rosen decided to repeat these experiments in a modified form. He infected hatchlings of trout (Trutta species), salmon (Salmo salvelinus), burbot (Lota vulgaris), perch (Perca fluviatilis) and pike (Esox lucius) with large numbers of ciliated D. latum larvae. Rosen then examined them carefully each day for up to three months between October 1916 and April 1917, both directly under the dissecting microsocope and in histological sections made from paraffin blocks and stained. The results were absolutely negative70. When his attempts at direct infection were unsuccessful, Janicki between April and August 1917 examined the stomach contents of 82 Lota vulgaris, 998 Perca fluviatilis and 3 Esox lucius obtained from the market in Lausanne. By this means he hoped to determine the nature of their food which might give him some clue to a possible primary intermediate host then, if possible, to trace the development of the worm from its appearance in the primary intermediate host to the plerocercoid stage. In the stomach of Lota vulgaris, he mostly found enormous quantities of Gammarus; 40% of the Lota were infected, mostly with plerocercoids in the stomach. Many of the perch were infected and in their stomachs he found mostly water fleas and copepods (small crustaceans). When he searched the youngest perch, Janicki found tiny worms, little more than half a millimetre long but which were clearly very young larvae of D. latum, encapsulated within the stomach wall. Encouraged by this discovery, he began to examine small perch systematically for even younger stages of plerocercoids. On 25 June 1917, he found two of these worms lying free in the stomach mucus of a tiny perch, the stomach contents of which revealed mainly the copepods, Cyclops, Diaptomus and Bosmina. A few days later, he found another worm in a perch which contained only Cyclops and Diaptomus in its stomach. This led him to the conclusion that a copepod must be the primary intermediate host: "Thanks to this evidence, I was able to formulate the idea that the primary

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intermediary host must be sought among the copepodae" 38. Further observations revealed to Janicki that, while still free in the stomach lumen, these young worms carried a caudal appendage furnished with hooks and that this was cast off before the parasite penetrated the mucosa38. Meanwhile, Rosen in Neuchâtel arrived at a similar conclusion, having approached the problem from a different angle. Rosen decided that the first intermediate host must lie within one of the following four types of food: plankton, insect larvae; the Gammaridae, and the Oligochaetae. Plankton seemed to him to be the least likely since Lota vulgaris, being a fish of the deep, did not eat much plankton, whereas other plankton eating fish such as the Coregonae were never infected. He therefore examined the latter three groups, all with negative results. Undismayed, he began experiments with plankton on 17 June 1917. This time his efforts were to be crowned with success. He collected plankton form Lake Neuchâtel then mixed it with large numbers of larvae. Again, he had no luck until he turned his attention to the copepods in the plankton. At first, all seemed hopeless, particularly when Cyclops viridis ingested then actually digested the larvae. On 24 June, however, he found large numbers of C. strenuus infected with one to ten oncospheres in the body cavity: At first I did not observe anything special. The numerous fat droplets which filled the body of these crustaceans, moreover, prevented a very detailed observation. In rapidly draining the water from beneath the cover slip, so that the pressure of the latter removed the little fat droplets, the examination had no more obstacles. My astonishment was then immense. By examination of some of these fat droplets at a higher power....I confirmed that several were nothing more than oncospheres which were already in the body cavity. One after the other, all the specimens examined were found infected....There was no longer any doubt that we were in the presence of the primary intermediary host, or in any case of a species very closely related to the true host.70

Rosen then found that Diaptomus gracilis was also infected, but to a lesser degree. Subsequent studies revelealed that after the ciliated larvae, 0.024 mm in diameter, was ingested by a Cyclops, it lost its embryonic envelope, penetrated the gut wall and reached the body cavity. In that location, it grew and became more elongated in shape. By the tenth day, it had reached 0.2 mm in size and the structure had begun to differentiate, particularly at each extremity. At one end, a spherical appendage containing the hooks evolved; it became attached by a narrow neck then finally fell off when the larva was between two and three weeks of age and 0.5-0.6 mm in length. In the meantime, a primordial mouth developed at the other end. This stage he called a procercoid 70. These findings were confirmed two years later by Galli-Valerio when he infected successfully C. strenuus with D. latum eggs obtained from the faeces of a dog30, then Redlich showed that D. graciloides was a very efficient intermediate host67 In order to complete the life cycle experimentally, Rosen infected six small trout on 6 August 1917 by placing them in an aquarium containing large numbers of copepods which had been infected for six weeks. One trout was

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killed six hours later and free procercoids were found in the stomach contents, some with and some without caudal appendages. In a fish killed the next day, Rosen found procercoids in the stomach wall. Four days after infection, he believed that the larvae could be considered plerocercoids and they migrated from the gut into the muscles and viscera. Rosen concluded his paper by writing: The life cycle of Dibothriocephalus latus is now completed: (1) by the negative result of the direct infection of fish by ciliated larvae; (2) by the positive result of a mode of development in cestodes unknown until now; that is, the existence of two intermediate hosts....The development passes from the oncosphere to the plerocercoid by an intermediate larva,....the procercoid.70

The following year, Rosen published another paper which provided further details. In particular, the ciliated body emerging from the D. latum egg was called a coracidium and the plerocercoid was defined by the development of two suckers71. Unfortunately, what had begun in friendship and teamwork between Janicki and Rosen turned sour. In this latter paper71, Rosen, because he had carried out the last decisive experiment, tried to take the whole credit for himself and launched a violent diatribe against Janicki. An unpleasant controversy between the two followed, with Janicki replying to Rosen's attack39. Von Bonsdorff has portrayed succinctly their subsequent paths: "Janicki, who was an eminent parasitologist, became professor of zoology at Warszawa; Rosen made no further scientific career"14.

RECOGNITION OF THE CLINICAL FEATURES Felix Platter was remarkably accurate in his summation of the clinical features of this infection when he wrote in 1609: While taeniae remain in the body, unless something else happens, few serious symptoms occur from which it can be perceived that an individual carries this foulness in his body before they pass unexpectedly, at which time they occasion great fright on being found. There is a pressing desire to rake food much more often than was customary and a certain heaviness in the stomach. If anything is in the stomach, it is felt. The symptoms become worse when an intestinal worm dies or if a segment is broken off from the others and putrefies.63

With the passage of time, however, all manner of ills were ascribed to this worm. Thus, Abbotts Smith in 1863 wrote that anal itching, an itchy nose, swollen abdomen, nausea, vertigo, palpitations during the night, fainting and epigastric pain could all be caused by D. latum 1. The clinical manifestations were put on a more certain basis when humans were infected experimentally. The medical students infected by Braun17 developed malaise and abdominal pain three weeks after ingestion of plerocercoids. Le Bas has described in detail the clinical features in three humans infected experimentally, and concluded that the effects were little more than discomforting with transient diarrhoea at the onset of patent infection after two

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to three weeks, followed by vague dyspeptic symptoms46. The most usual symptom was of patients complaining of passing segments of worms intermittently. Even more valuable than this study was a comparison of symptoms between infected and non-infected persons living in an endemic area. Statistical analysis revealed increased frequencies of a sensation of hunger, diarrhoea, fatigue, numbness of the extremities and a craving for salt in infected persons74. In endemic areas, the majority of patients had small numbers of relatively short tapeworms. Some patients, however, had very large tapeworms or incredible numbers of them. One Russian woman living in the USA passed a single worm 8.7 metres in length after treatment78. In Switzerland, a 21 year old woman passed at least 90 adult worms after therapy. The worms passed out in a bundle, the patient assisting at the delivery by tearing at the mass with both hands while at the same time shrieking like a woman in labour; the agonizing delivery lasted ten minutes and the parasites filled up half a chamber pot72. Even more heavily infected was a 66 year old man who passed 106 tapeworms weighing 400 grams33. Perhaps the record in terms of total length, though, was set by the Russian man who passed 14 worms totalling 83 metres in length62. The duration of D. latum infections was at one time put at 20 years or more. This was based largely upon the finding of infected patients in North America many years after emigration, but before it was realized that diphyllobothriasis is endemic in parts of that continent. There is no doubt that infection may last as long as six years. One of three volunteers infected by Le Bas in 1922 was RT Leiper, professor of helminthology in London. Whereas the other two subjects were cured completely by carbon tetrachloride administration soon after infection, Leiper passed less tapeworm heads than the number of plerocercoids he ingested. Nevertheless, he was well for the next few years and did not notice any proglottids in his stools. While in Cairo in 1928, however, he had an acute attack of dysentery and on examination of his stools, was astonished to find vast numbers of D. latum ova. He continued to observe the passage of these eggs in his stools for the next ten months until termination of the infection with anthelmintics. Leiper believed that this was a persistent infection as he had had no opportunity for acquiring a natural infection during the interval47. These observations suggest that little immunity to challenge infection develops, and this concept has been supported by a number of other investigations. In one such study, 125 of the 143 inhabitants of a village in Karelia, USSR, were found to be infected with D. latum, most of the uninfected persons being young children. Sixty of the infected people were treated with anthelmintics - three years later, 20 were reinfected whilst 40 were not; this was interpreted as evidence for the development of partial immunity86, but many other factors, such as changes in eating and cooking habits, could have accounted for this result. Tarassov, who had carried out this study, infected himself in 1932, treated himself, then challenged himself with six plerocercoids 3.5 months after the original infection; a patent infection developed and treatment five weeks after challenge produced two heads and 6.3 metres of

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worm. Similar challenges one and two years later failed to produce patent infections. In 1936, four years after the original infection, he again infected himself with six plerocercoids and patent infection occurred; anthelmintic therapy seven weeks later resulted in four heads and 26 metres of tapeworm. Finally, Tarassov infected himself with seven more plerocercoids; he began to pass eggs in his faeces 14 days later. While harbouring the worms, he had much abdominal pain, lost 8 kg in weight, and weakness forced him into a sanatorium. Five weeks after infection, he treated himself and expelled 38 metres of tapeworm with seven heads86. While these results could be interpreted as indicating transient immunity one and two years after the initial infection, it is far more likely that those challenges were made with non-infective plerocercoids. Certainly, there was no significant immunity several months and several years after the first exposure to D. latum, and this is probably the normal state of affairs.

CORRELATION OF PERNICIOUS ANAEMIA WITH D. LATUM INFECTION In July 1877, Gustav Reyher in Dorpat (Tartu), Estonia (USSR), saw a 66 year old woman who became steadily weaker and paler during the course of a year. He diagnosed her as suffering from pernicious anaemia, a disease which had been defined by Biermer in 1872. She also complained of intermittent diarrhoea and on one such occasion had passed a segment of D. latum. Reyher therefore treated her with extract of filix mas and was surprised to find that not only was the worm expelled, but that within a few weeks, her general health had returned to normal. Six months later, Reyher encountered a similar situation in a 30 year old man; treatment resulted in an equally striking cure. Rehyer then began to collect a series of such cases and by 1884 had seen 12 patients. In late 1883, he began to examine the wet blood films and found that although the numbers of red cells were reduced markedly, they were often larger than normal, and he also noted that the white cells were often reduced in number. The results of this serendipitous bedside observation, which was skilfully followed up, were finally published in June 188668 Independently of Reyher, JW Runeberg in Helsingfors (Helsinki), Finland had been following a similar line. In 1883, he had seen a number of cases of pernicious anaemia, all with a fatal outcome, and had been struck by the fact that the majority of patients had D. latum in their intestines. Thereafter, the faeces of patients who were seen in his clinic were examined systematically for D. latum eggs and, if they were found, an anthelmintic was given. In September 1886, he reported his experiences at a Congress in Berlin; 12 of 19 patients with pernicious anaemia were also infected with D. latum and all of these persons were cured by expulsion of the worm73. Nevertheless, the Congress received his communication with reserve. It seems probable, however, that in addition to these two investigators, the

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idea of a causal relationship between broad tapeworm infection and pernicious anaemia arose simultaneously in the minds of a number of other investigators, including Hoffman, professor of medicine in Dorpat, and Albrecht, a pathologist in St. Petersburg. According to Wiltschur (1893) (cited in14), Albrecht used to indicate in his reports, even before 1883, whether D. latum was found in the intestines of patients dying from pernicious anaemia. However, he never published his observations. In retrospect, it seems that Reyher ought to be accorded the greatest credit for the discovery, followed closely by Runeberg. The contention that some cases of pernicious anaemia were dependent upon the presence of diphyllobothria in the intestines was supported strongly by some authorities but disputed hotly by others who claimed that the association was a mere coincidence. Nevertheless, it gradually became apparent that a small proportion of infected persons did become anaemic. This anaemia was not the type recognized in iron deficiency, and in contrast to the anaemia seen in hookworm infection, the erythrocytes were enlarged and there was a mild leucopenia with the white cells being hypersegmented. This anaemia could not be differentiated clinically or haematologically from idiopathic Addisonian pernicious anaemia, but in many patients, the anaemia resolved after elimination of the tapeworms, thus confirming an aetiological relationship. The prognosis for the vast majority of patients was good, but in the small number of persons with severe tapeworm anaemia, the outcome in the early years of treatment depended upon elimination of the parasites. For example, a 13 year old boy who presented in 1887 with a severe anaemia, the haemoglobin concentration being only one sixth of normal, made a rapid recovery after anthelmintic administration produced the passage of a large quantity of D. latum segments75. In some instances, patients were deemed to be so ill that they were subjected to blood transfusion (with all its attendant complications in those days), prior to anthelmintic treatment. The demonstration of the efficacy of liver (which contains vitamin B12) then the preparation of pure vitamin B12 for injection, and the development of safe blood transfusion procedures has revolutionized management of such patients. Finally, the discovery of effective anthelmintics has ensured a favourable outlook for patients with this infection.

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INVESTIGATIONS OF THE PATHOGENESIS OF TAPEWORM PERNICIOUS ANAEMIA The recognition of anaemia in association with diphyllobothriasis led to attempts to both delineate the nature of the anaemia and to define the mechanisms by which it was produced. The anaemia was clearly quite different to that seen in hookworm disease where the red cells were small (microcytic) and depleted in haemoglobin (hypochromic) and the body stores of iron were greatly reduced. In tapeworm anaemia in contrast, the red cells were large (macrocytic), the white cells were slightly reduced in number and their nuclei were hypersegmented, and the iron stores were normal. The similarities between this anaemia and idiopathic pernicious anaemia were striking, but it must be remembered that, at that time, the genesis of idiopathic pernicious anaemia itself was unknown. A number of theories were proposed, including the production of toxins by worms and allergic reactions, but these did not stand the test of time, even though the allergic theory was held tenaciously for many years by Tötterman87. Understanding of the nature of tapeworm anaemia followed, step by step, elucidation of the pathogenesis of idiopathic pernicious anaemia. In 1926, Minot and Murphy showed that patients with idiopathic pernicious anaemia could be restored to health by eating half a pound of raw liver daily. Thereupon, Isaacs and co-workers tried this treatment in tapeworm anaemia and found that the anaemia resolved, even though the parasite persisted 37. Further studies of patients with idiopathic pernicious anaemia indicated that the anaemia was a consequence of a deficiency of an extrinsic factor, a high concentration of which occurred in the liver. It was then discovered in 1929 by Castle and his colleagues that the production of an intrinsic factor in the stomach was requisite for absorption of the extrinsic factor; the intrinsic factor was secreted into the gut, combined with the extrinsic factor in the diet, then the complex was absorbed in the terminal ileum. In 1948, vitamin B12 was discovered and found to be identical with extrinsic factor. In that same year, von Bonsdorff suggested that tapeworms interfered with the interaction between extrinsic factor and intrinsic factor. He then found, using a biological assay, that tapeworms competed with the host for dietary vitamin B12 and accumulated large quantities of the vitamin within their substance 15. This observation was then confirmed using radiolabelled vitamin B12. Indeed, there was a transient fashion for treating patients with idiopathic pernicious anaemia by parenteral administration of an extract of dried fish tapeworm, as this contained a high concentration of vitamin B12 (some fifty times that seen in T. saginata). Later laboratory studies showed that the parasite was able to take up both free vitamin B12 as well as that bound to intrinsic factor (reviewed in14). It was recognized that only a small proportion of infected persons became anaemic. Thus, in Finland, a mere 0.1-0.5% of infected persons were anaemic.

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Furthermore, the intensity of infection did not necessarily correlate with severity of anaemia. For example, the woman with 90 tapeworms cited earlier was not anaemic, having a haemoglobin level of 95% on the old Sahli scale, whereas the man with 106 worms was grossly anaemic with a haemoglobin concentration of 25%. In 1932, Birkeland reviewed the literature and suggested that there may be a racial and familial predisposition to the development of anaemia, for this complication was seen more commonly in Finns than in persons of other nationalities 10. In 1956, Nyberg and Östling confirmed that vitamin B12 levels were low in the serum of persons with tapeworm pernicious anaemia61. This was followed by the demonstration that absorption of radiolabelled vitamin B12 (Schilling test) from the bowel was impaired in both patients with tapeworm pernicious anaemia and in the majority of tapeworm carriers who had normal haemoglobin levels59,60. Thus, it became apparent that a number of other factors were necessary to precipitate anaemia in the small proportion of infected persons who became anaemic. These included a low dietary intake of vitamin B12, the location of the worms in the gut (von Bonsdorff has proferred some evidence to suggest that anaemia is more common in people in whom tapeworms are sited in the jejunum rather than lower down in the bowel), and finally, the coincidental presence of atrophic gastritis with a consequent reduction in the production of intrinsic factor5.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of infection with D. latum was obvious if patients passed proglottids and brought them along for identification. With the discovery that helminth eggs are passed in the faeces, it became possible to diagnose infection by microscopical examination of the stools. It is uncertain who first applied this to diphyllobothriasis, but Davaine in his textbook of 1860 provided an illustration of the appearances of such eggs in the faeces23. When the association between D. latum infection and pernicious anaemia was appreciated later that century, physicians in endemic areas realized that it was necessary to exclude diphyllobothriasis in patients with this form of anaemia.

THE SEARCH FOR EFFECTIVE TREATMENT The anthelmintic therapy of diphyllobothriasis has been similar to that of the other major tapeworm infections of humans (see chapter 13). Küchenmeister in his textbook of 1855 regarded diphyllobothriasis as the most easily treated of the tapeworm infections and considered that filix mas and pomegranate root were the most satisfactory medicaments45. A large number of anthelmintics with

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variable efficacy and toxicity followed, including thymol, carbon tetrachloride, areca nut, dichlorophen, mepacrine and a preparation of the Finnish broad buckler fern. In the 1960's, niclosamide was introduced and was shown to cure about 70-80% of patients66,79. In 1977, praziquantel was used in diphyllobothriasis 6,19, and subsequent experience has shown that almost all patients are cured with this drug.

UNDERSTANDING THE EPIDEMIOLOGY Investigators of diphyllobothriasis realized that the infection was endemic in areas where people were in the habit of eating improperly cooked fish and where there were inadequate facilities for the disposal of waste products. Although many animals have been found infected in nature, or have been infected experimentally, most workers came to the conclusion that humans were the most important reservoirs of infection. Considerable efforts were then expended on locating endemic areas and on identifying the primary and secondary intermediate hosts in those areas (reviewed in14). It has now been shown that Diphyllobothrium infections have been present in Europe for many hundreds of years. In 1944, Szidat reported that the characteristic eggs were seen in the intestinal contents of a cadaver which had been recovered from a peat bog in East Prussia; the body was thought to have been buried about 500 AD84. More recently, D. latum eggs were found in faeces at a location near Bremerhaven (Feddersen Wiere), where excavations brought to light remains dated between 100 BC and 500 AD41. At the time Cobbold wrote his textbook in 1864, diphyllobothriasis had never been found outside of Europe21. In the latter part of the nineteenth century, however, sporadic cases of infection were noted in patients in North America, particularly around the Great Lakes. Since all of these people were immigrants, it was believed at first that these infections were merely caused by long-lived tapeworms acquired before emigration. This idea became less tenable when in 1901 a case of native infection was reported in a French Canadian who had never been outside of Canada and rarely outside the province of Quebec35. Five years later, Nickerson reported D. latum infection in a three year old boy who was born in Minnesota of Finnish parents, and who had never left the country57. Since freshwater fish were not imported into the United States from Finland, it was concluded that the infection must have been acquired locally. In support of this view, larvae of D. latum were found in a number of fish caught in the Great Lakes. As more such cases were reported, it passed beyond doubt that broad tapeworm infection had been introduced and become endemic in North America. Stiles predicted in 1907 that this would happen in upper Michigan since its population contained immigrants who not only brought their tapeworms with them, but retained their Baltic habit of eating uncooked fish, either fresh, dried, smoked or cured. In fact, however, the majority of infections

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occurred in female Jews who were in the habit of tasting raw fish to test their skill in flavouring it. A number of studies were consequently undertaken to determine the primary and secondary intermediate host of infection in this region. Procercoids were shown to develop in D. oregonensis 29, D. silicis and D. silicoides53 , while plerocercoids were found in Stizostedeon canadense-griseum, S. vitreum, Esox lucius and Lota maculosa 88. Moreover, it was found that heavy infections in fish occurred in some lakes near which there was a very sparse human population. Since it was known that carnivores, including dogs, foxes, otters, bears and cats can harbour adult D. latum, the high frequency of dogs in the area suggested that these animals may be an important reservoir of infection. On the other hand, eggs from dog faeces were much less likely to hatch active coracidia (1.5%) c.f. ova in human faeces (80%)53. The relative contributions of the various definitive hosts remains obscure, however, as their inputs have not been subjected to precise mathematical analysis. In any case, investigations in the USSR subsequently showed that eggs from dogs developed almost as frequently as eggs from humans, albeit more slowly85. Continued observations revealed that infection was not only endemic in fish in Lake Superior and its surrounds, but also in lakes which drained through Lake Winnipeg into Hudson Bay53. Eventually, endemic foci of infection were found in Eskimos in northwest Canada and in Alaska. Similarly, the parasite was introduced into Chile and became established in the Andean Lake District some 800 kilometres south of Santiago, with Salmo lacustris and S. irideus proving to be secondary intermediate hosts56. In 1947, Stoll estimated that there were just over 10 million people infected with D. latum, about one quarter of them in Europe and most of the rest in the USSR with small foci in North America, South America and Japan83. Within the Soviet Union, the broad tapeworm had been first reported by Pallas in St. Petersburg (Leningrad) in 1781. Subsequent surveys indicated that the prevalence of infection in Leningrad before the Second World War was somewhere between 5 and 10% of the population. This region was at first regarded as the centre of infection, but it became apparent that the worm was widespread within the USSR, including Siberia62. Very high rates of infection were found in the Baltic region, for example, around 70% of the population of the western shore of Lake Peipus in Estonia were infected in 1926. Similarly, in Finland,which had long been one of the best known zones of endemic diphyllobothriasis, frequencies varying between 0 and 100% were found in different parts of the country; parasitism was most frequent in the Finno-Ungarian linguistic group, probably as a result of their dietary customs10. In some areas, industrialization altered the ecology and favoured the spread of infection. Increased intensities of infection sometimes occurred around new reservoirs in regions where D. latum was infrequent previously, such as on the Volga River in the USSR69. Similarly, construction of the Moscow Canal allowed the development of permanent new foci of infection. On the other hand,

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construction of water power plants sometimes had a helpful effect. Thus, in Japan the installation of dams prevented the second intermediate host, Onchorhynchus species, from migrating and spawning27.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Although D. latum infections have spread in some locations such as in North America, they have regressed in other regions. At one time, it was said that: "no good citizen of Geneva was without his tapeworm"4 but by the end of the nineteenth century, the infection had become rare in that city. The reasons for this welcome disappearance of the parasite are by no means clear4. What is clear is that infection could have been prevented by thorough cooking of fish. Habit and custom, however, have militated against this hygienic practice in many places. Apart from health education, a number of other ways have been mooted to impede the spread of infection. Some of these were quite impractical, such as a proposal to ban the importation of Canadian fish into the USA89. More important was the demonstration that freezing fish for 48 hours at -10oC killed plerocercoids 53. Not only was this of value in the domestic environment, but it provided a tool which could be exploited commercially. The two other major weapons which could be used in some situations were improvements in sewage disposal systems and the mass administration of anthelmintics. Some doubts surrounded the value of these measures, though, in places where a significant animal reservoir of infection was thought to be present, whether it be wild feral animals or domesticated dogs and pigs85. Thus, Magath in 1933 included among his recommendations for the control of infection in North America, treatment of sewage with a killing solution such as formaldehyde or chlorine before discharge into lakes or streams, education of people to cook fish properly, freezing of fish in commercial houses, reporting of all human cases to a central register, examination of the stools of all Baltic immigrants, undertaking a campaign to discourage feeding of raw fish to dogs, and further surveys of the extent of infection52. Needless to say, these recommendations were not put into practice in any organized way. Nevertheless, diphyllobothriasis does not now seem to be of major importance in that region. The same cannot always be said for diphyllobothriasis in more recent times in parts of Europe and Asia. When Petrushewsky and Tarassow described their field investigations in Soviet Karelia in 1931-32, they recommended the following measures: investigation of infection in copepods and fish, studies of the dietary habits of the population, mass examination of the people for tapeworm eggs in faeces, organized treatment campaigns, destruction of expelled parasites, improved sanitation, health education, and periodical review of the results62. Using these principles, an energetic campaign has been carried

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out in the USSR ever since World War II and about 65 million people are examined annually. The results have been gratifying in some places but discouraging in others, particularly in the Volga river region64. In Finland, the attitude was passive for many years, particularly because people cherished the idea that an absence of the worm was a sign of poor health. In 1949, however, a pamphlet was published by a hygienist named Savonen who pointed out that the abundance of D. latum blemished the repute of Finnish public health. In the next few years, educational campaings were begun and registration of new cases was made compulsory in 1955. In 1963, the State Medical Board issued instructions that educational campaigns should be expanded. The result was that the number of cases registered dropped from nearly 34,000 in 1959 to just under 3,000 in 197514.

OTHER SPECIES OF DIPHYLLOBOTHRIUM D. PACIFICUM The adult tapeworm, which is normally a parasite of fur seals, was first described by Nybelin in 193158, then renamed D. pacificum by Margolis in 195654. All the cases of human infection with this parasite have been reported from the western border of South America (Peru and Chile) and from Japan, the first ones being described by Baer and colleagues in 19677. The infection was acquired by eating undercooked saltwater fish. The clinical features were similar to those seen in diphyllobothriasis latum and the condition was found to respond to treatment with praziquantel 51. D. URSI This parasite was described in the brown bear (Ursus arctos) in Alaska by Rausch in 1954. It has been described in a human recently55. OTHER SPECIES D. dendriticum, D. lanceolatum and D. dalliae have been found very rarely in humans65.

REFERENCES 1. ABBOTTS SMITH M. On human entozoa: comprising the description of the different species of worms found in the intestines and other parts of the human body and the pathology and treatment of the various affections produced by their presence, HK Lewis, London, pp 245, 1863 2. ABILDGAARD PC. Almindelige Betragntninger over Indvoldeorme, Bemaerkninger ved

Diphyllobothriasis

3.

4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

14. 15. 16.

17. 18.

19. 20.

21. 22. 23. 24. 25. 26. 27. 28.

415

Hundsteilens Baendelorm, og Beskrivelse med Figurer of nogle nue Baendelorme. Skrivter af Naturhistorie-Gelskabet, Kjøbenhavn 1: 26-64, 1790. German translation in Shriften der Naturforschen der Gesellschaft, Köpenhagen 1: 24-59, 1793. Partly translated in 42. ANDRY de BOISREGARD N. De la génération des vers dans le corps de l'homme etc., Laurent d'Houry, Paris, pp 468, 1700. An account of the breeding of worms in human bodies etc., translated by H Rhodes and A Bell, London, pp 266, 1701 ANONYMOUS. The spread of Bothriocephalus latus. British Medical Journal ii: 809-810, 1891 ANONYMOUS. Pathogenesis of tapeworm anaemia. British Medical Journal ii: 1028, 1976 APAJALAHTI J. Tratamiento de infecciones por Diphyllobothrium latum con una dosis oral unica de praziquantel. Boletin Chileno de Parasitologia 32: 43, 1977 BAER JG, MIRANDA CH, FERNANDEZ RW, MEDINA TJ. Human diphyllobothriasis in Peru. Zeitschrift für Parasitenkunde 28: 277-289, 1967 BERTOLUS. Sur la développementdu bothriocéphale de l'homme. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 57: 569-571, 1863 BERTOLUS. Cited in 48 BIRKELAND IW. "Bothriocephhalus anaemia". Diphyllobothrium latum and pernicious anemia. Medicine, Baltimore 11: 1-139, 1932 BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1691, 1885-1890 BONNET C. Sur le ver nommé en Latin Taenia et en français Solitaire. Mémoires de Mathématique et de Physique présentés à l'Académie Royale des Sciences, par divers sçavans, & lus dans les assemblées, Paris, 1: 478-521, 1750. Partly reproduced in 42. BONNET C. Nouvelles recherches sur la structure du taenia. Observations sur la physique sur l'histoire naturelle et sur les arts, IX, L'Abbé Rozier, Paris, pp 243-267, 1777. Partly translated in 42 von BONSDORFF G. Diphyllobothriasis in man, Academic Press, London, pp 189, 1977 von BONSDORFF G, GORDIN R. Antianemic activity of dried fish tapeworm. Acta Medica Scandinavica, Supplement 266: 283-292, 1952 BRAUN M. Zur Frage des Zwischenwirthes von Bothriocephalus latus Brems. Zoologischer Anzeiger 4: 593-597, 1881; 5: 39-43, 1882; 5: 194-196, 1882; 6: 97-99, 1883. Partly translated in 42 BRAUN M. Bothriocephalus latus und seine Herkunft. Archiv für pathologische Anatomie und Physiologie und fur klinische Medicin (Virchow) 92: 364-366, 1883 BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst einem Anhage über Pseudo-Helminthen, Carl Schaumburg und Comp., Wien, pp 284, 1819 BYLUND G, BANG B, WIKGREN K. Tests with a new compound (praziquantel) against Diphyllobothrium latum. Journal of Helminthology 51: 115-119, 1977 COBBOLD TS. Observations on entozoa, with notices of several new species, including an account of two experiments in regard to the breeding of Taenia serrata and T. cucumerina. Transactions of the Linnean Society of London 22: 155-172, 1857 COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference, more particularly, to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 CREPLIN FC. Novae observationes de entozois, Berolini, pp 134, 1829 DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, J-B Baillière et fils, Paris, pp 838, 1860 DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, second edition, J-B Baillière et fils, Paris, pp 1003, 1877 DIESING CM. Systema helminthum, Wilhelmum Braumüller, Vindobonae, two volumes, pp 1267, 1849-1851 DUNUS T. De lumbrico lato (mirae longitudinis) Thaddei Duni Locarnensis medici epistolae medicinales....Miscellaneorum de re medica liber, Tiguri, p 155, 1592 EGUCHI S. Diphyllobothrium latum (Linnaeus, 1758). Progress of medical parasitology in Japan, volume 5, Meguro Parasitological Museum, Tokyo, pp 125-144, 1973 ESCHRICHT DF. Anatomische-physiologische Untersuchungen ueber die Bothryocephalen.

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Nova Acta Leopoldino-Carolinae Academiae (Breslau) 119, Suppl. 2: 3-152, 1841 29. ESSEX HE. Early development of Diphyllobothrium latum in northern Minnesota. Journal of Parasitology 14: 106-109, 1927 30. GALLI-VALERIO B. Untersuchungen ueber den Entwicklungszyklus von Dibothriocephalus latus L. des Hundes. Archiv für Schiffs- und Tropen-Hygiene 23: 602-605, 1919 31. von GLEICHEN-RUSWORM WF. Zergliederung und microscopishe Beobachtungen eines Bandwurmes, Taenia lata L. und eines Kürbiswurmes, Cucurbitinus. Beschäftigungen der Berlinischen Gesellschaft naturforschender Freunde 4: 203-224, 1779 32. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, P A Pape, Blankenburg, pp 471, 1782 33. GRANT F. 106 Bothriocephalusketten bei einem Kranken. Klinische Wochenschrift 9: 502, 1930 34. GRASSI B, FERRARA. Zur Bothriocephalusfrage. Deutsche medicinische Wochenschrift 12: 699, 1886 35. HAMILTON WF. A specimen of Bothriocephalus latus. Montreal Medical Journal 30: 350-351, 1901 36. HARTMANNUSPJ. Anatome glandiorum. Miscellanea Curiosa, sive Ephemeridum MedicoPhysicarum Germanicarum Academiae Imperialis Leopoldinae Naturae Curiosorum. Decuriae II. Annus VII, Anni 1688, Observatio XXIX, PP 58-59, 1689 37. ISAACS R, STURGIS CC, SMITH M. Tapeworm anemia. Therapeutic observations. Archives of Internal Medicine 42: 313-321, 1928 38. JANICKI C. Observations sur quelques espèces de poissons afin d'arriver à connaître plus à fond le contenu de leur estomac et pour trouver des stades encore inconnus de plerocercoide. Bulletin de la Société Neuchâteloise des Sciences Naturelles 42: 22-29, 1917. Partly translated in 42 39. JANICKI C. Der Entwicklungscyklus von Dibothriocephalus latus L. offene Antwort an meinem früheren Mitarbeiter Herrn Dr. F. Rosen. Zugleich ein Beitrag zur Methodologie eines helminthologischen Problems, Imprimerie Georges Jeanrichard, Sainte-Croix, pp 33, 1919. 40. JANICKI C, ROSEN F. Le cycle évolutif du Bothriocephalus latus L. Bulletin de la Société Neuchâteloise des Sciences Naturelles 42: 19-21, 1917. Partly translated in 42 41. JANSEN S, OVER HJ. Het voorkomen van parasitien in terpmateriaal uit noordwest Duitsland. Tijdschrift voor Diergeneeskunde 87: 1377-1378, 1962 42. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 43. KNOCH J. Vorläufige Mittheilung über den Bothriocephalus latus, die Entwickelung desselben, die Wanderung und endliche Uebertragung seines Embryo's in den Menschen. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 24: 453-461, 1862 44. KÖLLIKER. Zeitschrift für wissenschaftliche Zoologie 3: 86, 1851 45. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 46. LE BAS GZ. Experimental studies on Dibothriocephalus latus in Man. Journal of Helminthology 2: 151-166, 1924 47. LEIPER RT. Some experiments and observations on the longevity of Diphyllobothrium infections. Journal of Helminthology 14: 127-130, 1936 48. LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, C F Winter'sche Verlagshandlung, Leipzig, volume 1, pp 766, 1863 49. LÜHE M. Zur Anatomie und Systematik der Bothriocephaliden. Verhandlungen der Deutschen Zoologische Gesellschaft 9: 30-55, 1899 50. LÜHE M. Die SüsswasserfaunaDeutschland, Heft 18, II. Parasitische Plattwurmer. Cestodes,

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Jena, pp 153, 1910 51. LUMBRERAS H, TERASHIMA A, ALVAREZ H, TELLO R, GUERRA H. Single dose treatment with praziquantel (Cesol R, Embay 8440) of human cestodiasis caused by Diphyllobothrium pacificum. Tropenmedizin und Parasitologie 33: 5-7, 1982 52. MAGATH TB. The relation of Diphyllobothrium latum infestation to the public health. Journal of the American Medical Association 101: 337-341, 1933 53. MAGATH TB, ESSEX HE. Concerning the distribution of Diphyllobothrium latum in North America. Journal of Preventive Medicine 5: 227-242, 1931 54. MARGOLIS L. Parasitic helminths and arthropods from Pinnepeda of the Canadian Pacific coast. Journal of the Fisheries Research Board of Canada 13: 489-505, 1956 55. MARGOLIS L, RAUSCH RL, ROBERTSON E. Diphyllobothrium ursi from man in British Columbia - first report of this tapeworm in Canada. Canadian Journal of Public Health 64: 588589, 1973 56. NEGHME A, DONCKASTER R, SILVA R. Diphyllobothrium latum en Chile, primer caso autoctono en el hombre. Revista Médicade Chile 78: 410-411, 1950 57. NICKERSON SD. The broad tapeworm in Minnesota with the report of an infection acquired in the state. Journal of the American Medical Association 46: 711-713, 1906 58. NYBELIN O. Säugetier- und Vogelcestoden von Juan Fernandez. The natural history of Juan Fernandez and Easter Islands 3: 493-523, 1931 59. NYBERG W. The influence of Diphyllobothrium latum on the vitamin B12-intrinsic factor complex. I. In vivo studies with the Schilling test technique. Acta Medica Scandinavica 167: 185187, 1960 60. NYBERG W. The influence of Diphyllobothrium latum on the vitamin B12-intrinsic factor complex. II. In vitro studies. Acta Medica Scandinavica 167: 189-192, 1960 61. NYBERG W, ÖSTLING G. Low vitamin B12 concentrations in serum in fish tapeworm anaemia. Nature 178: 934-935, 1956 62. PETRUSCHEWSKY GK, TARASSOW W. Die Bekämpfung des Diphyllobothrium latum in Karelien. Archiv für Schiffs- und Tropen-Hygiene 37: 307-315, 1933 63. PLATERUS F. Praxeos seu de cognoscendis, praedicendis praecauendis curandiso affectibus homini incommodantibus tractatus tertius et ultimus. De vitiis, libris duobus agens: quorum. Primus corpis: secundus. Excretorum via continet, Typis Conradi Waldkirchii, Basel, pp 679, 1602; second edition, three volumes, 609, partly translated in 42. A golden practice of physick, translated by A Cole and N Culpepper, P Cole, London, 1662 64. PROPOPENKO LI. In, "Diphyllobothriasis symposium", Moscow, pp 3-6, 1968. Cited in 14 65. RAUSCH RL, HILLIARD DK. Studies on the helminth fauna of Alaska. XLIV. The occurrence of Diphyllobothrium latum (Linnaeus, 1758)(Cestoda: Diphyllobothriidae) in Alaska, with notes on other species. Canadian Journal of Zoology 48: 1201-1219, 1970 66. RAZUMOVA EP, OCHKUROVA EF, LAPSHINA IG, GUSEVA MK (Effectiveness of treatment of diphyllobothriasis with dichlosale and phenasale.) Meditsinskaya Parazitologia i Parazitarn e Bolezni 36: 159-161, 1967. In Russian. Abstracted in Tropical Diseases Bulletin 64: 993, 1967 67. REDLICH E. Diaptomus graciloides (Lilljeborg), ein neuer erster Zwischenwirt von Dibothriocephalus latus, nebst Bemerkungen zur experimentellen Entwicklung des Procercoids dieses Cestoden. Archiv für Wissenschaft und praktische Tierheilkunde 53: 353-361, 1925 68. REYHER G. Beiträge zur Aetiologie und Heilbarkeit der perniciosen Anamie. Deutsches Archiv für klinische Medicin 39: 31-69, 1886 69. ROMANOV IV. In, "Diphyllobothriasis symposium", Moscow, pp 58-63, 1968. Cited in 14 70. ROSEN F. Recherches expérimentales sur le cycle évolutif du Dibothriocephalus latus. Bulletin de la Société Neuchâteloise des Sciences Naturelles 42: 29-49, 1917. Partly translated in 42 71. ROSEN F. Recherches sur le développement des Cestodes. I. Le cycle évolutif des Bothriocéphales. Etudes sur l'origine des cestodes et leurs états larvaires. Bulletin de la Société Neuchâteloise des Sciences Naturelles 43: 1-55, 1918 72. ROUX. Evacuation de quatre-vingt-dix bothriocéphales ou une seule fois. Correspondenz-Blatt für schweizer Aertze 17: 488-491, 1887. Abstracted in British Medical

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Journal ii: 911, 1887 73. RUNEBERG JW. Bothriocephalus latus und perniciöse Anämie. Deutsches Archiv für klinische Medicin 41: 304-308, 1887 74. SAARNI M, NYBERG W, GRASBECK R, von BONSDORFF B. Symptoms in carriers of Diphyllobothrium latum and in uninfected controls. Acta Medica Scandinavica 173: 147-154, 1963 75. SCHAPIRO HA. (Cure of pernicious Biermer's anaemia by expulsion of Bothriocephalus latus.) Vrach 8: 95-96, 1887. In Russian. Abstracted in Lancet ii: 724, 1887 76. SCHUBART. Cited in 44 77. SCHUBART. Cited in 90 78. SINGER JJ. A case of Bothriocephalus latus infection. Journal of the American Medical Association 66: 1618-1619, 1916 79. SOININEN V. Leveän heisimadon esiintyminen ja joukkohääto Puumalassa. Suomen Lääkarilehti 18: 2359-2361, 1963 80. SPIGELIUS A. De lumbrico lato liber (cum ejusdem lumbrici icone et notis), L Pasquati, Patavii, pp 88, 1618 81. SPÖRING HD. Beråttelse om en Qvinna, hos hvilken et stycke af Binnike Masken kommit utur en bålde i liumskan. Bihand till Kongliga Svenska Vetenscaps-Adakemiens Handlingar, Stockholm, 8: 103-112, 1747 82. STEIN ST. Die parasitaren Krankheiten des Menschen. Part 1, Lahr, pp 52, 1882 83. STOLL NR. This wormy world. Journal of Parasitology 33: 1-18, 1947 84. SZIDAT L. Zeitschrift für Parasitenkunde 13: 165-174, 1944 85. TARASSOW W. Das Schwein und der Hund als endgültige Träger des Diphyllobothrium latum. Eine experimentelle Untersuchung. Archiv für Schiffs- und Tropen-Hygiene 38: 156-159, 1934 86. TARASSOV V (TARRASOW W). De l'immunité envers le bothriocéphale Diphyllobothrium latum (L.). Annales de Parasitologie Humaine et Comparée 15: 524-528, 1937 87. TÖTTERMAN G. On the pathogenesis of pernicious tapeworm anaemia. Annals of Clinical Research Supplement 18: 1-48, 1976 88. VERGEER T. Diphyllobothrium latum (Linn 1758), the broad tapeworm of man: experimental studies. Journal of the American Medical Association 90: 673-678, 1928 89. VERGEER T. The broad tapeworm in America with suggestions for its control. Journal of Infectious Diseases 44: 1-11, 1929 90. VERLOREN M C. Umhüllung von Flimmer-Epithelium bei den Embryonen von Bothryocephalus (sic) latus. Secretary's abstract. Amtliche Bericht über 33 Versammlung Deutschen Naturforscher und Aertze (1857), p 147, 1859 91. VOGT C. La provenance des entozoaires de l'homme et leur évolution; Conférence faite au Congrès international des sciences médicales à Genève, le 15 Septembre 1877, H Georg, Genève, pp 55, 1878

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Table 15.1. Landmarks in diphyllobothriasis ___________________________________________________________________ BC

Tapeworm infections in humans were known but the species were not distinguished. Various anthelmintics were used 1592 Dunus described tapeworms with morphological features now recognized as those of Diphyllobothrium 1602 Platter differentiated Diphyllobothrium from Taenia on the basis of the shape of the proglottids 1700 Andry described Diphyllobothrium as "Taenia à épine" to indicate the central "spine" due to the medially placed genital pores of Diphyllobothrium c.f. the lateral pores of Taenia 1747 Spöring drew attention to the relationship between broad tapeworm infection and human habitation near water with an increased consumption of fish 1777 Bonnet illustrated the head of the adult worm 1860 Davaine described diagnosis by finding eggs in the faeces 1881 Braun found larvae (plerocercoids) resembling Diphyllobothrium in pike, burbot and other fish, then produced patent infection with adult worms in dogs fed with plerocercoids 1882 Braun produced patent infections in humans who ingested plerocercoids 1877-86 Reyher found that pernicious anaemia was cured in patients who were also infected with D. latum and in whom the worm was eradicated with anthelmintics 1883-86 Runeberg made observations similar to those of Reyher 1901 Hamilton reported a case which had been unequivocally acquired in North America 1917 Janicki found very young larvae of Diphyllobothrium (procercoids) in the stomach of fish which also contained many copepods and thought that copepods may be the primary intermediate host 1917 Rosen independently found procercoids in the body cavity of certain species of copepods, observed the development of coracidia obtained from D. latum eggs in these copepods, then obtained plerocercoids in fish by infecting them with procercoids 1928 Isaacs and colleagues treated successfully tapeworm pernicious anaemia by the administration of raw liver, even though the parasite persisted 1948 von Bonsdorff showed that tapeworms competed with the human host for dietary vitamin B12 1963 Soininen showed that niclosamide was effective therapy 1977 Praziquantel was introduced for treatment by various investigators __________________________________________________________________

Chapter 16

CESTODE INFECTIONS IMPORTANCE

OF

LESSER

INFECTION WITH BERTIELLA SPECIES B. STUDERI This cyclophyllidean tapeworm was first recovered from an orang-utan (Pongo pygmaeus pygmaeus), then was described by Raphael Blanchard in 1891 as Bertia studeri (after Dr Paul Bert)15. Because this generic name was already occupied, it was renamed Bertiella studeri by Stiles and Hassall in 1902105. Since that time, it has also been found in other subhuman primates and in dogs in the Philippines. A number of other species of Bertiella have been described, including B. mucronata, B. polyordus and B. satyri. Some authorities have considered that these species are all synonymous with B. studeri 1, but current opinion separates B. mucronata. The life cycle of B. studeri was described by Stunkard in 1940; he showed that cysticercoids developed in the mites, Scheloribates laevigatus and Galumna species107. Infection in a human was reported for the first time in 1913 by Blanchard, although he named the parasite B. satyri ; fragments of worm were passed by an eight year old girl in Mauritius18. Since that time, sporadic cases of human infection have been reported from a number of regions of the world, particularly India and Indonesia. Treatment with niclosamide was found to be successful29. B. MUCRONATA The adult tapeworm was first recovered from a howler monkey (Alouatta nigra) in Paraguay by Meyner in 189578. The first human infection was described in 1928 by Cram who studied specimens recovered from a young Spaniard by Dr Alberto Recio in Cuba25. A number of further cases have been reported from the Americas, some being described as B. studeri, but the modern view is that they were probably B. mucronata 9.

421

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INFECTION WITH DIPLOGONOPORUS SPECIES D. GRANDIS This pseudophyllidean tapeworm, which is normally a parasite of whales, was first described by R Blanchard in 1894 as Krabbea grandis 17, then renamed Diplogonoporus grandis by Lühe in 189973. The generic name is derived from a combination of the Greek words (DIPLOOS), (GONOS) and (POROS), meaning "double", "gonad" and "pore", respectively. Occasionally, infections with adult worms occur in humans; most patients have been Japanese, which presumably reflects their penchant for eating raw fish. The first such patient was described by Ijima and Kurimoto in 1894 on the basis of a specimen found in a 28 year old man by Nakamura in 189250. By 1971, 55 cases had been reported in Japan. The clinical features are similar to those seen in taeniasis. Recently, Kamo and his colleagues have shown experimentally that certain species of copepods act as the first intermediate host59. The second intermediate host remains uncertain. D. FUKUOKAENSIS In 1970, Kamo and Miyakai described this worm as a new species. The parasite was recovered from a girl in Japan60.

DIPYLIDIASIS A cyclophyllidean tapeworm of dogs and cats, 10-70 cm long, has been known for generations. It was named Taenia osculis marginalibus oppositus by Linnaeus in 1748, Taenia canina by him in 175873, T. cucumerina by Bloch in 1782 19 Dipylidium cucumerinum by Leuckart in 186370 , then Dipylidium caninum by Railliet in 189288. The generic name is derived from a combination (DIS) and (PYLIS) meaning "two" and "gate", of the Greek words respectively. The life cycle of the parasite was first investigated by Melnikov who showed in 1869 that when eggs were ingested by the dog louse, Trichodectes canis, the hexacanth embryos were liberated in the intestines then migrated to the body cavity where they tranformed into cysticercoids 77. Although this was later disputed by Zimmerman122, who could not infect these lice experimentally, the validity of this vector is generally accepted. Sonsino, in 1888, examined the possible role of fleas in transmission but convinced himself that the mouthparts of fleas were too small to allow ingestion of Dipylidium eggs100. In the following year, however, Grassi and Rovelli showed that eggs hatched in the intestines of the dog flea, Pulex serraticeps (= Ctenocephalides canis), and the

Miscellaneous Cestode Infections

423

human flea, Pulex irritans, then migrated into the body cavity where they developed into procercoid then cysticercoid larvae43. They noted that the itch induced by these arthropods caused the dogs to paw and gnaw at the skin, then bite and swallow the vectors. The first human case of dipylidiasis was seen by in 1751 by Godefridus Dubois, a pupil of Linnaeus. Dubois wrote: "est Taenia species quae.... vulgarites in canibus et saepissime apud homines invenitur"31 meaning that this tapeworm was commonly found in dogs but rarely in humans. A second specimen recovered from a 13 year old boy in Blasius, then deposited by Mekel in the Museum of Comparative Anatomy in Halle, was re-examined by Leuckart who concurred with its identification as D. caninum 70. Salzmann of Esslingen then found the parasite in a 16 month old child in 186194. Infections have since been reported sporadically from many parts of the world, most of the affected individuals being children. The clinical manifestations are similar to those seen in taeniasis, and niclosamide has been found to be an effective remedy55.

HYMENOLEPIASIS HYMENOLEPIS DIMINUTA The cyclophyllidean adult worm, 20-60 cm long, normally lives in the intestines of rats and mice. It was named Taenia diminuta by Rudolphi in 181992. The worms were recovered from a human for the first time in 1842 by Dr E Palmer of Boston, USA, when he found them in a 19 month old child; the parasite was not described until 1858 when Weinland named it T. flavopunctata 114. A second case of human infection was reported by E Parona in 1882 as occurring in a two year old girl in Varese, Italy87; this worm was sometimes referred to as T. varesina. The third case was described by Joseph Leidy in the USA in 1884. Since then it has been reported sporadically from many parts of the world. The parasite was transferred to the genus Hymenolepis of Weinland (see next section) and named H. diminuta by Blanchard in 189116. In 1892, Grassi and Rovelli showed that cysticercoids developed in a moth, Asopia farinalis, as well as in its larval stage, in the othopteran arthropod, Anislabis annulipes, and in the beetles, Acis spinosa and Scannus striatus 44. These results were confirmed by Joyeux56 who also demonstrated that the beetle, Tenebrio molitor, and the larval stages of the fleas, Ceratophyllus (= Nosopsyllus) fasciatus, Xenopsylla cheopis, Pulex irritans, and Ctenocephalides canis, were also susceptible. Joyeux then transferred these infections experimentally to rats that ingested infected arthropods. A number of other arthropods have since been shown to also act as intermediate hosts; they are all eaters of faeces or are scavengers during their larval or adult stages.

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The clinical features are usually minimal, and the infection has been shown to respond to treatment with niclosamide 55. H. NANA This tapeworm was discovered in 1851 by Theodor Bilharz during the autopsy of a boy in Egypt who had died from meningitis. He wrote to his mentor, von Siebold, in Germany, describing his findings: The first incision into the intestine....disclosed immediately large numbers of a small tapeworm. The worm was a fully developed Taenia with broad segments; it was the width of a sewing thread and length of hardly 10 mm.13

Von Siebold duly reported this discovery in his journal, and after noting that Bilharz had wanted to call it Taenia aegyptiaca in view of the country in which it was discovered and suggested that "it be named Taenia nana because this tapeworm differs by its smallness so greatly from the other two species of man"13. In 1858, Weinland proposed dismembering the genus Taenia and established the genus Diplocanthus for T. nana and the genus Hymenolepis for T. murina and related species114. The name Diplocanthus, however, had already been used by Agassiz for a genus of fish, so this name was invalid. Meanwhile, Bilharz had provided some of his worms to museums in Vienna and Halle. Leuckart then used these specimens to improve the morphological description of the parasite, and renamed it Taenia (Hymenolepis) nana in 186370. Eventually, it was designated Hymenolepis nana in 1891 by Blanchard, who accepted the identity of T. nana and T. murina 16. The generic name, Hymenolepis, is derived from a combination of the Greek words µ (HYMEN) and (LEPIS) meaning "membrane" and "shell", respectively. Although Spooner may have found these worms in the USA in 1873101, they were not met again with certainty until 1885 when Dr Hoelz in Belgrade recovered 50 small tapeworms from a seven month old girl after treatment with ethereal extract of male fern; he sent the worms to Leuckart who recognized them as H. nana 72. A similar parasite in rodents was described by Dujardin 1845 as Taenia murina 32 . Since this worm and H. nana were so similar morphologically, speciation was based upon the susceptibility of rats and humans to the strains of parasite derived from each species. Grassi (1887) was of the view that T. nana was merely a variety of T. murina because when he gave mature proglottids of T. murina to six persons, one individual developed a patent infection42. This experiment proved little, however, since H. nana infection was endemic in humans in that district. In 1906, Stiles separated H. nana into a human variety, H. nana, and a murine variety, H. nana var. fraterna 103. Since repeated attempts to infect the heterologous host species were unsuccessful, and as the human and rodent forms appeared to have different geographical distributions, however, Joyeux (1919) again proposed to separate them into

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two distinct species, H. nana and H. fraterna 57. The name, H. fraterna, was chosen since the prior designation, T. murina of Dujardin, was invalid; this nomenclature had been used by Gmelin in 1790 to describe the worm related to Cysticercus fasciolaris of Rudolphi (1808). To confuse the nomenclature even further, the name Taenia nana had also been used by van Beneden in 185212 for a parasite that was subsequently identified as being the adult form of Echinococcus granulosus. In contrast to Joyeux's contention that there were two species, however, Saeki in 1920 showed that infection could occur across species. He obtained Hymenolepis eggs from a nine year old girl, then infected successfully mice, rats and one out of two monkeys93. These results were confirmed by Uchimara111and Woodland117,118 . Uchimara111 and Kiribayashi then did the reverse experiment and infected children with Hymenolepis eggs from murine sources. Thus, these results, together with the morphological similarities, indicated that H. nana and H. fraterna (or T. murina) were identical. Studies designed to elucidate the life cycle of both the murine and human forms of the parasite were pursued concurrently with attempts to define their host specificity. Grassi in 1887 showed that transmission from rat to rat was direct without the mediation of a vector42; this was confirmed several decades 117 later by Joyeux56, Scott (as H. longior)96 and Woodland . In 1920, Saeki examined the kinetics of infection in mice and also proved that humans could be infected directly93. On microscopical examination of the intestines of infected rodents, oncospheres were seen in the villi ten hours after infection, cysticercoids were noted in the mucosa at four days, then after five days, worms could be found in the intestinal lumen; proglottid formation began on the eighth day and eggs were found in the faeces 16-17 days after infection. Saeki then swallowed 1,000 eggs himself on four occasions, but all his efforts to infect himself failed. When he tried again and infected a four year old girl, however, he found eggs in her faeces after 19 days. When she was treated 62 days after infection, large numbers of adult worms were found. It is possible that heavy infections are at times the result of autoinfection, for Heynemann47 found that previously uninfected mice infected with as few as 10-25 larvae developed up to 1,500 adult worms. In addition to this direct cycle, Nicholl and Minchin found the cysticercoids of the parasite in the body cavities of the fleas, Xenopsylla cheopis and Ceratophyllus fasciatus 85. This was confirmed by Johnston54, then later Bacigalupo in Argentina demonstrated that the fleas, Ctenocephalides canis and Pulex irritans, and the mealworms, Tenebrio molitor and T. obscurus, were also capable of transmitting the infection5. In all these vectors, however, the cysticercoids differed morphologically somewhat from those developing directly in the intestine of the definitive host. H. nana is now well-recognized as being widespread and common in children in certain parts of the world. Contrary to initial impressions, the

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infection has usually been found to be asymptomatic, even when parasites are present in large numbers. Treatment at first was difficult. The early anthelmintics were generally ineffective63. Mepacrine was only moderately efficacious, but then niclosamide was shown to be partially effective11 and praziquantel was then found to be even better95.

INFECTION WITH INERMICAPSIFER MADAGASCARIENSIS This cyclophyllidean tapeworm was first described by Davaine in 1870 as Taenia madagascariensis 27. The specimen had been recovered from an 18 month old child in the Comoros Islands in the Indian Ocean by Grennert in that year. In 1891, Blanchard renamed the worm Davainea madagascariensis 15. This was changed to Raillietina madagascariensis by Joyeux and Baer in 192958, then finally it was classified as Inermicapsifer madagascariensis by Baer in 19566. The generic name is derived from a combination of the Latin words "inermis", "capsa" and "fero", meaning "unarmed", "case" and "to carry", respectively. Infected patients have been reported from Africa and Central and South America. In Africa, rodents were found to the major definitive host, but elsewhere is appears to be a parasite of humans only6. The life cycle has not yet been elucidated. The clinical features resemble those seen in taeniasis, and the infection has been observed to respond to treatment with niclosamide 48.

INFECTION WITH MESOCESTOIDES SPECIES M. LINEATUS The cyclophyllidean adult tapeworm is normally a parasite of dogs, cats, foxes and other mammals. It was first described as Taenia lineata by Goeze in 1782 41. In 1893, Railliet89 transferred it to the genus Mesocestoides that had been erected by Vaillant in 1863112. The generic name is derived from a (MESOS), (KESTOS, combination of the Greek words µ CESTOS) and (EIDOS) meaning "middle", "tape", and "similar", respectively. Larvae are found in the body cavity and tissues of reptiles, birds and small mammals. Adult worms rarely infect humans. Most patients have been reported from Japan, the first patient being described in 1942 by Kosaka65. M. VARIABILIS The adult worm is normally a parasite of the intestinal tract of foxes, skunks and similar mammals. It was first described by Mueller in 192881. The larval

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stages are found in a wide variety of carnivorous animals. Adult worms are found rarely in humans. The first case, recorded by Chandler in 1942, was of a 13 month old child in Texas who passed more than 25 feet of tapeworm segments when treated with oleoresin of aspidium; these segments were thought to represent at least four worms22. Subsequently, patients were reported from Denmark (in a Greenlander), from East Africa (in a European) and from the USA.

INFECTION WITH RAILLIETINA SPECIES R. CELEBENSIS This cyclophyllidean tapeworm was first found in the long-tailed mouse, Lenomys myeri, and described by Janicki in 1902 as Davainea celebensis (the genus being named in honour of Casimir Davaine)52. In 1920, Fuhrmann transferred the worm to the genus Raillietina (named in honour of Professor A Railliet)37. In 1916, Akashi in Taiwan again recorded infection with the parasite, this time naming it Davainea formosana 2. Human infections, mostly in young children, have been reported from Asia and the Pacific. In these regions, the adult worm is a common parasite of rats. In 1964, Tang and Tang showed that the intermediate host is ants of the genus Cardiocondyle; adult ants carry proglottids to the nest and feed them to the young ants in which the cysticercoids develop109. Rats (or humans) acquire infection by ingesting infected ants, and worms up to 40 cm long develop in the intestines. The clinical manifestations are usually minimal and the infection was found to respond to treatment with niclosamide. In 1891, Leuckart described a worm recovered from an infant in Bangkok as Taenia madagascariensis 71; this was probably R. celebensis, as was the infection found in an adult in Manila and described as Davainea madagascariensis by Garrison in 191138. R. DEMERARIENSIS The adult tapeworm, about 60 cm in length, was first found by CW Daniels in Demerara, British Guiana (now Guyana) in 1895; he named it Taenia demerariensis 26. A number of other names were then used, but all were recognized as R. demerariensis by Dollfus in 1939-1940 30. Infections have since been seen frequently in parts of South America, especially in Ecuador.

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INFECTION WITH SPIROMETRA SPECIES (1) HUMANS AS THE INTERMEDIATE HOST - SPARGANOSIS In 1881, Patrick Manson in Amoy, China, was in quest of an adult filarial worm (Wuchereria bancrofti) in order to support his view that elephantiasis was a consequence of an infection with this worm (see chapter 23). Post-mortem examinations were extremely difficult to carry out as the populace was opposed to them and a previous attempt by Manson to perform one had had unfortunate consequences. When a 34 year old man with elephantiasis, lymph-scrotum and dysentery died in September of that year, Manson carried out a secret autopsy with the aid of a trusted servant in the Chinese cemetery at the dead of night by the light of a flickering candle. Instead of finding adult filariae, he discovered a dozen ribbon-like worms 30 cm long by 5 mm wide in the retroperitoneal adipose tissue, similar worms in the pleural cavity, and large numbers of parasites in the gastrointestinal tract75,76. He sent these specimens to Spencer Cobbold in London who believed them "to be new to science" and named them Ligula mansoni ; this name was noted by the editor of The Lancet 3 in an addendum to Manson's report, the formal description by Cobbold following the next year23. The worm was renamed Bothriocephalus liguloides by Leuckart in 1884 then Bothriocephalus mansoni by Blanchard in 1886. A number of workers, including Manson himself, believed that these worms were an immature form of cestode, possibly related to Diphyllobothrium. In 1854, Diesing28 had raised the genus Sparganum, the name being derived from the Greek word (SPARGANOS) meaning "ribbon", to house worms with similar morphological features. Although this genus could not stand with the acceptance of the theory of alternation of generations and the recognition that these worms were immature, Verdun in 1907 suggested that each immature form of the "Bothriocephaliden" (i.e. diphyllobothriids), whose adult state was unknown, should be placed provisionally in this genus until the adult form was ascertained. This had, in fact, already been done by Stiles and Tayler-Jones106 who in 1902 called the parasite, discovered by Manson, Sparganum mansoni. In June 1916, Yoshida and his collaborator, Yamada, fed a Sparganum removed from the abdominal wall of a female patient to a dog that was coincidentally infected with Diphyllobothrium cordatum. Thirteen days later, different eggs began to appear in the faeces. When the dog was killed two months after infection, the investigators recovered a single, large, pseudophyllidean, adult tapeworm which they took to be a Dibothriocephalus (= Diphyllobothrium)119. The complete natural life cycle was then elucidated by Okumura in Japan in 191986. He found adult tapeworms in naturally-infected dogs that were identical with those raised by Yamada and Yoshida. He took ova from these worms and infected Cyclops leuckarti, then recovered procercoids as had been shown two

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years earlier for Diphyllobothrium latum (see chapter 15). The procercoids were then fed to experimental frogs and mice and were found to pierce the intestinal wall, migrate into the body cavity of these hosts, and develop into plerocercoids or spargana. Furthermore, Okumura showed that similar parasites were to be found in 30-60% of frogs in that region of Japan, as well as in the snake, Elaphe climacophora. When plerocercoids from these naturally infected animals were in turn fed to dogs, similar adult tapeworms developed in the intestines. In 1922, Yoshida showed that as well as being host to adult worms, cats and dogs also harboured the larval stages. Further, he found spargana in chickens and ducks and concluded that humans acquire infection either by drinking water containing infected Cyclops or from eating raw, contaminated chicken120. Sparganosis was prone to afflict the eye, particularly in patients in Indochina. In May 1927, Casaux presented, to the Indochinese MedicoChirurgical Society, such a case and recounted that the woman had been in the habit of applying dismembered frogs to her eyes; he suggested that there may be direct entry of spargana into the orbital tissues. Evanno arrived at the same conclusion; he placed a sparganum in the conjunctival sac of a monkey and recovered it 11 days later from the upper lid. Both of these experiences are recorded by Motais80 who also reported four similar cases in which ocular sparganosis again followed application of split frogs to the eyes. Independently, Faust and his colleagues35 noted that AS Campbell of Foochow, China, had extracted spargana from the fingers of two patients who had applied split frog poultices to themselves. The possibility of being infected in such a way was confirmed by Kobayashi64 who infected himself percutaneously. Penetration of the larvae caused itching and erythema, then excision of the skin revealed three plerocercoids in tunnels in the dermis and hypodermis. Two further excisions, the second 47 days after infection, of hard, rounded, painless, subcutaneous nodules disclosed more plerocercoids. Mueller and Coulston84 carried this experiment one stage further. They obtained spargana from a monkey, inoculated themselves subcutaneously, then excised some of the parasites ten or more weeks later, and transferred one of them to a cat where it was able to continue its natural evolution. By these means, it was determined that infection could be acquired in one of three ways - by drinking infected water (procercoids), by ingestion of contaminated flesh (plerocercoids), and by direct penetration of plerocercoids from poultices through the skin. In 1929, Faust pointed out that although the term Sparganum mansoni had been used for all the unbranched spargana recovered from man, there were several species, all of which had an identical appearance in the sparganum stage, and which could only be identified after generation of the adult form in experimental dogs35. Moreover, he declared that the larvae should be referred to as the larval stage of the appropriate adult worm, thus Sparganum mansoni indicated the sparganum stage of Diphyllobothrium mansoni. By the early

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1930's, six other species were recognized - D. decipiens, D. erinacei, D. houghtoni, D. okumari, D. ranarum and D. reptans. There were dissenters, however. Iwata51, for example, believed that all these forms could be found in different parts of the one strobila, and thus recognized only one species. The balance of opinion has swung against his view. In 1935, Mueller showed that those spargana found in North America were in fact not the larval stage of D. mansoni, but of a new species which had a procercoid stage in C. leuckarti and other species of Cyclops, a sparganum stage in mice, and a definitive stage in cats and bobcats, and to a lesser degree in dogs82. This worm he named D. mansonoides. Several years later, Mueller partitioned the genus Diphyllobothrium and transferred all of the worms mentioned into a new genus, Spirometra 83. Reports of human infection from many parts of the world allowed a picture of the clinical features to be built up. In Asia, where S. mansoni was the dominant species, most spargana were found in the subcutaneous tissues, although they have been recorded from the brain and viscera as well. When located superficially, they often caused recurrent attacks of inflammation. In the Americas where S. mansonoides was the most frequent species, patients usually presented with a subcutaneous nodule which may or may not have migrated and which may or may not have become inflamed. The most usual treatment has been by surgical excision which also allows the diagnosis to be made. In Vietnam, where ocular sparganosis was common, the injection of 40% ethanol into the worm was recommended by Cornet24. Neither this therapy nor surgical excision was favoured by the director of the Ophthalmic Institute in Hanoi, Keller, who had experience of 60 cases, because the former frequently did not work, and the latter was often complicated by ophthalmia which necessitated removal of the eye. He claimed excellent result in 12 patients treated with a course of intravenous injection of novarsenobenzol 62. The usual treatment today, however, is surgical excision with antibiotic cover, if necessary. The place of praziquantel has not yet been established. A different form of Sparganum was reported by Ijima in 1905. He named the parasite Plerocercoides prolifer 49, then this was reclassified as Sparganum proliferum by Stiles in 1908104. The adult form of this sparganum is still unknown. The sparganum is peculiar in that it proliferates or multiplies by forming branches which become detached. Most of the few patients reported have resided in Japan; thousands of spargana have been recovered from their tissues10. (2) HUMANS AS THE DEFINITIVE HOST - SPIROMETROSIS S. houghtoni The adult form of this pseudophyllidean tapeworm was first recovered from a

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patient in Shanghai by Dr HS Houghton and described as D. mansoni by Faust and Wassell in 192136. Faust and his colleagues renamed this worm as D. houghtoni in 192935. S. erinacei This tapeworm was first recovered from a hedgehog (Erinacea europaea) and described as Dobium erinacei-europaei by Rudolphi in 181992, then renamed Sparganum erinacei-europaei by Diesing in 185428, then called Diphyllobothrium erinacei by Faust and colleagues in 192935. Finally, it was transferred to the genus Spirometra by Mueller in 193783. It has been recorded as a parasite of man in five cases, all in Japan108.

INFECTION WITH TAENIA SPECIES (1) HUMANS AS THE INTERMEDIATE HOST - COENUROSIS Coenurosis is an infection with the larval stages of one of several tapeworms. Coenuri are characterized as bladder worms with multiple scolices, each in its own separate and inverted canal. In human infections, it is often impossible to tell which species is the causative organism, unless the adult worm is generated by feeding experiments. The first authentic, recorded, human infection, in a Paris locksmith who presented with convulsions and aphasia, was described by Brumpt in 1913. At autopsy, two coenuri (probably T. multiceps) were found in the brain, one being degenerate and the other containing 75 scolices21. The first proven case of human coenurosis due to T. serialis was reported in a 59 year old Frenchwoman by Bonnal and colleagues in 193320; the coenurus was fed to a dog and seven characteristic scolices were obtained. In the Western hemisphere, T. multiceps has been absent for many years, so the human cases in that region are probably caused by the larval form of T. serialis; the first such infection reported was in 1950 of a two year old Californian boy with cerebral coenurosis53. T. brauni may cause the African form of coenurosis, the first such patient being reported by Fain and colleagues in 195633. Turner and Leiper in 1919, however, reported a human infection in Nigeria with a coenurus which they called Coenurus glomerulatus 110. Similar coenuri had been noted previously in gerbils by Railliet and Henry90; the adult form and the definitive host are unknown and the worm is possibly identical with T. brauni or T. serialis. Most of the infections reported subsequently have been in the brain, in the connective tissues of the muscles or subcutaneous tissues, or in the eye. The clinical features are usually those of a space-occupying lesion. Diagnosis and treatment both depend upon surgical excision. The effectiveness of praziquantel

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in the management of human coenurosis is not yet established. T. brauni The adult worm was recovered from the intestines of a dog in northeast Africa and described by Setti in 189798. It was given its current name of T. brauni by Fain and colleagues in 195633. Some authorities have considered this species to be synonymous with T. serialis. T. multiceps The adult worm is a parasite of dogs, wolves and foxes. According to Küchenmeister and Zurn, Scultetten and Rentter in 1634-1645 were the first to refer to the bladder-worm stage of this parasite97. Wepfer stated that "gid" or vertigo in sheep and cattle was caused by a bladder in their brain and referred to an 69 40 epidemic which occurred in 1658115. In 1780, Leske then Goeze independently discovered the scolices with four suckers and a double row of hooks in the bladders of this parasite, with the former author naming it Taenia multiceps (multiceps meaning many-headed) and the latter calling it Taenia vesicularis, cerebrina, multiceps (meaning the many-headed, cystic worm in the brain). The cystic form was then renamed Coenurus cerebralis by Rudolphi in 180891. In 1853, Küchenmeister showed that C. cerebralis, which was common in herbivores, especially sheep, goats and cattle, was the intermediate stage of T. multiceps 67, then this was confirmed by Haubner46. In 1910, Hall erected the genus Multiceps and transferred the parasite to it, the worm's name thus becoming Multiceps multiceps 45. Finally, in 1967, Versteer transferred the worm back to the genus Taenia 113. T. serialis The adult worm, a parasite of dogs, was described as Coenurus serialis by 7 Gervais in 184739, then designated T. serialis by Baillet in 1863 . It was transiently known as Multiceps serialis, following Stiles and Stevenson. The larval stage of the parasite is found in horses. Some authorities have considered this species to be synonymous with T. multiceps. (2) HUMAN INFECTIONS WITH INTERMEDIATE FORMS OF OTHER TAENIA SPECIES T. crassiceps The adult worm is a parasite of foxes. It was described as Alyselminthus crassiceps by Zeder in 1800121, then renamed Taenia crassiceps by Rudolphi in 181091. The larval stage, Cysticercus longicollis, is found in small rodents and

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the morel; this form (metacestode) reproduces asexually by budding. Cysticercosis produced by this organism, in which there was proliferation of the parasite but in which infection was limited to the eye, has been reported in a young Canadian woman99. T. taeniaeformis The adult worm is a common parasite of cats. It was first described by Batsch in 1786 as Hydatigera taeniaeformis 8, then renamed Taenia crassicollis by Rudolphi in 181091. It was finally designated T. taeniaeformis by Wolffhügel in 1911116. The intermediate stage is a strobilocercus, i.e. a larval strobila with a cyst attached at the posterior end; it was long known as C. fasciolaris and is a common parasite of rats. Its metamorphosis into an adult Taenia was first observed by Küchenmeister in 185266. Two infections in humans have been recorded; in both cases, the strobilocercus was embedded in the liver. The first case was described by Bacigalupo in 1922 as T. infantis occurring in a five year old child in Argentina4, and the second patient was a 77 year old Czechoslovakian man102. (3). HUMAN INFECTION WITH ADULT FORMS OF OTHER TAENIA SPECIES T. longihamatus The adult worm was first described as Multiceps longihamatus by Morishita and Sawada in 196679. The mature forms were recovered from humans. All the patients were Japanese, the first being a three year old girl.

REFERENCES 1. ADAMS AR. Two further cases of human infestation with Bertiella studeri (Blanchard, 1891) Stiles and Hassall, 1902, with some observations on the probable synonymy of the specimens previously recorded from man. Annals of Tropical Medicine and Parasitology 27: 471-475, 1933 2. AKASHI S. Taiwan Igakkai Zasshi No. 167, 1916. In Japanese. Abstracted in China Medical Journal 31: 166-167, 1917 3. ANONYMOUS. Lancet ii: 617, 1882 4. BACIGALUPO J. Sobre una nueva especie de Taenia, Taenia infantis. Semana Médica 26: 726, 1922 5. BACIGALUPO J. Évolution de l'Hymenolepis fraterna Stiles, chez Pulex irritans L., Xenopsylla cheopis Rothschild et Ctenocephalides canis Curtis. Annales de Parasitologie Humaine et Comparée 9: 339-343, 1931 6. BAER JG. The taxonomic position of Taenia madagascariensis Davaine 1870, a tapeworm parasite of man and rodents. Annals of Tropical Medicine and Parasitology 50: 152-156, 1956 7. BAILLET C. Recherches sur un cystique polycéphale du lapin et sur le ver qui résulté de sa transformation dans l'intestin du chien. Mémoires de l'Académie des Sciences, Inscriptions et Belles-lettres de Toulouse (6) i: 452-482, 1863 8. BATSCH AJ. Naturgeschichte der Bandwürmgattung. Überhaupt und ihrer Arten

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insbesondere nach den neueren Beobachtungen in einem systematischen Ausuge, pp 298, Halle, 1786 BEAVER PC, JUNG RC, CUPP EW. Clinical Parasitology, ninth edition, Lea and Febiger, Philadelphia, pp 825, 1984 BEAVER PC., ROLON FA. Proliferating larval cestode in a man in Paraguay. A case report and review. American Journal of Tropical Medicine and Hygiene 30: 625-637, 1981 BELMAR R, FAIGUENBAUM J, SAPUNAR J, CUELLO E. Ensayo terapeutico de la teniasis por Hymenolepis nana con un derivado de la salicilamida (Yomesan Bayer 2353). Boletín Chileno de Parasitología 17: 69-71, 1962 van BENEDEN PJ. Mémoires sur les vers intestinaux. Supplement to Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences, tome 2, Paris, pp 376, 1858 (written 1852) BILHARZ T, von SIEBOLD CT. Ein Beitrag zur Helminthographia humana, aus brieflichen Mittheilungen des Dr. Bilharz in Cairo, nebst Bemerkungen von Prof. C. Th. von Siebold in Breslau. Zeitschrift für wissenschaftliche Zoologie 4: 53-76, 1852. Partly translated in 61 BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1691, 1885-1890 BLANCHARD R. Sur les helminthes des primates anthropoides. (Première note: Cestodes). Mémoires de la Société Zoologique de France 4: 186-196, 1891 BLANCHARD R. Histoire zoologique et médicale des téniades du genre Hymenolepis Weinland. Société d'éditions scientifiques, R Antoine Dubois, Paris, pp 112, 1891 BLANCHARD R. Notice sur les parasites de l'homme. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 46: 699-702, 1894 BLANCHARD R. Bertia satyri, de l'orang-outang, est aussi parasite de l'homme. Bulletin de l'Académie de Médecine, Paris, 69: 286-296, 1913 BLOCH M. Abhandlung von der Erzeugang der Eingeweidewürmer und den Mitteln wider dieselben etc., Sigismund Friedrich Hesse, Berlin, pp 54, 1782 BONNAL G, JOYEUX C, BOSCH P. Un cas de cénurose humaine du à Multiceps serialis (Gervais). Bulletins de la Société de Pathologie Exotique et de ses Filiales 26: 1060-1071, 1933 BRUMPT E. Précis de parasitologie, second edition, Masson et Cie, Paris, pp 1011, 1913 CHANDLER AC. First record of a case of human infection with tapeworms of the genus Mesocestoides. American Journal of Tropical Medicine 22: 493-497, 1942 COBBOLD TS. Description of Ligula mansoni, a new human cestode. Journal of the Linnean Society of London, Zoology, 17: 78-83, 1883 CORNET E. Essai de traitement de la sparganose rétrobulbaire. Bulletin de la Société MédicoChirurgicale de l'Indochine 11: 452-455, 1933 CRAM EB. A species of the cestode genus Bertiella in man and the chimpanzee in Cuba. American Journal of Tropical Medicine 8: 339-344, 1928 DANIELS CW. Taenia demerariensis. British Guiana Annual Medical and Hospital Reports, pp 4, 1895 DAVAINE CJ. Examen microscopique du Taenia receuilli à Mayotte. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 21: 236-240, 1870 DIESING C. Ueber eine naturgemässe Vertheilung der Cephaloctyleen. Sitzungsbericht der Akademie der Wissenschaften in Wien. Mathematische-naturwissenschaftliche Klasse 13: 556-616, 1854 DISSANAIKE AS, THOMAS V, NAGAPPAN N. Bertiella studeri (Blanchard 1891) Stiles and Hassal, 1902 infection in a child - first case from Malaysia. Southeast Asian Journal of Tropical Medicine and Public Health 8: 421-422, 1977 DOLLFUS RP. Cestodes du genre Raillietina trouvés chez l'homme en Amérique intertropicale. Annales de Parasitologie Humaine et Comparée 17: 415-442, 542-562, 1939-1940 DUBOIS G. Dissertatio de Taenia, pp 36, 1748. Also, Taenia, Linnaei Amoenitates Academicae; seu dissertationes variae physicae, medicae, botanicae, antehae seorsim editae, nunc collectae et auctae cum tabulis aenaeis, Lugduni Batavorum, Holmiae, etc 2: 59-99. 1751 DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairie Encyclopédique

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de Roret, Paris, pp 654, 1845 33. FAIN A, DENISOFF N, HOMANS L, QUESTIAUX G, van LAERE L, VINCENT M. Cénurose chez l'homme et les animaux du à Taenia brauni setti au Congo Belge et au Ruanda Urundi. II. Rélation de huit cas humains. Annales de la Société Belge de Médecine Tropicale 37: 679-696, 1956 34. FAUST EC. What is Sparganum mansoni. Journal of Tropical Medicine and Hygiene 32: 76-77, 1929 35. FAUST EC, CAMPBELL HE, KELLOGG CR. Morphological and biological studies on the species of Diphyllobothrium in China. American Journal of Hygiene 9: 560-584, 1929 36. FAUST EC, WASSELL CR. Intestinal parasites of man in the central Yangtze valley. China Medical Journal 35: 532-561, 1921 37. FUHRMANN O. Considérations générales sur les Davainea. Festchrift für Zschokke, No. 27, pp 19, 1920 38. GARRISON P. Davainea madagascariensis Davaine in the Philippine Islands. Philippine Journal of Science 6: 165-176, 1911 39. GERVAIS P. Sur quelques entozoaires taenioides et hydatides. Mémoires de l'Académie des Sciences et Lettres de Montpellier 1: 85-103, 1847 40. GOEZE JAE. Von dem Drehen der Schafe. Der Patriot. Gesellschaft in Schlesien neue öconom. Nachrichten auf das Jahr 1780 1: 21-27, 1780 41. GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, P A Pape, Blankenburg, pp 471, 1782 42. GRASSI B. Entwicklungscyclus der Taenia nana. Dritte Praliminarnote. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 2: 305-312, 1887 43. GRASSI B, ROVELLI G. Embryolische Forschungen an Cestoden. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 5: 370-377, 401-410, 1889 44. GRASSI B, ROVELLI G. Ricerche embriologiche sui cestodi. Atti dell'Accademia Gioenia di Scienze Naturali, Catania, volume 4, memoir 2, 1892 45. HALL MC. The gid parasite and allied species of the genus Multiceps. i. Historical review. Bulletin 125, Bureau of Animal Industry, United States Department of Agriculture, pp 68, 1910 46. HAUBNER GC. Ueber die Entwicklung der Band- und Blasenwürmer im Allgemeinen, und die des Coenurus cerebralis insbesondere. Magazin für die Gessamte Thierheilkunde 20: 243-260, 1854 47. HEYNEMANN D. Studies on helminth immunity. III. Experimental verification of autoinfection from cysticercoids of Hymenolepis nana in the white mouse. Journal of Infectious Diseases 109: 10-18, 1961 48. HIRA PR. Human and rodent infection with the cestode Inermicapsifer madagascariensis (Davaine, 1870) Baer, 1956 in Zambia. Annales de la Société Belgique de Médecine Tropicale 55: 321-325, 1975 49. IJIMA I. On a new cestode larva parasitic in man (Plerocercoides prolifer). Journal of the College of Science of the Imperial University of Tokyo, 20 (Article 7), pp 21, 1905 50. IJIMA I, KURIMOTO T. On a new human tapeworm Bothriocephalus species. Journal of the College of Science of the Imperial University of Japan 6: 372-385, 1894 51. IWATA S. Some experimental and morphological studies on the post-embryonal development of Manson's tapeworm Diphyllobothrium erinacei (Rudolphi). Reprinted from Japanese Journal of Zoology 5: 209-247, 1933 52. JANICKI C. Über zwei neue Arten der genus Davainea aus celebensischen Säugern. Archives de Parasitologie 6: 257-292, 1902 53. JOHNSTONE HE, JONES OW. Cerebral coenurosis in an infant. American Journal of Tropical Medicine 30: 431-441, 1950 54. JOHNSTON TH. Notes on some entozoa. Proceedings of the Royal Society of Queensland 24: 63-91, 1913 55. JONES WE. Niclosamide as a treatment for Hymenolepis diminuta and Dipylidium caninum infections in man. American Journal of Tropical Medicine and Hygiene 28: 300-302, 1979 56. JOYEUX C. Sur le cycle évolutif de quelques cestodes. Note préliminaire. Bulletins de la Société de Pathologie Exotique et de ses Filiales 9: 578-583, 1916

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57. JOYEUX C. Hymenolepis nana (v. Siebold 1852) et Hymenolepis nana var. fraterna Stiles, 1906. Bulletins de la Société de Pathologie Exotique et de ses Filiales 12: 228-231, 1919 58. JOYEUX C, BAER JG. Les cestodes rares de l'homme. Bulletins de la Société de Pathologie Exotique et de ses Filiales 22: 114-136, 1929 59. KAMO H, IWATA S, HATSUSHIKA R, MAEJIMA J. (Experimental studies of the life cycle of Diplogonoporus grandis. II. Experimental infection of marine copepods with coracidia.) Japanese Journal of Parasitology 22: 79-89, 1973. In Japanese, with English summary 60. KAMO H, MIYAKAI I. Diplogonoporus fukuokaensis sp. nov. (Cestoda: Diphyllobothriidae)from a girl in Japan. Japanese Journal of Parasitology 19: 635-644, 1970 61. KEAN BH, MOTT KE, RUSSELL AJ (Editors). Tropical medicine and parasitology: classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 62. KELLER. Note sur une nouvelle méthode de traitement de la sparganose oculaire. Bulletin de la Société Médico-Chirurgicale de l'Indochine 15: 524-536, 1937 63. KEVORKOV N P. (On some problems of the treatment of Hymenolepis nana.) Meditsinskaya Parazitologiya i Parazitarn e Bolezni 12: 83-88, 1943. In Russian. Abstracted in Tropical Diseases Bulletin 41: 498, 1944 64. KOBAYASHI H. (Studies on the development of Diphyllobothrium mansoni [Cobbold 1882] Joyeux 1927 [Third report]. Experimental studies on the mode of infection by the mature procercoid.) Taiwan Igakkai Zasshi 30: 3-8, 1931. In Japanese, with English summary 65. KOSAKA S. The first case of Mesocestoides lineatus parasitic on the human body. Japanese Journal of Parasitology 14: 212, 1942 66. KÜCHENMEISTER F. Ueber die Umwandlung der Finnen (Cysticerci) in Bandwuermer (Taenien). Prager Vierteljahrschrift für die praktische Heilkunde 33: 106-158, 1852 67. KÜCHENMEISTER F. Experimente über die Entstehung der Cestoden Zweiter Stufe zunächst des Coenurus cerebralis. Under Mitwirkung des Herrn Professor Haubner auf Befehl und Kosten des hohen königliche sächsischen Staatsminsiterii des Innern. Zeitschrift für klinische Medicin 4: 448-451, 1853 68. KÜCHENMEISTER F, ZÜRN FA. Die Parasiten des Menschen, Ambrosius Abel, Leipzig, two volumes, pp 582, 1878-1881 69. LESKE MG. Von dem Drehen der Schafe und dem Blasenbandwurme im Gehirn derselben als der Ursache dieser Krankheit, Leipzig, pp 52, 1780 70. LEUCKART R. Die menschlichen Parasiten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 1, pp 766, 1863 71. LEUCKART R. Über Taenia madagascariensis Davaine. Abhandlungen der deutschen zoologischen Gesellschaft pp 68-71, 1891 72. LEUCKART R. Cited in 14 73. LINNAEUS C. Systema naturae per regna tria naturae, secundum classes, ordines, genera, species cum characteribus differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 74. LÜHE M. Zur Anatomie und Systematik der Bothriocephaliden. Verhandlungen der deutschen zoologischen Gesellschaft 9: 30-55, 1899 75. MANSON P. Case of lymph scrotum associated with filariae and other parasites. Lancet ii: 616617, 1882 76. MANSON-BAHR P. Patrick Manson as a parasitologist. In, "A critical review". In, International review of tropical medicine, DR Linicombe (Editor), Academic Press, New York, pp 77-129, 1961 77. MELNIKOV NM. Ueber der Jugendzustände der Taenia cucumerinum. Archiv für Naturgeschichte 35: 62-70, 1869 78. MEYNER R. Zwei neue Taenien aus Affen. Ein Beitrag zur Kenntnis der Cestoden. Zeitschrift für Naturwissenschaft 68:1-106, 1895 79. MORISHITA K, SAWADA I. On tapeworms of the genus Multiceps hitherto unrecorded from man. Japanese Journal of Parasitology 15: 495-501, 1966 80. MOTAIS F. Considération sur la pathogénie de la sparganose oculaire. Bulletin de la Société Médico-Chirurgicale de l'Indochine 7: 363-368, 1929 81. MUELLER JF. The genus Mesocestoides in mammals. Zoologische Jahrbücher, Abteilung für Systematik, Oekologie und Geographie der Tiere, Jena 55: 403-418, 1928

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82. MUELLER JF. A Diphyllobothrium from cats and dogs in the Syracuse region. Journal of Parasitology 21: 114-121, 1935 83. MUELLER JF. A repartition of the genus Diphyllobothrium. Journal of Parasitology 49: 294-296, 1937 84. MUELLER JF, COULSTON F. Experimental human infection with the sparganum larva of Spirometra mansonoides (Mueller, 1935). American Journal of Tropical Medicine 21: 399-425, 1941 85. NICHOLL W, MINCHIN EA. Two species of cysticercoids from the rat flea (Ceratophyllos fasciatus). Proceedings of the Zoological Society of London 1: 9-13, 1911 86. OKUMURA T. An experimental study on the life-history of Sparganum mansoni, Cobbold. A preliminary report. Kitasato Archives of Experimental Medicine 3: 190-197, 1919 87. PARONA E. Di un caso di Taenia flavopunctata riscontrata in una bambina di Varese. Giornale dell'Accademia di Medicina di Torino 32: 99, 1882 88. RAILLIET A. Notices parasitologiques. Première series. Bulletin de la Société Zoologique de France 17: 110-117, 1892 89. RAILLIET A. Traité de zoologie médicale et agricole, second edition, Paris, pp 736, 1893 90. RAILLIET A, HENRY A. Sur un cénure de la gerbille à pieds velus. Bulletins de la Société de Pathologie Exotique et de ses Filiales 8: 173-177, 1915 91. RUDOLPHI CA. Entozoorum sive vermium intestinalium historia naturalis. Treuttel et Würtz, Paris, three volumes, pp 1370, 1808-1810 92. RUDOLPHI CA. Entozoorum synopsis cui accedunt mantissima duplex et indices locupletissima, Sumtibus Augusti Rücker, Berolini, pp 811, 1819 93. SAEKI Y. (Experimental studies on the development of Hymenolepis nana.) Jika Zasshi No. 238, pp 203-244, 1920. In Japanese. Abstracted in Tropical Diseases Bulletin 18: 112, 1921 94. SALZMANN. Ueber das Vorkommen der taenia cucumerina in Menschen. Jahrescheft des Vereins für Vaterland. Naturkunde in Württemberg 17: 102, 1861 95. SCHENONE H, GALDAMES M, RIVADENEIRA A, MORALES E, HOFFMAN MT, ASALGADO N, MENESES F, MORA M V, CABRERA G. Tratamiento de las infecciones par Hymenolepis nana en niña con una dosis oral unica de praziquantel (Embay 8440). Boletín Chileno de Parasitología 32: 11-13, 1977 96. SCOTT HH. A contribution to the experimental study of the life histories of Hymenolepis fraterna Stiles, 1906, and Hymenolepis longior Baylis, 1922, in the mouse. Journal of Helminthology 1: 193-196, 1923 97. SCULTETTEN, RENNTNER. Cited in 68 98. SETTI. Nuovi elminte dell'Eritrea. Bolletino dei Musea di Zoologia e Anatomia Comparata della Real Universita di Genova, pp 56, 1897 99. SHEA M, MABERLEY AL, WALTERS J, FREEMAN RS, FALLIS AM. Intraocular Taenia crassiceps (Cestoda). Transactions of the American Academy of Ophthalmology and Otorhinolaryngology 77: 778-783, 1973 100. SONSINO P. Ricerche sugli ematozoa del cane e sul ciclo vitate della di tenia cucumerina, Pisa, pp 47, 1888. Also, Atti della Società Toscana di Scienze Naturali Residente in Pisa 10: 20-64, 1889 101. SPOONER EA. Specimens of Taenia nana. American Journal of Medical Sciences 65: 136, 1873 102. STERBA J, BARUS V. First record of Strobilocercus fasciolaris (Taeniidae-larvae) in man. Folia Parasitologica 23: 221-226, 1976 103. STILES CW. Illustrated key to the cestode parasites of man. Bulletin 25 of the Hygiene Laboratories, United States Public Health and Marine Hospital Service, pp 104, 1906 104. STILES CW. The occurrence of a proliferating cestode larva (Sparganum proliferum) in man in Florida. Bulletin 40 of the Hygiene Laboratories, United States Public Health and Marine Hospitals Service, pp 7-18, 1908 105. STILES CW, HASSALL A. Bertiella, a new name for the cestode genus Bertia Blanchard, 1891. Science 16: 434, 1902 106. STILES CW, TAYLER-JONES L. A larval cestode (Sparganum mansoni) of man which may possibly occur in returning American troops. Bulletin 35 of the Bureau of Animal Industry, United States Department of Agriculture, pp 43-47, 1902

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107. STUNKARD HW. The morphology and life history of the cestode, Bertiella studeri. American Journal of Tropical Medicine 20: 305-333, 1940 108. SUZUKI N, KUMAZAWA H, HOSOGI H, NAKAGAWA O. A case of human infection with the adult of Spirometra erinacei (Rudolphi 1819), Faust, Campbell and Kellogg, 1929. Japanese Journal of Parasitology 31: 23-26, 1982 109. TANG CC, TANG CT. Raillietina (R.) celebensis (Janicki 1902), its development in intermediate host, epidemiology and taxonomy. Acta Parasitologica Sinica 1: 1-13, 1964 110. TURNER M, LEIPER RT. On the occurrence of Coenurus glomerulatus in man in West Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 13: 23-24, 1919 111. UCHIMARA R. (On the development of Hymenolepis nana and Hymenolepis murina.) Jikwa Zasshi No. 286, 1922. In Japanese. Abstracted in Japan Medical World 3: 53, 1923 112. VAILLANT L. Sur deux helminthes cestoïdes de la genette. Institut, Paris 31: 87-88, 1863 113. VERSTEER A. A taxonomic revision of the genus Taenia Linnaeus, 1758, s. str. Onderstepoort Journal of Veterinary Research 36: 3-58, 1969 114. WEINLAND DF. Human cestoides. An essay on tapeworms of man etc., Metcalfe and Co., Cambridge, Massachussetts, pp 93, 1858 115. WEPFERUS JJ. Observationes anatomicae, ex cadaveribus eorum, quos sustulit apoplexia, cum excertitatione de ejus loco affecto, JC Suteri, Scaffhusii, pp 304, 1658 116. WOLFFHÜGELK. Los zooparásitos de los animales domésticos en la República Argentina, Buenos Aires, pp 108, 1911 117. WOODLAND WN. On the life-cycle of the Hymenolepis fraterna (H. nana var. fraterna Stiles) of the white mouse. Parasitology 16: 69-83, 1924 118. WOODLAND WN. On the development of the human Hymenolepis nana (Siebold 1852) in the white mouse; with remarks on "H. fraterna", "H. longior" and "H. diminuta". Parasitology 16: 424-435, 1924 119. YOSHIDA S. The occurrence of Bothriocephalus liguloides Leuckart, with especial reference to its development. Journal of Parasitology 3: 171-176, 1917 120. YOSHIDA S. (On the morphology of the adult form of Sparganum mansoni found in the frog and other animals.) Tokyo Iji-Shinshi Nos. 2271 and 2272, 1922. In Japanese. Abstracted in Tropical Diseases Bulletin 20: 223, 1923 121. ZEDER JG. Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer von JAE Goeze mit Zusätzen und Anmerkungen herausgegeben von Zeder, Siegfried Lebrecht Crusius, Leipzig, pp 320, 1800 122. ZIMMERMAN HR. Life-history studies on cestodes of the genus Dipylidium from the dog. Zeitschrift für Parasitenkunde 9: 717-729, 1937

Chapter 17

Enterobius vermicularis and ENTEROBIASIS

SYNOPSIS Common names: threadworm, pinworm Major synonyms: Ascaris vermicularis, Oxyuris vermicularis Distribution: worldwide Life cycle: The adult worms live in the region of the caecum. The fertilized female worms, 2-5 mm in length, crawl out of the rectum at night, and deposit eggs on the perianal skin. When ova are ingested, each egg in the small intestine hatches a larva which passes to the caecal region and matures over 2-4 weeks Definitive host: humans Major clinical feature: pruritus ani Diagnosis: finding of eggs on a swab taken with sticky tape from the perianal skin Treatment: mebendazole, piperazine, pyrantel, viprynium

AWARENESS OF THE ADULT WORM The adult form of the helminth now called Enterobius vermicularis was one of the few worms known to ancient man, for it wa s both big enough to be seen and had that incontrovertible sign of life - independent motility. Records of it s existence may be found in the literature of several millenia go. Some authorities have interpreted the worm described as "Herxetef" in the Egyptian Papyrus Ebers (c.1550 BC) as indicating this parasite 70. With respect to the Greeks , Hippocrates (c.460-375 BC) in his Aphorisms (III, 26) mentions the occurrence of the worm in children 43, while Aristotle (384-c.320 BC) liste d among the three kinds of helminths of which he was aware: those which were large and flat, those which were cylindrical, and those which were thin 2. It is, the last mentioned worms, the "thin ones", which he called ascaris, tha t represent the worms now named E. vermicularis, whereas the "cylindrica l ones" are now designated Ascaris lumbricoides. Similarly, the Roman, Galen (129-c.200 AD) numbered the pinworm amongst the three species of human helminths he recognized 31. Knowledge of these worms continu ed down through the ages; the Arab, Avicenna (Ibn Sina), for example, described them 4. The nature and distinctiveness of this worm was not always understood clearly, however. Thus, St. Coulet in 1729 failed to distinguish well between E. vermicularis and cucurbitini and gave the impression that a tapeworm consisted of a large number of E. verm439

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icularis connected together22. Similarly, Contoli, believing that the structure of the cuticle of this worm was different from that of other nematodes, regarded the creature as a minute eel 21. In 1758 in his Systema Naturae, Linnaeus classified the organism among the Vermes, naming it Ascaris vermicularis 60. In 1819, Johann Bremser 10 transferred the human pinworm to the genus Oxyuris which had been erected by Rudolphi in 1803 72 for certain parasites of animals. Earlier, Bremser ha d found, in the large intestine of rabbits, a number of species of worms which he placed in this genus. He was then struck by the similarity between these worms and the worms found in the rectum of humans. After careful study, h e recognized that whereas ascarids always tapered towards the two extremities and had three papillae at the anter ior end, oxyurids terminated by a point at one end (especially in the female) and lacked the three papillae. This led him t o conclude: The result of these observations is that the worms known under the name of Ascaris vermicularis henceforth ought to be classed in the genus oxyuris and not in the genus ascaris.10

Even more importantly, Bremser distinguished clearly between the male and female forms. In his observations of oxyurids of animals, he noted that the male worms were one half to two thirds the size of the females, and that the termination of the tail in the two sexes were completely different, with the tail in the male worm being blunter and having a small spiculum. He deduced that male pinworms from humans ought to have similar characteristics, but initially, he could not find any such examples in the specimens he had at his disposal . Eventually, however, Dr. Soemmering sent him a small jar full of oxyurid s preserved in wine. These worms had been passed by his own son after having taken an olive oil enema; amo ng them, Bremser found undoubted male worms. He confirmed this observation when analysing further samples sent b y Soemmering and by Hermann. Thus, Bremser wrote: "The sexes of thes e oxyurids can be distinguished by the characteristics that we have reported" 10. In 1853, Leach56 erected the genus Enterobius, derived from a combination of the Greek words (ENTERON) and (BIOS) meaning "intestine" and "life", respectively, and transferred this worm to it. This name o f Enterobius vermicularis was accepted eventually, although Leiper 57 was later to argue unsuccessfully that it should be called Ascaris vermicularis Linnaeus, 1758 on the grounds of page p reference (and that Ascaris lumbricoides should be given a different generic name).

ELUCIDATION OF THE MODE OF TRANSMISSION The origin of threadworms was shrouded in mystery and for most of recorded history was generally ascribed to spontaneous generation. By the end of th e eighteenth century a number of helmint hologists including Goeze and Rudolphi

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had found and described eggs within the female worms. Nevertheless, ther e was not an instantaneous acceptance of th e idea that the adult worms developed from the eggs. Thus, Bremser (1819), who readily saw the eggs in femal e worms, thought it inconceivable that they could be transmitted through th e media of food, air or water and still clung to the theory of spontaneou s generation10. Several years earlier (1812), JM Barry in Ireland rejecte d spontaneous generation and proffered his own explanation, albeit a fallacious one, as to how transmission might occur. He saw no difficulty with the concept that minute germs might be imbibed in food or water then grow and develop within the human body and described an incident which he felt supported his belief. Twenty years earlier, a patient had come to him seeking removal of the threadworms which he, his wife, children, servant and visitors had all bee n afflicted with since moving to a new house four years before. Worms that were similar in appearance except in col our were found in the water of a nearby well and he concluded that they may have been the source of the affliction, despite the objections of a naturalist acquaintance that the creatures were likely to be of a different species 5. As late as 1855, Friedrich Küchenmeister was quite astray in his under standing of the life cycle of these worms. He had kept ova in water for si x months, yet after that time, could discern no trace of segmentation, let alone the formation of a mature embryo. This led him to deduce that development must take place within the warm milieu of an animal body. Küchenmeister the n suggested that infection might be transmitted by the adult worms themselves; he postulated that they crawled out of the anus at night, wandered about th e bedding, then entered the gut of a bed-fellow (though whether he thought that this was via the mouth or the anus he did not say), whereupon eggs wer e released which in turn developed into adult worms: the emigration of a single pregnant female is sufficient to explain the infection of whole families with Oxyurides....The sleeping of a married couple, one of whom is affected with Oxyurides, in the same bed, which is expecially the case amongst the poor who only possess one bed, the sleeping of these parents and their children, or of several children together, one of which is troubled with Oxyurides is sufficient to infect whole families with these worms. For if only a single female which emigrated at night, has wandered into the intestine of one of these bedfellows who had hitherto been free from Oxyurides, the perpetual infection is established in consequence of the abundant reproduction of this parasite.55

Küchenmeister was in fact most unlucky with the Enterobius eggs he chose to study and the way in which he dealt with them. He saw in the interior of each egg two large hyaline globules surrounded by finely granular detritus . Presumably, he was looking at either unfertilized eggs or ova which ha d degenerated in the water in wh ich he placed them. Several years later, in 1858, Claparède discovered that the most advanced eggs sometimes containe d tadpole shaped embryos whilst still within the body of the pregnant femal e worm17. In 1860, Vix reported that he had seen such eggs in the rectal mucus and had recovered them from the perianal skin; they were ripe and in th e

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process of hatching. This led him to surmise that young Enterobius were capable of developing directly in the r ectum without having to have a freeliving phase of existence 85. This view, of course, was very similar to the one already propagated by Küchenmeister. Spencer Cobbold writing in 1864 was little more enlightened than either of the previously mentioned investigators. After noting that it was generall y supposed that the egg may be reared to an adult in the one and same bearer, he remarked (perhaps having the precedents of intermediate hosts for trematodes and cestodes in mind): "I believe this notion to be entirely fallacious" 18. The only way in which the question as to whether mature eggs could develop directly when ingested by a human, or whether they first had to pass through an intermediate hosts, could be resolved was by experiment. In October, 1865 , Rudolf Leuckart and three of his students each swallowed a few dozen egg s which had been kept in a humified incubator. Nearly two weeks later, three of the investigators found some young adult E. vermicularis 6-7 mm long in their faeces; Leuckart himself recovered 18-20 worms over four weeks 59. A similar experiment was repeated by Grassi in 1879. He first assured himself that h e was free from infection with E. vermicularis, then he ingested six femal e worms taken from an individual who had died 24 hours previously. After fifteen days, he became troubled by pruritus ani and he found a number of femal e worms full of eggs in his faeces; they continued to be passed in each stool for over a month 36. Thus, there was no question that an intermediate host was quite unnecessary or that humans became infected by ingesting mature eggs. The role of mal e worms in the generation of these eggs had been a matter of controversy fo r many years, however. As men tioned earlier, Bremser at first could not find any male threadworms in humans and speculated that reproduction might occur by parthenogenesis. Despite the eventual discovery of the male sex, the apparent rarity of this sex encouraged some authors such as Rudolphi and von Siebold to believe that this hypothesis may well be true. Many years later, however , Zenker (1868) proved that it was easy to find many male worms at autopsy by scraping lightly the mucosal surface of the intestinal canal after removal o f faecal matter92. There was therefore no longer any reason to doubt that bot h male and female worms were involved in the reproductive process. Some uncertainty remained, however, as to whether adult worms coul d develop directly from eggs laid within the human body. In 1922, Goebe l claimed that he had succeeded in observing the development of ova that ha d been deposited in the intestine into mature worms in the lowest parts of th e small intestine and in the appendix 33. On the other hand, Wundt several years later collected eggs from the appendix and was unable to stimulate hatching of eggs with granular contents under any experimental conditions. Moreover, she found that those ova which contained embryos liberated them in the gastri c juice but that the larvae were killed by duodenal, jejunal or appendiceal fluid.

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This led her to conclude that it was highly improbable that E. vermicularis could develop within the gut without the eggs first passing out in the faeces , undergoing development in the external environment, then entering again b y the mouth91. This conclusion was reinforced by the finding of Philpot wh o showed that the "tadpole" larva was destroyed by digestive juices whereas a later stage of the parasite, which had developed an oesophagus, becam e resistant to those juices 68. Koch in 1925 then investigated the hypothesis put forward that adult worms might re-enter the anus and produce infection by that means. He injected adult female worms into the rectum of a child be means of an enema, and took elaborate precautions to prevent infect ion by mouth. The child became infected and Koch concluded that worms multiplied in the intestine without externa l reinfection involving passage through the stomach. Koch did not, however , observe such a phenomenon happening naturally 51. A different means of retrograde infection was proven experimentally by Schüffner an d Swellengrebel. They showed that larvae could hatch on the perianal skin, then migrate back through the anus and develop into adult worms, a process which they called "retrofection" 80. How important this mode of infection is in nature remains uncertain.

LOCALIZATION OF THE HABITAT OF THE WORMS Some of the ancient writers such as Galen 31 were able to differentiate the parts of the intestinal tract in whic h the three commonly recognized intestinal worms were located. Enterobius was thought to be localized chiefly in the rectum near the anus whereas Ascaris lumbricoides was assigned to the upper smal l intestine and tapeworms were deemed to extend over a considerable length of the small bowel. The placement of threadworms in the rectum seeme d eminently reasonable since many practitioners were familar with their habit of crawling out of the anus at night. This became the accepted dogma until th e middle of the ninteenth century although there were occasional remarks tha t worms could be found in the colon and especially in the caecum 46,89. In the middle of the nineteenth century, however, Dr Gros of Moscow , having ascertained on the basis of autopsy studies in Russia, Germany, France and Italy that these worms resided not in the rectum but in the distal parts of the small intestine and in the caecum, publicized this finding 37. This observation was confirmed shortly thereafter by Stricke r in Frankfurt 84, then amplified a few years later by Zenker. Zenker examined in detail the mode of development of worms following the ingestion of eggs. He showed that when eggs were swallowed, the embryo s hatched in the stomach, then passed into the upper small intestine where they increased rapidly in size and moulted. Worms i n all stages of development were

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found in the small bowel. After copulation, the fecund female worms passe d into the caecum where they congregated whilst most of the male helminth s remained in the jejunum and ileum. When the female worms were fully grown and distended with eggs, they commenced their descent into the large intestine and finally deposited their eggs in the rectum and on the perianal skin 92. The behaviour of these worms was studied further by Koch who reported his observations on ten infected children i n 1925. The external migration of worms began in the early hours of sleep and lasted about three hours. Koch observed as many as 65 worms migrating in this fashion from one child. The laying of eggs began almost immediately and was completed within 15-20 minute s depending upon the amount of moisture present. Many worms wandered into the female genitalia, but Koch never observed any returning to the bowel 51. It had in fact been known for yea rs that female adult worms sometimes wandered into the female genitalia, on occasion reaching the peritoneal cavity 53.The observations of Koch were confirmed a few years later by Reardon who also showed that each female worm deposited about 11,000 eggs 69. When it was shown in 1916 by Stewart that Ascaris lumbricoides larvae liberated from eggs in the stomach migrated through the tissues of the hos t before returning to the bowel, attent ion turned to determining whether a similar phenomenon occurred with E. vermicularis. No evidence of such larva l migration was found in mice and other animals infected with E. vermicularis 41,44,68. The number of worms in the bowel is extremely variable. Perhaps the most ever recorded is that reported by Bijlmer in 1946; he found at autops y approximately 10,000 worms in the bow el of a 40 year old emaciated man who had died in Holland 7.

RECOGNITION OF THE CLINICAL FEATURES The cardinal feature of Enterobius infection, perianal itching which is worst at night, was recognized two and a half thousand years ago by Hippocrate s (Epidemics, Book 2, Section 1) 43. He understood that worms crawled out onto the perianal skin at night, and that they sometimes "lost their way" and could be found in the vulva (Diseases of Women, Book 2, 76) 43. This exacerbation of symptoms at night has led some commentators to conclude that Avicenna was referring to E. vermicularis when he wrote: "The symptoms are aggravated in the evenings and at bedtime" 4. The habits of these worms became well-known and passed into folk-lore with one writer remarking: They will crawl out, and old women sometimes amuse themselves by seeing how many they can catch in a night, in order that they may shew their exploits to the doctor in the morning.28

The accuracy of Hippocrates' appreciation, moreover, is attested to by it s

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similarity with the description provided by Date in 1872: Threadworms may exist in considerable numbers without their presence being marked by any very striking symptoms; but they generally excite a good deal of local irritation, and, by the intolerable itching which they occasion, they render the patient's life miserable....In females they sometimes escape into the vagina, and cause troublesome leucorrhoea....Beyond the local irritation which they occasion, and which is often annoying enough, threadworms do not cause much harm. 25

This account would be just as acceptable in any textbook published today. Whether or not enterobiasis caused other clinical manifestations became a matter of controversy. An unrealistic attempt was made to link Enterobius infection with trichotillomania (hair-pulling) 81. Debate raged for years as t o whether E. vermicularis infection caused appendicitis. In 1899, Still dre w attention to an apparent relationship between appendicitis and the presence of E. vermicularis 82. In 1902, von Moty reported that he had found threadworms either in the appendix itself or in the intestine in three out of five cases o f appendicitis in his own practice. He believed that this frequency could hardly be accidental and suggested that E. vermicularis, T. trichiura and A. lumbricoides may play a role in the genesis of appendicitis 64. In this view, von Moty was supported enthusiastically by Blanchard and Metchnikof f (reviewed in1). Many articles appeared subsequently, some for and som e against this hypothesis, but tending towards the belief that enterobiasis was so frequent that the association was merely coincidental 27,29,34. In 1939, Brady and Wright reviewed 200 cases of enterobiasis and claimed that in addition to pruritus ani, the infection may cause enuresis, vaginitis , restlessness, insomnia, behavioural disturbances and scholastic difficulties . Further they believed that: "Many infested children showed gains in weight , improved in color, and disappearance of dark circles under the eyes afte r treatment"8. In contrast, Weller and Sorenson published their observations of 505 children two years later; 1 9% of the children were infected. There were no significant differences in symptomatology, including the frequency of pruritus ani, between the infected and uninfected groups 87. The consensus of opinio n now is that the majority of infectio ns with this worm are asymptomatic, but that some infections may cause pruritus a ni, particularly if the worm burden is high.

DEVELOPMENT OF DIAGNOSTIC METHODS Until relatively recent times, the diagnosis of enterobiasis was dependent upon the discovery, either by the patient, a clinician, or another observer, of adul t worms passed spontaneously. Küchenmeister has recounted one such case: a shoemaker came to me for advice as the Oxyurides disturbed him at night. As soon as he went to bed and got warm, the Oxyurides began to march out of his anus, with violent itching, and wander about in the anal folds, and even, in his opinion, attempted to free themselves by biting. Once when he did not know what to do with himself, he

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wakened his wife and begged her to see whether she could not discover what it was that troubled him so much. By means of a light, the woman found the little white worms, and picked them off, and since then, whenever he was again troubled, she always did him the same service.55

The discovery of Enterobius eggs, however, provided an alternative approach and in his review in 1877, Heller put forward the possibility of diagnosin g infection by means of finding eggs in rectal mucus 42. In 1929, Oleinikow showed that E. vermicularis infection could be diagnosed easily by scraping perianal skin with a spatula and then cleaning the spatula on the edge of a slide; further, this method was much more reliable than looking for eggs in faeces 67. In 1937, Maurice Hall described the "NIH swab" for the diagnosis of enterobiasis. This consisted of a glass rod wrapped in cellophane at the point and perforating a rubber cork at the other end, the latter being used to seal the cellophane in a test tube for transport. The cellophane was the n flattened out on a glass slide, a couple of drops of caustic soda added, then a cover slide placed in position and the specimen examined microscopically for eggs39 . A few years later, Graham described a modification of this swab i n which the cellophane was replaced by transparent Scotch cellulose tape 35; this has become the most popular and enduring of the diagnostic techniques used in enterobiasis, particularly after B eaver indicated that the preparation could be cleared with toluene 6. The finding of eggs in the faeces has been used recently to demonstrate the prehistoric existence of infection. The oldest record is of Enterobius ova found in coproliths, dated approximately 8,000 BC, that were discovered in Utah , United States of America 30. It is generally held that Enterobius infections do not produce an eosinophilia, although there is an isolated report of doubtful significance by Schmidt wh o infected himself with the worm and observed his blood eosinophil level ris e from within normal limits to 28% five weeks later 77.

UNDERSTANDING THE EPIDEMIOLOGY It had long been recognized that although persons of all ages may be infected with threadworms, children were infected much more frequently. Thus, D r Elliotson in his "Lectures on Worms" in 1833 wrote: "There can be no doubt that children are much more disposed to ascarides [= E. vermicularis] and to lumbrici [= A. lumbricoides] than others; and not only so, but as age advances, the constitution frequently becomes so unfit for the continuance of these worms that they are absolutely shaken off without any physic at all....Thousands have ascarides when they are young and never have them afterwards. 28

The clustering of infection, particularly in families became understandabl e when the direct transmission of infection was demonstrated by Leuckart 59, and with the recognition that eggs could be fully embryonated soon after discharge

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into the external environment. Not only was the carriage of eggs in bedding , food, air and so on feasible, but Zenker and Heller showed how easily auto infection could occur, particularly in persons plagued with pruritus ani, for they found eggs and even whole adult worms under the nails and the skin fold s around the nails93. It was then an easy matter to transfer these eggs to th e mouth. Cobbold has recounted what he considered to be a remarkable an d foolproof method of ensuring such reinfection: One aristocratic person, who was infected by myriads of these entozoa, confessed to me that in his extreme distress, and consequent rage, he had freely bitten the live worms in halves between his teeth. He had thus exposed himself to a terrible revenge since multitudes of the ova entering his mouth subsequently found their way into the stomach and intestines.20

Although it had been known since the time of Zenker and Heller that egg s were transmitted commonly by the fingers, being caught under the finger nails and in the nail-folds, Lentz was not satisf ied that this was the whole explanation for infections often recurred despite all appropriate precautions bein g taken. He then carried out some experiments which showed conclusively that the ova could become airborne following activities such as restless movements under bedclothes and changing the bedding 58. His findings were confirme d several years later when investigators in the United States revealed that house dust was frequently contaminated with ova 66. Subsequently, it was determined that most eggs survived for 48 hours when kept in cool, moist air, but that the majority were dead after this period in dry, cool air, while all were kille d rapidly by a dry, warm atmosphere 47. Proof that such eggs were viable wa s provided by Schüffner and Swellengrebel in 1949 when they infected seve n doctors and students with eggs which had lain in room dust for three days o r longer80. The increased ease with which enterob iasis could be diagnosed following the introduction of the NIH swab resulted in a new appreciation of how common the infection was. Many surveys showed that a third or more of the population in a number of countries was infected. Futhermore, it became apparent that in these countries, E. vermicularis had little respect for sex, age, race o r socio-economic status23. Infection was found to be less common in tropica l countries that in nations in temperate zones. Thus, only 1% of schoolchildren on the island of Guam in the Pacific Ocean were infected in 1947 83 whereas all of the schoolchildren surveyed in Amsterdam during World War II wer e infected79.

THE SEARCH FOR EFFECTIVE TREATMENT AND PREVENTIVE MEASURES Countless remedies have been used do wn through the ages for the management

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of threadworm infection. Bremser recorded in 1819 that Sömmering had used an olive oil enema on his son with success 10. Elliotson (1833) considered that oil of turpentine was the most effic acious agent and should be given by the anal route: In the case of ascarides (= E. vermicularis)....it is best to give the oil of turpentine by injection. You thus send it immediately on the parts where the worms reside, you save the patient the trouble of a filthy dose and you save the stomach from great disturbance. From a drachm to half an ounce may be given to a child, mixed with gruel, and it will often bring away thousands. Adults will take a larger dose in an infection - an ounce of more.28

Küchenmeister (1855) listed a number of drugs including oil, garlic and wormwood, and noted the common belief that the best time for administration o f these agents was when the moon was on the wane 55. The difficulties of treating enterobiasis were emphasized in 1874 by Cobbold in his usual verbose an d pompous style: Gentlemen, - If, in the curative treatment of ascarides, or oxyurides, as they are more properly termed, you cannot expect an amount of success equal to that which ought to be obtained in the case of tapeworms, it is at least some satisfaction to know that the worst of cases may be overcome by perserverance in the application of appropriate remedies in combination with the employment of hygienic measures ....Patients also will come to you, especially ladies, requesting both immediate and permanent relief, some of them, at the same time, taking care to impress upon you the impossibility of their swallowing active aperients or cathartics.19

He then went on to list drugs which had been recommended including assa foetida and aloes, various preparations of steel, santonin, quassia, lime-water, salt, castor oil, chloric ether, iron sulphate and gentian, usually in the form of an enema. He emphasized the irrationality of giving enemas alone when it was known that worms could be found throughout the length of the bowel, particularly the caecum; oral medicaments were required which would bring th e parasites within reach of the clysters. Cobbold went on to say, though: For my own part, I may say that I have ransacked the Pharmacopoeia for permanently effective remedies, but I have satisfied myself that no single drug, or any combination of drugs, can be employed with any certainty of success. You cannot find any remedial agent that exerts what may be called a specially poisonous or specific action upon the threadworm....I am free to admit that, do what we will, some cases prove obstinant and apparently incurable.19

He concluded, however, that relapse was alm ost certainly the result of ingesting more eggs, either from the patient's own person, or from other individuals. It was clear to him that treatment and hygiene had to go hand in hand: Obviously, therefore,....it is part and parcel of adequate treatment to recommend such prophylactic measures as should be likely to reduce the liability of reinfection within the lowest possible limits. In this view, I am in the habit of enforcing the utmost attention to cleanliness, not only as regards the person of the patient himself or herself....but also in respect of household arrangements. Frequent lavaments, purity of the water used for drinking and other domestic purposes, local washings after defaecation, frequent changes of linen, especially bed-clothing, the removal and

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beating of the bedroom carpets, washing of the floors....in short, every kind of procedure which shall operate to prevent the re-introduction of the eggs of these very common entozoa.19

Over the new few decades, a wide array of drugs was put forward for th e treatment of enterobiasis, presumably indicating that each of them lef t something to be desired. These included thymol 9, butolan75, aluminium subacetate76, salvarsan (arsenic) 38 , vermitacet (extract of Tanacetum vulgare)54 , chloramin86, cupronat (copper) 50, oxylax (Tubera jalapae plus dihydrooxyphthalophenon)12, tetrachlorethylene 90, hexylresorcinol and gentian violet 24. In 1940, following the recognition of its anthelmintic properties by Harwood and colleages in 193840, Manson-Bahr reported that phenothiazine was ver y effective in six children and three adults with enterobiasis, all of whom were cured62. This observation was soon confirmed by a number of investigators but unacceptable side-effect became apparent and led to abandonment of the drug. In 1942, Giroud noted that a patient undergoing piperazine treatment fo r another condition was cured clinically and parasitologically of enterobiasis 32. The value of the drug was then investigated by Mehrez who wrote a thesis on the subject in 1947 63. In 1951, Mouriquand and colleagues published, for the first time in the more accessible literature, the observation that piperazine was effective in the treatment of enterobiasis 65, then this was confirmed by White and Standen who demonstrated in a controlled trial that piperazine hydrate was more effective (83% cures) than gentian violet (70%) and a lactose placeb o (17%)88. A number of antibiotics including tetracycline 61 and combinations of bacitracin and succinylsulphathiazole 15, neomycin and phthalysulphathiazole 3, and spiramycin and diphetarsone 78 were shown to be effective. Tetracycline is now contra-indicated because of the recognition of its propensity to stai n permanently the teeth of children. In 1956, the efficacy of a derivative o f cyanide dye, pyrvinium (viprynium), was reported71,74. In 1965, Davis indicated that thiabendazole was effecti ve26 while shortly thereafter, the value of pyrantel was described13 as was the administration of mebendazole 11. Recently, Cho and colleagues have shown that viprynium and mebendazole remove worms at all stages or development whereas py rantel and piperazine are inactive against the larval stages of the parasite 16.

"OXYURIS INCOGNITA" - A SPURIOUS SPECIES OF ENTEROBIUS In 1919, Koford and White rep orted the discovery of eggs of an unknown type. They had found these ova in the faeces of 429 of 140,000 soldiers examined in the laboratory car Metchnikoff during the course of a hookworm survey o f troops. Since they presumed that the eggs were derived from an unknow n species of Oxyuris (i.e. Enterobius), Koford and White gave them the name of Oxyuris incognita 52. Several years later, however, Sandground showed tha t

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they were merely eggs of the plant nematode, Heterodera radicicola , which had been ingested and had passed through the bowel to cause a spuriou s infection73.

REFERENCES 1. ANONYMOUS. Intestinal worms and appendicitis. British Medical Journal ii: 1595-1596, 1906 2. ARISTOTLE. Opera omnia, graece et latine, cum indice nominum et rerum absolutissimo, F Dübner, E Heitz and U C Bussemaker (Editors), Didot, Parisiis, five volumes, 1848-1874 3. ASKUE E, TUFTS E, DROUGHMAN V. Pthalyl-sulfathiazole (sulfathalidine) in the treatment of enterobiasis. Journal of Pediatrics 44: 380-385, 1954 4. AVICENNA. Libri in re medica omnes, qui hactenus ad nos pervenere etc., V Valgrisius, Venetiis, pp 966, 1564. Original Arabic version, "Al Canon fi Al Tib" c. 1,000 AD. Cited in 49 5. BARRY JM. On the origin of intestinal worms particularly the Ascaris vermicularis. Transactions of the Association of Fellows and Licentiates of the King's and Queen's College of Physicians in Ireland 2: 392-396, 1812 6. BEAVER PC. Methods of pinworm diagnosis. American Journal of Tropical Medicine 29: 577-587, 1949 7. BIJLMER E. Exceptional cases of oxyuriasis in the intestinal wall. Journal of Parasitology 32: 359366, 1946 8. BRADY FJ, WRIGHT WH. Studies on oxyuriasis. XVIII. The symptomatology of oxyuriasis as based on physical examinations and case histories. American Journal of Medical Science 198: 367372, 1939 9. BRAU. De l'oxyurose en Indochine. Bulletin de la Société Médico-Chirurgicale de l'Indochine 3: 582-584, 1912 10. BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst einem Anhage über PseudoHelminthen, Carl Schaumburg und Comp., Wien, pp 284, 1819. Translated from the 1824 French version of CLF Panoucke in 48 11. BRUGMANS JP, THIENPONT DC, van WIJNGAARDEN I, VANPARIJS OF, SCHUERMANS VL, LAUWERS HL. Mebendazole in enterobiasis. Radiochemical and pilot clinical study in 1,278 subjects. Journal of the American Medical Association 217: 313-316, 1971 12. BUCHOLZ CH. Zur Behandlung des Oxuriasis mit Oxylax. Deutsche medizinische Wochenschrift 51: 1914-1915, 1925 13. BUMBALO TS, FUGAZZOTTO DJ, WYCZALEK JV. Treatment of enterobiasis with pyrantel pamoate. American Journal of Tropical Medicine and Hygiene 18: 50-52, 1969 14. CAVIER R. Chemotherapy of intestinal nematodes. In, International encyclopaedia of pharmacology and therapeutics, section 64, volume 1, Chemotherapy of helminthiasis, R Cavier and F Hawking (Editors), Pergamon Press, Oxford, pp 215-436, 1973 15. CHAN KF, BROWN HW. The treatment of pinworm (Enterobius vermicularis) infection with bacitracin and sulfasuxidine. Journal of Pediatrics 43; 290-293, 1953 16. CHO SY, HONG ST, KANG SY, SONG CY. Morphological observations ofEnterobius vermicularis expelled by various anthelmintics. Korean Journal of Parasitology 19: 18-26, 1981 17. CLAPARÈDE. De la formation et de la fécondation des oeufs chez les vers nématodes, Genève, pp 101, 1859 18. COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference more particularly to the internal parasites of man, Groombridge and Sons, London, pp 480, 1864 19. COBBOLD TS. A lecture on the treatment of threadworm. British MedicalJournal i: 167,

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1874 20. COBBOLD TS. Parasites: a treatise on the entozoa of man and animals including some account of the ectozoa, J&A Churchill, London, pp 500, 1879 21. CONTOLI. Cited in 45 22. COULET E St. Disputatio medica inauguralis de ascaridibus et lumbrico lato etc., Lugduni Batavorum, pp 8, 1728. Also, Tractatus historicus de ascaridibus et lumbrico lato etc.,G Potuliet, Lugduni Batavorum, pp 228, 1729 23. CRAM EB, REARDON L. Studies on oxyuriasis. XII. Epidemiological findings ni Washington, D.C. American Journal of Hygiene 29: 17-24, 1939 24. D'ANTONI JS, SAWITZ W. The treatment of oxyuriasis. American Journal of Tropical Medicine 20: 377-383, 1940 25. DATE W. Intestinal worms. Lancet i: 145-146, 184-185, 1872 26. DAVIS JH. Thiabendazole in pinworm infestations. American Journal of Diseases of Children 109: 567-570, 1965 27. EASTWOOD EH. The relationship between appendicitis, Oxyuris vermicularis and local eosinophilia in the appendix wall. Journal of Pathology and Bacteriology 26: 69-81, 1923 28. ELLIOTSON J. Lectures on the theory and practice of medicine: worms. London Medical Gazette 12: 689-695, 1833 29. FISCHER W. Oxyuren und Appendicitis. Deutsche Zeitschrift für Chirurgie 183: 222-245, 1924 30. FRY GF, MOORE GJ. Enterobius vermicularis: 10,000 year old human infection. Science 169: 1620, 1969 31. GALENUS CC. In, Medicorum graecorum opera quae extant, edited by K G Kühn (Greek text with Latin translation), 20 volumes, Leipzig, 1821-1833 32. GIROUD. Cited in 14 33. GOEBEL F. Die Oxyuriasis. Ergebnisse der Inneren Medizin und Kinderheilkunde 22: 106-138, 1922 34. GORDON H. Appendiceal oxyuriasis and appendicitis based on a study of 26,051 appendixes. Archives of Pathology 16: 177-194, 1933 35. GRAHAM CF. A device for the diagnosis of Enterobius infection. American Journal of Tropical Medicine 21: 159-161, 1941 36. GRASSI GB. I malefazi delle mosche. Nota preliminare. Gazzetta degli Ospedali, Milano 4: 467468, 1883 37. GROS G. Études progressives d'helminthologie. Gazette des Hôpitaux, Paris 27: 538-539, 1854 38. HAJOS K. Die Behandlung der Oxyuriasis mit Salvarsan. Medizinische Klinik 18: 1619-1620, 1922 39. HALL MC. Studies on oxuriasis. I. Types of anal swabs and scrapers, with a description of an improved type of swab. American Journal of Tropical Medicine 17: 445-453, 1937 40. HARWOOD PD, JERSTAG AC, SWANSON LE. The efficacy of phenothiazine for removal of ascarids from swine. Journal of Parasitology 24 (Suppl.): 16-17, 1938 41. HASEGAWA T. (On some observations on the development of Oxyuris vermicularis.) Tokyo Iji Shinshi No. 2367, pp 861-870, 1924. In Japanese. Abstracted in Japan Medical World 4: 203, 1924 42. HELLER A. Oxyuris vermicularis. In, Cyclopaedia of the practice of medicine, volume 7, Diseases of the chylopoietic system, H von Ziemssen (editor); translated by AH Buck, Sampson Low, London, pp 752-770, 1877 43. HIPPOCRATES. Works of, translated by WH Jones and ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953 44. HIRAISHI S. Some experiments on the growth of Oxyuris vermicularis. Japan Medical World 4: 118-119, 1924 45. HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 46. HOOPER R. Observations on human intestinal worms being an attempt at their arrangement into classes, genera and species. Memoirs of the Medical Society of London 5: 224-285, 1799

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47. JONES MF, JACOBS L. Studies on oxyuriasis. XXIII. The survival of eggs of Enterobius vermicularis under known conditions of temperature and humidity. American Journal of Hygiene 33: 88-102, 1941 48. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, pp 677, 1978 49. KHALIL M. An early contribution to medical helminthology translated from the writings of the Arabian physician Ibn Sina (Avicenna) with a short biography. Journal of Tropical Medicine and Hygiene 25: 65-67, 1922 50. KNOLLER G. Behandlung der Oxyuriasis mit Cupronat. Deutsche medizinische Wochenschrift 51: 1664, 1925 51. KOCH EW. Oxyurenfortpflanzung in Darm ohne Reinfektion und Magenpasse. Zentralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 94: 208-236, 1925 52. KOFOID CA, WHITE AW. A new nematode infection of man. Journal of the American Medical Association 72: 567-569, 1919 53. KOLB R. Ueber den Befund van auf dem Peritoneum des Cavum Douglasii angewachsenen Oxyuriden. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 31: 268-272, 1902 54. KRIMER M. "Vermitacet" gegen Oxyuris vermicularis. Deutsche medizinische Wochenschrift 50: 803-804, 1924 55. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 56. LEACH. In, Catalogue of the species of entozoa, or intestinal worms, contained in the collection of the British Museum, W Baird (Editor), pp 132, 1853 57. LEIPER RT. Discussion on the validity of certain generic names at present in use in medical helminthology. Archiv für Schiffs- und Tropen-Hygiene 30: 484-491, 1926 58. LENTZ FA. Zur Biologie des Oxyuris vermicularis. Zentralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 135: 156-159, 1935 59. LEUCKART R. Die menschlichen Parasiten unddie von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscherund Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876 60. LINNAEUS C. Systema naturae per regna tria naturae, secundum classes,ordines, genera, species cum characteribus differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 61. LOUGHLIN EH, RAPPAPORT I, MULLIN WG, WELLS HG, SHOOKHOFF HB. The treatment of enterobiasis with terramycine base. Antibiotics and Chemotherapy 1: 588-593, 1951 62. MANSON-BAHR P. Phenothiazine as an anthelmintic in threadworm and roundworm infections. Lancet ii: 808-809, 1940 63. MEHREZ R. Les nouveaux traitements de l'oxyurose, Thèse, Paris, 1947 64. von MOTY. L'appendicite parasitaire. Écho Médical du Nord 6: 217-221, 1902 65. MOURIQUAND G, ROMAN E, COISNARD J. Essai de traitement de l'oxyurose par al pipérazine. Journal de Médecine de Lyon 32: 189-195, 1951 66. NOLAND MO, REARDON L. Studies on oxyuriasis. XX. The distribution of the ova of Enterobius vermicularis in household dust. Journal of Parasitology 25: 173-177, 1939 67. OLEINIKOW SV. (Sur le diagnostic et l'épidémiologie dans l'enterobiase.) "Russian Journal of Tropical Medicine" 7: 393-401, 1929. In Russian with French summary. Abstracted ni Tropical Diseases Bulletin 27: 983, 1930 68. PHILPOT F. Notes on the eggs and early development of some species of Oxyuridae. Journal of Helminthology 2: 239-252, 1924 69. REARDON L. Studies on oxyuriasis. XVI. the number of eggs produced by the pinworm,

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91. 92.

93.

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Enterobius vermicularis, and its bearing on infection. Public Health Reports 53: 978-984, 1938 RIAD N. La médecine au temps des Pharaons. La médecine à travers le temps et l'espace, Librairie Maloine, Paris, pp 319, 1955 ROYER A. Preliminary report on a new antioxyuritic, Poquil. Canadian Medical Association Journal 74: 297, 1956 RUDOLPHI CA. Neue Beobachtungen über die Eingeweidewürmer. Archiv für Zoologie und Zootomie 3: 1-32, 1803 SANDGROUND JH. "Oxyuris incognita" or Heterodera radicicola. Journal of Parasitology 10: 92-94, 1923 SAWITZ WG, KARPINSKI FE. Treatment of oxyuriasis with pyrrovinyquinium chloride (Poquil). American Journal of Tropical Medicine and Hygiene 5: 538-543, 1956 SCHICKHARDT E. Butolan, ein neues Mittel gegen Oxyuriasis. Münchener medizinische Wochenschrift 67: 722, 1920 SCHMIDT WT. Zur Therapie der Oxyuriasis. Münchenener medizinische Wochenschrift 69: 400-401, 1922 SCHMIDT WT. Neue Beiträge zur Oxyuriasis. Münchener medizinische Wochenschrift 70: 495-496, 1923 SCHNEIDER J, BIGUET J, MACHEZ J M. Traitement de l'oxyurose par le diphétarsone speramycine et par le diphétarsone. Thérapie 15: 648-654, 1960 SCHÜFFNER W. Die Bedeutung der Staubinfektion für die Oxyuriasis. Richtlinien der Therapie und Prophylaxe. Münchener medizinische Wochenschrift 91: 411-414, 1944 SCHÜFFNER W, SWELLENGREBEL NH. Retrofection in oxyuriasis. A newly discovered mode of infection with Enterobius vermicularis. Journal of Parasitology 35: 138-146, 1949 SEMON HC. Trichotillomania due to threadworms. British Medical Journal i: 641, 1922 STILL GF. Observations on Oxyuris vermicularis in children. British Medical Journal i: 898-900, 1899 STOLL NR, CHENOWETH BM, PECK JL. Low incidence ofEnterobius vermicularis in natives of Guam, M.I. Puerto Rico Journal of Public Health and Tropical Medicine 22: 235-253, 1947 STRICKER W. Physiologisch-pathologische Bemerkungen über Oxyuris vermicularis. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 21: 360-361, 1861 VIX E. Ueber Entozoen bei Gesiteskranken, ins Besondere Quber die Bedeutung, das Vorkommen und die Behandlung von Oxyuris vermicularis. Allgemeine Zeitschrift für Psychiatrie 17: 1-31, 149-198, 225-302, 1860 WEINBERGER. Eine Einfache und Zuverlassige Oxyurenbehandlung. Medizinische Klinik 20: 750, 1924 WELLER TH, SORENSEN CW. Enterobiasis: its incidence and symptomatology in a group of 505 children. New England Journal of Medicine 224: 143-146, 1941 WHITE RH, STANDEN OD. Piperazine in the treatment of threadworms in children. Report on a clinical trial. British Medical Journal ii: 755-757, 1953 WOLF. De vermibus intestinorum, Giessae, pp 27, 1763 WRIGHT WH, BOZICEVICH J, GORDON LS. Studies on oxyuriasis. V. Therapy with single doses of tetrachlorethylene. Journalof the American Medical Association 109: 570-573, 1937 WUNDT N. Ueber Möglichkeit der intraintestinalen Entwicklung von Oxyuren unter Umgeung der Magenpassage. Münchener medizinische Wochenschrift 71: 546-548, 1924 ZENKER F. Ueber die Naturgeschichte des Oxyuris vermicularis. Verhandlungen der physicalisch-medicinischen Societät zu Erlangen, pp 20-21, 1870 (presented 20 July 1868). Also, Tageblatt der 42. Versammlung deutscher Naturforscher und Aertze zu Dresden, p 140, 1868 ZENKER F, HELLER A. Cited in 42

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Table 17.1. Landmarks in enterobiasis ___________________________________________________________________ BC

Adult worms have been known from ancient times and various anthelmintics have been employed 1819 Bremser discovered the male adult worm 1854 Gros showed that adult worms were located primarily in the caecum 1860 Vix recovered eggs from the perianal skin 1865 Leuckart infected himself and three students with ova and recovered adult worms from their stools two weeks later 1868 Zenker observed the stages of development of larvae in the intestines at autopsy and found male adult worms in the colonic mucus 1924 Philpot showed that the larva within the eggshell developed further in the external environment and became resistant to digestive juices 1937 Hall described the "NIH swab" for diagnosis 1941 Graham modified the swab by substituting Scotch tape for cellophane 1956 Viprynium was introduced for treatment 1969 Pyrantel was introduced for treatment 1971 Mebendazole was introduced for treatment ___________________________________________________________________

Chapter 18

Trichuris trichiura and TRICHURIASIS

SYNOPSIS Common name: whipworm Major synonyms: Trichocephalus dispar, Trichocephalus trichiurus Distribution: tropics and subtropics Life cycle: The adult worms, 30-50 mm in length, live attached by the head to the wall of the caecum and adjacent parts of the bowel. Eggs are excreted in the faeces and embryonate over 2 weeks or more, depending upon the temperature. When embryonated eggs are ingested by a human, each larva hatches in the small intestine, enters the crypts in the region of the caecum, and matures over 1-3 months Definitive host: humans Major clinical features: dysentery, rectal prolapse in very heavily infected persons (usually children) Diagnosis: finding eggs in the faeces; rarely, observation of adult worms on proctoscopy, sigmoidoscopy or colonoscopy Treatment: mebendazole

DISCOVERY OF THE ADULT WORM Despite the relatively large size of Trichuris trichiura and its not infrequent occurrence, the ancient writers seem to have been unaware of the existence of this parasite. The first reference to the worm is found in the works of Joannes Actuarius, a Byzantine physician who lived during the reign of Andronicus II (1328-1341 AD). Actuarius mentioned that some worms resembling thi n strings were sometimes "excreted" from the intestinal wall; he appears to have believed that they were a stage in the development of the roundworm, Ascaris lumbricoides, which he considered was generated spontaneously 4. This report received little recognition and the same fate was to befall the next description of the parasite. In 1623, the Portuguese physician and adventurer, Alexei de Abreu, wrote Tratado de las siete enferme dades (Treatise on the seven diseases ) which has been described as the earliest book on tropical medicine 34. In this book, de Abreu discussed certain maladies which he had observed in Angola and Brazil between 1594 and 1606. One of these conditions appears to be trichuriasi s which he described in his section on yel low fever, since the worms were almost invariably found in patients dying from that disease: 455

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In those same interior parts wrinkled corrupted and ulcerated in some patients, a little worm or worms are bred (white like earthworms, the size of a thumb in the length, the width of sewing thread, not very thick, they have a mild, soft body, the head hard and black) which eroding that flesh, together with the corruption it keeps rotting, and eroding, and soon leaves the lower part of the rectum exposed. 3

Only a limited number of copies of this book was printed (perhaps less tha n 20034), and this discovery and descrip tion did not receive the acknowledgement it deserved. No further allusion was made to the existence of this worm until Morgagni in his anatomical letters (published in about 1760) recorded his discovery of the parasite in 1740: I dissected 11 cadavers consecutively, and in six of them....I definitely found worms. The first three or four that I saw were white, very thin, and at most a thumb's breadth in length. They lay hidden inside feces at the base of the appendix....In another corpse I found several, all longer than those mentioned, but equal in length to the last two joints of the little finger; these....were....in the part of the caecum which adjoined the appendix....They were very pointed at one end and gradually became a little thickened, turning from white to somewhat dark at the tail which comprised half their length; otherwise they were totally white and as thin as a hair. 52

This observation of Morgagni was unknown to the Germans who rediscovered the parasite in 1761. During the winter of 1760-1761, an epidemic o f mucoid diarrhoea (? cholera) raged in Göttingen and killed many of th e inhabitants as well as French troopers who were stationed there. Whil e dissecting the body of a five year old girl, one of the medical student s accidentally opened the caecum and several worms crawled out. One of th e students, HA Wrisberg, believed that these were worms of a new species but the prosector, DT Wagler, and some of the other young doctors, after th e fashion of Actuarius, considere d them to be merely developing E. vermicularis or A. lumbricoides. The specimens were then taken to Roederer and Buttner to settle the argument. They pronounced the worm to be previously undescribed and gave it the name "trichuris" because of the hairlike shape of the tail, th e name being derived from the Greek words (THRIX) [combining for m - (TRICH-)] and (OURA) meaning "hair" and "tail", respectively. Many further examples were found in subsequent autopsies and Roedere r presented the findings to a meeting of the Academy of Science at Göttingen on 10 October 1761: The worm is round and cylindrical and at one end has a blunted point; at the other end it elongates into a thin, threadlike tail. The greatest thickness amounts to about one-third of a line [1 line = the 12th part of a Rhenish inch; about 2 mm] the length of the body is seven lines and the tail 15 lines....some (were) rolled together like spirals; others were less bent. The former are males, the latter females. In all them the tail is bent. Body and tail are transparent, shiny and white. 61

Not only did Roederer manage to separate the two sexes, but he also saw the small white eggs which could be expressed together with mucus through th e genital opening. The marked differences in appearance between the two sexes, in fact, misled some later investigators into believing that there were tw o

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different species. Roederer, however, made one major error when he mistook the head for the tail. The true anatomical arrangement was recognized b y Goeze32 who in 1782 thought it necessary to change the name to Trichocephalos, meaning "hair-like head", but Goeze but did not use binary nomenclature and gave it no specific name. Meanwhile, however, Linnaeus (1771 ) had called the worm Ascaris trichiura 48. In 1788, Schrank named it Trichocephalus hominis and Hooper later named it Trichuris vulgaris 38. In 1800, Zeder renamed the parasite Fusaria, and gave it the specific epithet, dispar, from the same Latin word meaning "unlik e" or "unequal" 74. In 1810, Rudolphi 65 reverted to the modification by Schrank of Goeze's name for the parasite and called it Trichocephalus dispar. This remained the popular name for more than a century until 1941 when the American Society of Parasitologists 59 declared that the Rules of Zoological Nomenclature concerning priority require d reversion to the generic name Trichuris of Roederer and Buttner and th e specific designation trichiura of Linnaeus.

ELUCIDATION OF THE MODE OF TRANSMISSION The manner in which the infection was transferred from one person to another remained a mystery for many years, despite the fact that the eggs of the parasite were found almost as soon as the adult worms were rediscovered in 1761. In 1855, Küchenmeister put forward an entirely fallacious, albeit ingenious , hypothesis to explain the life cycle. T wo recent observations provided him with stimuli for his idea. First, Leidy had discovered the larvae of Trichinella spiralis (which Diesing called Trichina affinis) in the muscles of swine (se e chapter 22). Second, Küchenmeister himself had recently demonstrated tha t human tapeworm infection was acquired by ingesting Cysticercus cellulosae in undercooked pork (see chapter 14). He sugg ested, therefore, that T. trichiura eggs excreted in human faeces were ingested by pigs and the liberated larvae migrated to the muscles (as T. spiralis). These larvae were in turn ingested by humans in poorly cooked meat and developed into adult Trichuris in the intestines45. Küchenmeister attempted to prove this hypothesis by experiments on dogs but had no success. The untenability of this theory was shown late r when Virchow and Leuckart discovered adult T. spiralis in the intestines of experimental animals (see chapter 22). Küchenmeister did, however, try to observe the fate of eggs and recorded : "After preserving the eggs of Trichocephalus for six months in water, n o embryos appeared, but only numerous, clear, but pretty regularly arrange d globules"45. He was out of luck for he did not observe the ova for long enough, or at the right season of the year. Several years later, Casimir Davaine in Paris took up the same problem and reached the following conclusions: eggs were expelled unembryonated, development only took place outside of the huma n

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body, this process took four to six months or more to complete, and the larvae within each egg may live for over one year 22. Indeed, he later showed that the larvae could remain alive for five years 23. Davaine thought it unlikely that an intermediate host was required and that hatching and development probably took place directly following ingestion of mature eggs23, but this remained an open question for a number of years . Eventually, Leuckart undertook some experiments with related species o f Trichuris in animals. He fed embryonated eggs of Trichocephalus (= Trichuris) affinis to a lamb and 16 days later found several hundred youn g trichocephali about 1 mm in length in the intestine. In a similar experiment , Leuckart fed T. crenatus ova to pigs and four weeks later recovered 50-8 0 worms, 10-30 mm long, which were close to sexua l maturity47. Railliet then had a similar experience. He collected eggs of T. depressiusculus on 19 February 1884, kept them in water until 28 July 1884 and then fed them to a dog. Three months later, on 27 October 1884, he obtained 150 mature worms 57. Thus, these experiments proved that related species of Trichuris developed without an intermediate host but evidence of the same phenomenon happening with T. trichiura in humans was lacking. In 1886, Salvatore Calandruccio, an associate of Grassi in Italy, having assured himself that he was not infected with T. trichiura by examining microscopically his faeces repeatedly over si x months, swallowed some embryonated T. trichiura eggs on 27 June 1886. Twenty seven days later, on 24 July, he found whipworm eggs in his faeces for the first time, thus proving that direct infection occurred in humans an d showing that the incubation period was nearly four weeks. These results were published, with minimal acknowledgement to Calandruccio, by Grassi 33 in the following year, much to the disgust of the former who some years later wrote a bitter letter to the Journal of Tropical Medicine and Hygiene : Calandruccio discovers the cycle of evolution of the Ascaris lumbricoides and of the Trichocephalus dispar, and shows the experiments to Grassi who praises them and says: 'I shall publish a note under your name in a German paper.' This preliminary note duly appeared, but not under my name but his, thus expressed 'my pupil Calandruccio', implying that I had studied under his direction, whereas I had not made my observations in his laboratory and he was ignorant of them before my communication.16

For whatever reason, Grassi never replied in the same forum to this attack.

STUDIES OF THE BEHAVIOUR OF WORMS IN THE HOST AN D PATHOLOGICAL REACTIONS TO THEM Following the discovery by Stewart that larvae of A. lumbricoides liberated from eggs in the stomach of the host migrated through the tissues befor e returning to the gut to mature (see chapter 19), attention turned to the question of whether a similar phenomenon occurred in T. trichiura infections. Fülleborn

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examined the route of migration a nd in 1923 reported the result of experiments with species of Trichuris from man, monkeys and rabbits. He showed tha t when fed to normal hosts, the larvae developed directly within th e gastro-intestinal tract. He also found that T. trichiura ova hatched in the gut, principally in the caecum, of guinea pigs, but that the larvae only survived for about four days, giving rise to worms s ome 200 um in length 30. In the following year, Hasegawa reported the results of similar experiments; he fed white rats with T. trichiura ova then found that larvae hatched within 20 hours an d penetrated the villi of the intestine, especially in the caecum, but failed t o develop. When Hasegawa gave T. depressiusculus to puppies, similar hatching and penetration took place, with the larvae remaining in the mucosa fo r approximately two days. By three days after ingestion, they returned to th e lumen of the bowel. Thereafter, they remained coiled in the neighbourhood of the crypts of Lieberkühn, the cells of whic h were destroyed; the worms matured and mated, with eggs appearing in the faeces after five weeks 36. The interaction between the worms and the intestinal mucosa was the n investigated by a number of pathologists. Some suggested that the head of a T. trichiura bored its way into the intestinal mucosa to form tunnels in the bowel wall. Similarly, Sagredo found that adult worms were not always free in th e intestinal canal, nor merely buried in the mucus, but that the head, sometimes the tail, and occasionally the whole worm were buried in a sort of tunnel in the intestinal mucosa 66. Oudendal (1924) could not accept these views, however. He studied material obtained from the bodies of Indians and Chinese infected with the helminth, and concluded that the worm did not bore or tunnel its way into the mucosa. Rather, he believed that the parasite inserted its way into the lumen of a gland, became fixed, then rolled its anterior end around it s longitudinal axis. Oudendal considered that in so doing, the epithelial cell s which gathered around the worm lost their individuality and became a syncitium, and together with polymorphonuclear leucocytes, formed a closed groove simulating a tunnel 54,55. A number of years later, Hartz examine d histological sections of the colonic mucosa of children with massive Trichuris infections and could find no l esions which could be attributable to the infection except for mechanical compression of the mucosal cells 35.

RECOGNITION OF THE CLINICAL FEATURES The coincidence of finding many examples of Trichuris infection at the same time as an epidemic of diarrhoea was occurring led Roederer and Wagler t o speculate on the possibility that these worms may have been the cause of the latter affliction. They found, however, that many persons who died from cholera were not infected with Trichuris whereas the worms were often found i n persons who had died from other causes, so they were forced to abandon this hypothesis62.

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In 1838, Bellingham in Ireland set himself the task of determining: whether the mere presence of these animals in the intestines must of necessity be injurious or whether they may not exist in considerable numbers even in the human subjects without causing the slightest inconvenience. 11

He examined 29 successive individuals at autopsy and found the worms in 26 of them. Yet in none of these cases could be found evidence of any symptoms which could have been ascribed to Trichuris infection11. Thus, by the time Abbotts Smith came in 1863 to publish his book (which was largely a translation of much of the first edition of Davaine's textbook), he concluded that the clinical manifestations, if any, were "almost unknown" 2. Furthermore, Date, in his review of intestinal worms in 18 72, apparently thought Trichuris of so little importance that he did not even mentio n it20. Attempts were made subsequently to link T. trichiura infection with beriberi 28, appendicitis (see chapter 17) and a predisposition to typhoid fever 14, but none of these postulates stood up t o critical analysis. In 1895, Moosbrugger, after referring to the prevailing view that this parasite was of no clinical significance, detailed three cases of Trichuris infection in whom he observed severe complications. Moosbrugger concluded that infections of light or medium intensity were asymptomatic, but that heavy infection (he instanced one with 900 worms) may produce a fairly well-defined clinical picture consisting of anaemia, prolonged and obstinate diarrhoea with mucus plus or minus blood in the stools, colicky abdominal pains and debilitation 51. This view was supported by Kahane (1907) who reported the case of a fou r year old girl with intransigent anaemia in whom innumerable whipworms were found in the appendix, caecum and co lon, some being embedded in the mucous membrane while others were swimming freely in the intestinal contents 41. Similarly, Musgrave and colleagues described a "diathesis" of anaemia , diarrhoea, cramps, dizziness, oedema and indigestion as a consequence o f heavy Trichuris infection53. Some writers went to extreme lengths in ascribing pathogenic roles to whipworms. For example, Fernán-Nuñez (1927) considered that trichuriasis might cause dysentery, purpura, acrocyanosis dystrophica, pernicious anaemia , urticaria and goitre29. Swartzwelder in 1939 analysed 81 patients who wer e infected with Trichuris but no other intestinal parasites. He concluded tha t abdominal pain, usually right-sided, and vomiting were the commones t symptoms, that constipation was more frequent than diarrhoea, and that most cases showed a mild anaemia 68; this study was uncontrolled, however, as he had no uninfected subjects with whom he could compare the frequency o f symptoms. Nevertheless, it gradually became apparent that massive infections (mor e than 1,000 worms) in children may cause dysentery, anaemia, malnutrition and rectal prolapse31,44,72. The importance of the relationship between intensity of infection and severity of disease was underlined by the investigations of Jung and Beaver that were reported in 1951. Those authors divided their cases into

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three grades; patients with light infections (< 7,500 eggs/g faeces) usually had no symptoms, those with moderate worm burdens (7,500-30,000 eggs/ g faeces) sometimes had vague abdominal pains, usually in the right lowe r quadrant, and urticaria, while those with heavy infection (> 30,000 eggs/ g faeces) had dysentery, abdominal pain, tene smus and sometimes rectal prolapse with the worms being visible easily to the naked eye on the mucosa of th e prolapsed bowel 39.

DEVELOPMENT OF DIAGNOSTIC METHODS For almost a century after the re-discovery of T. trichiura by Roederer and his colleagues, a diagnosis of trichuriasis was made only occasionally in livin g patients, and that was when worms were passe d spontaneously, usually with the faeces, as recorded by Roederer: "sometimes they were passed by the patient" 61. A most unusual way of diagnosing Trichuris infection was recounted by Wedl in 1854. H Ulrich removed a concretion about the size of cherry stone from an inguinal abscess which had resulted from an intestinal perforation . Microscopical examination of this material disclosed ova of T. trichiura in the midst of other material derived from faeces 71. Diagnosis was put on a simple and sound basis, however, when Ransom in 1856 and then Davaine in 1857 reported that int estinal helminthiasis, especially trichuriasis, could be diagnosed by microscopical examination of faeces fo r ova. In the summer of 1852, while examining the faeces of cats and dogs for ova of nematodes, it occurred to WH Ransom that intestinal helminthiasis i n humans might be diagnosed by a similar means. In July 1854, he found eggs of Trichuris and of an unknown tapeworm in the stools of a nine year old girl 58. In 1853, while examining the stools of dogs with cholera, Davaine foun d Trichuris eggs in the excrement. He had the opportunity to confirm thi s observation in humans several years later when he found large number o f Trichuris eggs in the faeces of an individual with meningitis; the patient died and large numbers of adult Trichuris were found in the caecum at autopsy 21. Davaine noted that the characteristic eggs were recognized easily by thei r brown colour, ovoid shape, the small bulges at each end, the absence of a n operculum, and length of 0.05 mm. This description by Davaine has bee n hailed incorrectly as the foundation of the diagnosis of intestinal helminthiasis by microscopical examination of the stools 5,69. The finding of eggs in faeces has been used to demonstrate the prehistori c existence of infection. Thus, Aspöck and colleagues found ova in faeces (dated between 800 and 350 BC) obtained from saltmines in Austria 6. Trichuriasis can sometimes be diagnosed and an assessment made of th e damage produced by proctoscopic or sigmoidoscopic examinations. Perhaps the first person to record the use of this technique was Ross who in 194 2 described the sigmoidoscopic appearances in a 2 8 year old woman with chronic

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diarrhoea: This confirmed the diagnosis in a remarkable manner, showing a little reddening and thickening of the mucosa of the lowest 9 in. of the bowel, most conspicuous about 7 in. from the anus where the mucous membrane was seen to be covered by a layer of sticky mucus, underlying which were several haemorrhagic spots 1-2 mm. in diameter; attached to some of these spots moving whipworms could be seen, and several were removed with forceps.64

THE SEARCH FOR EFFECTIVE TREATMENT When compared with A. lumbricoides and E. vermicularis, relatively little attention was paid during the nineteenth century to the treatment of Trichuris infection. Elliotson (1833) remarked vague ly, after discussing various intestinal worms including T. trichiura, that oil of turpentine given orally was one of the best anthelmintics 27. In the early part of this century, benzine enemas9 , garlic enemas41, thymol41 and "latex of Higueron" (fig-tree sap or juice prepared from Ficus glabrata)12 were employed. In 1922, Duque Lince reported his trials of various drugs including kousso, male fern, eucalyptus, betanaphthol, thymol, oil of chenopodium and latex of higueron as remedies for trichuriasis an d concluded that only the last had any specific effect on T. trichiura 26. Spruit67 supported the view that latex of higueron was active, then the effectiveness of the elixir was investigated further by Caldwell and Caldwell in 1929. In a preliminary survey of nine cases, one patient passed 1956 worms afte r treatment. Accordingly, a series of 234 patients were treated with eithe r higueron latex or oil of chenopodium; the two drugs produced cure rates o f 54% and 2%, respectively, and the reductions in egg counts were 85% an d 17%, respectively17. The active agent in the latex was held by Robbins to be a proteolytic enzyme, ficin 60. Unfortunately, the crude latex needed to b e prepared freshly in order to prevent fermentation, and its restricte d geographical distribution inhibited wide usage. In the following few decades, a number of drugs including hexylresorcinol 46, emetine15, papain50 and pentavalent arsenicals 7 were recommended, but these frequently did not live up to expectations. In 1957, Hoekenga reported that he had tried 13 drugs or combinations of drugs and that none was ver y successful37. Dithiazanine was introduced in the early 1960's and wa s moderately successful but two children treated with the drug died 1,63 and the drug was withdrawn from the market. With the exception of this agent an d diphetarsone 40, none of the various anthelmintics introduced after World War II was found to be effective agains t T. trichiura until mebendazole appeared on the scene. This benzimidazole compound was synthesized by Jansse n Pharmaceutica in Belgium and shown in 1971 to be active against Enterobius vermicularis (see chapter 17). A number of investigators then proved that i t was effective in trichuriasis as well 56,73.

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UNDERSTANDING THE EPIDEMIOLOGY; PREVENTION AN D CONTROL It was recognized early that Trichuris infection was more common in children than in adults. As helminthiasis su rveys were undertaken in various parts of the world, it became obvious that the infection was more frequent in tropical than temperate countries. The discovery by Calandruccio that infection wa s transmitted directly without the mediation of an intermediate host paved th e way for investigations of the factors controlling the epidemiology of infection. These included the demonstration that the time taken for development of eggs was dependent upon temperature. Dinnik and Dinnik showed that larva e developed within 11 days at 35 oC, but that 180 days were required when they were kept at 15oC24. The other major factor determining the spread an d intensity of infection was the usage of infected human excreta to fertiliz e vegetable gardens, for it had been known since the times of Davaine that eggs were able to survive for many months under moist conditions. Similar factors determined the epidemiology of ascariasis, and it was realized that the tw o infections tended to go hand in hand. Little attention has been paid specifically to the prevention and control of trichuriasis, but where it has, it has depended largely upon general environmental sanitary measures.

OTHER SPECIES OF TRICHURIS T. SUIS Although some authorities have failed to differentiate between Trichuris species from humans and pigs, it is accepted generally that whipworms from these two different hosts are distinct species. Dinnik, for example , demonstrated minor morphological variations, including the sizes of the eggs and the infective larvae, and differences in chromosome numbers 25. In 1940, Tukalevski swallowed 87 infective eggs of T. suis but isolated only two larvae from his stools 51 days later 70. In 1971, Beer reported that a 23 year old male (presumably himself) had been infected expe rimentally with 1,000 T. suis eggs. This resulted 60 days afterwards in a light patent infection (20 eggs/gram o f faeces) which lasted for at least ten weeks; no clinical manifestation s occurred10. Interactions between human and porcine trichuriasis in nature , however, remain unclear. T. VULPIS From time to time, human infections with T. vulpis have been reported, with the diagnosis being based upon t he increased size of T. vulpis eggs compared with

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those of T. trichiura. For example, de Carneri and colleagues in 1971 reported two such infections, separated by an interval of over one year, in the same five year old girl; she was living on a farm in Italy 18. Similarly, Kenney and Termakov have reported the i nfection of a human with the dog whipworm 43. T. trichiura, however, sometimes produces eggs which are larger and resemble those of T. vulpis. Little in 1968 recovered such eggs from human faeces then fed 22 of them to a human volunteer who fifteen weeks later developed a patent infection which produced eggs of both normal and large sizes 49. This observation was confirmed subsequently by Correa and his colleagues 19, so it remains uncertain whether any of the infections reported as due to T. vulpis were really caused by this species.

REFERENCES 1. ABADIE SH, SAMUELS M. A fatality associated with dithiazanine iodide therapy . Journal of the American Medical Association 192: 326-327, 1965 2. ABBOTTS SMITH W. On human entozoa: comprising the description of the differen t species of worms found in the intestines and other parts of the human body, and th e pathology and treatment of the various affections produced by their presence, HK Lewis, London, pp 245, 1863 3. de ABREU A. Tratado de las siete e nfermedades, Pedro Craesbeeck, Lisboa, 1623. Partly translated in 34 4. ACTUARIUS J. Methodi medendi libri sex, quibus omnia, quae ad medicina m factitandam pertinent, fere complectitur, CH Malthisius interprete, Venetiis, pp 399, 1554 5. ANONYMOUS. The week. British Medical Journal ii: 65, 1863 6. ASPÖCK H, FLAMM H, PICHER O. Darmparasiten in menslichen Exkrementen au s prähistorischen Salzbergwerken der Hallstatt-Kultur (800-350 v. Chr.). Zentralblatt fü r Bakteriologie, Abteilung originale 223: 549-558, 1973 7. BASNUEVO JG. Tricocefaliasis y arsenicos organicos pentavalentes. Revista Kub a Medicina Tropical y Parasitologia 4: 185-188, 1948 8. BEAVER PC, JUNG RC, CUPP EW. Clinical parasitology, ninth edition, Lea an d Febiger, Philadelphia, pp 825, 1984 9. BECKER E. Ueber die durch Trichocephalus dispar verusachten krankheitszustande . Deutsche medizinische Wochenschrift 28: 468-470, 1902. Abstracted in British Medical Journal, epitome of the current medical literature p 13, 1903 10. BEER RJ. Experimental infection of man with pig whipworm. British Medical Journal i: 44, 1971 11. BELLINGHAM O'B. On the frequency of the presence of the Trichocephalus dispar in the human intestines. Dublin Journal 12: 341-347, 1838 12. BERRIO LP. Contribution à l'étude de la trichocéphalose et de son traitement par le latex d'higueron. Revue de Médecine et d'Hygiene Tropicale 9: 178-184, 1912 13. BLANCHARD R. Traité de zoologie médicale. J-B Baillière et fils, Paris, two volumes, pp 1691, 1885-1890 14. BLANCHARD R. Sur un travail de M. le Dr. J. Guiart intitulé: Rôle du trichocéphal e dans l'étiologie de la fièvre typhoïde. Archives de Parasitologie 9: 122-128, 1904 15. BURROWS RB. MOREHOUSE WG, FREED JE. Treatment of trichuriasis wit h "enseals" of emetine hydrochloride. American Journal of Tropical Medicine 27: 327-328, 1947 16. CALANDRUCCIO S. Unicuiq ue suum, Prof. J.B. Grassi! (Every man his own Professor

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18.

19.

20. 21.

22.

23.

24.

25.

26. 27. 28. 29. 30. 31. 32. 33. 34.

35. 36. 37.

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Grassi). Translated by P. Falcke. Journal of Tropical Medicine and Hygiene 4: 218-221, 1901 CALDWELL FC, CALDWELL EL. A study of the anthelmintic efficiency o f higuerolatex in the treatment of trichuriasis, with comment as to its effectiveness against Ascaris infestation. American Journal of Tropical Medicine 9: 471-484, 1929 de CARNERI I, GAZZOLA E, BIAGI F. Ripetute infestazioni presumibilmenta d a Trichuris vulpis in una bambina residente in una zona endemica de tricocefalosi. Rivista di Parassitologia 32: 135-136, 1971 CORREA LL, YAMANAKA MT, CORREA M, SILVA M, SILVA R. Ocorrência de ovos grandes de Trichuris trichiura em fezes humanas. Revista do Instituto Adolfo Lutz 40: 59-64, 1980. Abstracted in Tropical Diseases Bulletin 76: 1418, 1980 DATE W. Intestinal worms. Lancet i: 145-146, 184-185, 1872 DAVAINE C. Sur le diagnostic de la présence des vers dans l'intestin par l'inspectio n microscopique des matières expulsées. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie, second series, 4: 188-189, 1857 DAVAINE C. Recherches sur le développement et la propogation du trichocéphale d e l'homme et de l'ascaride lombricoïde. Journal de la Physiologie 2: 295-300, 1859 . Translated in 42 DAVAINE C. Nouvelles recherches sur le développement et la propogation de l'ascaride lombricoïde et du trichocéphale de l'homme. C omptes Rendus Hebdomadaires des Séances de l'Académie des Sciences, third series, 4: 261-265, 1862 DINNIK JA, DINNIK NN. (Influence de la temperature, de l'absence d'oxygène et d u desséchement sur les oeufs de Trichocephalus trichiurus (L).) Meditsinskaya Parasitologiya i Parazitarn e Bolezni 6: 603-617, 1937. In Russian, with French summary DINNIK NN. (Indépendence des espèces Trichocephalus trichiurus (L 1771) et Trichocephalus suis (Schrank 1788).) Meditsinskaya Parastilogiya i Parazitarn e Bolezni 7: 907-917, 1938. In Russian, with French summary DUQUE LINCE E. Colitis trichocefaliana. Repertorio de Medicina y Cirugía 13 : 246-274, 1922 ELLIOTSON J. Lectures on the theory and pract ice of medicine. Worms. London Medical Gazette 12: 689-695, 1833 ERNI H. Trichocephalus dispar , ein Beitrag zur Beri-Beri-Frage. Berliner klinisch e Wochenschrift 23: 614-616, 1886. Abstracted in Lancet i: 545, 1886 FERNÀN-NUÑEZ M. The pathogenic role of Trichocephalus dispar (Trichuris trichiura). Archives of Internal Medicine 40: 46-57, 1927 FÜLLEBORN F. Ueber die Entwicklung von Trichozephalus im Wirte. Archiv fü r Schiffs- und Tropen-Hygiene 27: 413-420, 1923 GETZ L. Massive infection with Trichuris trichiura in children. Report of four cases, with autopsy. American Journal of Diseases of Children 70: 19-24, 1945 GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, PA Pape, Blankenburg, pp 471, 1782 GRASSI B. Trichocephalus und Ascarisentwicklung. Preliminarnote. Centralblatt fü r Bakteriologie und Parasitenkunde, Abteilung originale 1: 131-132, 1887 GUERRA F. Alexio de Abreu (1568-1630), author of the earliest book on tropica l medicine describing amoebiasis, malari a, typhoid fever, scurvy, yellow fever, dracontiasis, trichuriasis and tungiasis in 1623. Journal of Tropical Medicine and Hygiene 71: 55-69, 1968 HARTZ PH. Histopathology of the colon in massive trichocephaliasis of children . Documenta de Medicina Geographica et Tropica 5: 303-313, 1953 HASEGAWA T. Beitrag zur Entwicklung von Trichozephalus in Wirte. Archiv fü r Schiffs- und Tropen-Hygiene 28: 337-340, 1924 HOEKENGA MT. Experiments in the therapy of human trichuriasis and hookwor m disease. American Journal of Tropical Medicine and Hygiene 5: 529-533, 1956

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38. HOOPER R. Observations on human intestinal worms, being an attempt at thei r arrangement into classes, genera and species. Memoirs of the Medical Society of London 5: 224-285, 1799 39. JUNG RC, BEAVER PC. Clinical observation s on Trichocephalus trichiurus (whipworm) infection in children. Pediatrics 8: 548-557, 1951 40. JUNOD C. Essai de traitement de la trichocéphalose par la diphétarsone. Bulletin de la Société de Pathologie Exotique 58: 653-660, 1965 41. KAHANE R. Beitrag zur Trichozeph aliasis. Correspondez-Blatt für Schweizer Aertze 37: 235-241, 1907. Abstracted in British Medical Journal, an epitome of the current medical literature p 45, 1907 42. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 43. KENNEY M, YERMAKOV V. Infec tion of man with Trichuris vulpis, the whipworm of dogs. American Journal of Tropical Medicine and Hygiene 29: 1206-1208, 1980 44. KOUR P, VALDÉS-DIAS R. Concepto actual sobre el papel patógeno del Tricocéfalo dispar (Trichuris trichiura). Revista Kuba de Medicina Tropical y Parasitologia 8: 37-41, 1952 45. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Mensche n vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung de r thierischen und pflanzischen Pa rasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1985. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to th e group entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 46. LAMSON PD, BROWN HW, ROBBINS, BH, WARD CB. Field treatments o f ascariasis, ancylostomiasis and trichuriasis with hexylresorcinol. American Journal o f Hygiene 13: 803-822, 1931 47. LEUCKART R. Die menschlichen Paras iten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876 48. LINNAEUS C. Mantissa plantarum altera generum, editiones VI et specierum editionis II, Holmiae, pp 143-588, 1771 49. LITTLE MD. A strain of Trichuris trichiura having large eggs. Presented at the 43r d Annual meeting of the American Society of Parasitologists, Madison, Wisconsin, 1968. Cited in 8 50. McCARTHY E. Infestation with Trichocephalus dispar. Ten cases in an Irish orthopaedic hospital. Lancet i: 436, 1954 51. MOOSBRUGGER. Ueber Trichoceph aliasis. Münchener medizinische Wochenschrift 42: 10971099, 1895. Abstracted in British Medical Journal, epitome of the current medical literature p 17, 1896 52. MORGAGNI GB. Epistolarum anatomicarum duodeviginti ad scripta pertinentiu m celeberrime viri Antonii Marie Valsalvae pars altera. Epistola Anatomica XIV, Apu d Franciscerum Pitteri, Venice, p 45, 1740. Partly translated in 42 53. MUSGRAVE WE, CLEGG MT, POLK M. Tr ichocephaliasis (with a report of four cases including one fatal case). Philippine Journal of Science B 3: 545-566, 1908 54. OUDENDAL AJ. Over slijmvlies-veranderingen door den Trichocephalus dispa r veroorzaakt. Herinneringsbundel Instituut voor Tropische Geneeskund te Leiden, p p 110-124, 1924 55. OUDENDAL AJ. About changes of the mucous membrane caused by Trichocephalus dispar. Mededeelingen van den Dienst der Volksgezondheid in Nederlandsch-Indië, p p 333-344, 1926 56. PEÑA CHAVARRIA A, SWARTZWELDER JC, VILLAREJOS VM, ZELED N R. Mebendazole, an effective broad-spectrum anthelmintic. American Journal of Tropica l Medicine and Hygiene 22: 592-595, 1973

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57. RAILLIET A. Cited in 13 58. RANSOM WH. On the diagnosis of, and treatment for, roundworm; and on the occurrence of a new species of taenia in th e human body. Medical Times and Gazette, new series, 12: 598-600, 1856 59. REPORT OF THE COMMITTEE ON NOMENCLATURE, 16th annual meeting of the American Society of Parasitologists. Trichuris Roederer 1761 vs. Trichocephalus Schrank 1788. Journal of Parasitology 27: 279-282, 1941 60. ROBBINS BH. A proteolytic enzyme in ficin, the anthelmintic principle of leche d e higueron. Journal of Biological Chemistry 87: 251-257, 1930 61. ROEDERER JG. Nachrichten von der Trichuriden der Societät der Wissenschaften i n Goettingen. Göttingische Anzeigen von Gelehrten Sachen: Unter der Aufsaicht de r königliche Gesellschaft der Wissenschaften, part 25, pp 243-245, 1761. Translated in 42 62. ROEDERER JG, WAGLER JC. De morb o mucoso liber singulis, quem nuper speciminis inauguralis loco ediderunt, V Bossigelium, Goettingae, pp 211, 1762 63. RODRIGUEZ de CURET H, del PILAR ALIAGA M. Dithiazanine intoxication, a case report. Boletin de la Asociacion Médica de Puerto Rico 55: 469-473, 1963 64. ROSS DF. Chronic diarrhoea due to Trichocephalus trichiurus . Lancet ii: 97-98, 1942 65. RUDOLPHI CA. Entozoorum sive vermium intestinalium historia naturalis, Treuttel e t Würtz, Paris, three volumes, pp 1370, 1808-1810 66. SAGREDO N. Trichocephalus dispar in der Darmwand. Archiv für pathologisch e Anatomie und Physiologie und für klinische Medizin (Virchow) 256: 268-274, 1925 67. SPRUIT CB. The treatment of trichuriasis with Leche de Higueron. American Journal of Tropical Medicine 1: 375-380, 1921 68. SWARTZWELDER JC. Clinical Trichocephalus trichiurus infection. An analysis of 81 cases. American Journal of Tropical Medicine 19: 473-481, 1939 69. THEORIDES J. Un centenaire en parasitolo gie. Davaine et le diagnostic des helminthiases par l'examen microscopiques des selles (1857). La Presse Médicale 65: 2124, 1957 70. TUKALEVSKI IM. Meditsinskaya Parasitologiya i Parasitarn e Bolezni 9: 444, 1940 71. WEDL C. Grundzuge der patho logischen Histologie, Carl Gerold & Sohn, Wien, pp 825, 1854. Rudiments of pathological histology, translated by G Busk, The Sydenham Society, London, pp 637, 1855 72. WHITTIER L, EINBORN NH, MI LKLER JF. Trichuriasis in children. A clinical survey of fifty cases and reports of three cases with heavy infection and striking clinica l symptoms. American Journal of Diseases of Children 70: 289-292, 1945 73. WOLFE MS, WERSHING JM. Mebendazole: treatment of trichuriasis and ascariasis in Bahamian children. Journal of the American Medical Association 230: 1408-1411, 1974 74 ZEDER JG. Erster Nachtrag zur Naturgeschicht e der Eingeweidewürmer von J A E Goeze mit Zusätzen und Anmerkungen herausgegeben von Zeder, Siegfried Lebrecht Crusius , Leipzig, pp 320, 1800

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Table 18.1. Landmarks in trichuriasis ___________________________________________________________________ c.1330 1623

Actuarius described worms that were probably Trichuris de Abreu described the adult worms that he had found 20 years earlier in the bowel of patients dying from yellow fever 1760 Morgagni reported his finding 20 years earlier of the adult worms in the large bowel 1761 Wagler, Roederer and others independently rediscovered the adult worms in the large intestine of patients dying from what was probably cholera 1856 Ransom described microscopical diagnosis by finding eggs in the faeces 1886 Calandruccio swallowed embryonated eggs and found T. trichiura ova in his stools 27 days later 1923 Fülleborn showed in experimental animals that development of larvae took place solely within the gastrointestinal tract 1973 Mebendazole was shown to be an effective treatment by a number of investigators __________________________________________________________________

Chapter 19

Ascaris lumbricoides and ASCARIASIS

SYNOPSIS Common name: roundworm Distribution: widespread, especially in tropics and subtropics Life cycle: the adult worms, 15-30 cm long, live in the lumen of the upper small intestine. Eggs are passed in the faeces and embryonate over several months, the duration depending upon the temperature. When an egg is ingested, the larva hatches in the small bowel, penetrates the intestinal mucosa, and passes via the portal system to the liver, then to the lungs where it enters the alveolar spaces, ascends the airways to the pharynx, is swallowed, and returns to the small intestine where it matures over 8-12 weeks Definitive host: humans Major clinical features: occasionally - abdominal pain, intestinal obstruction; rarely jaundice, pancreatitis Diagnosis: finding eggs in the faeces Treatment: levamisole, mebendazole, piperazine, pyrantel

AWARENESS OF THE ADULT WORM Ancient man must have been w ell aware of, if not terrified by, the large, motile creatures resembling earthworms that he pass ed in the faeces from time to time, or, more rarely, escaped through other orifices. These large roundworms were mentioned in the Egyptian Papyrus Ebers (c.155 BC) 95, and were discussed by a number of Greek and Roman writers including Hippocrates (c.460-375 BC) in his Aphorisms (III,26)57, Aristotle (384-c.320 BC) 6, and Pliny (23-79 AD) 21. The Greeks called these roundworms µ (HELMINS STRONGYLE) meaning "worm" and "rou nd", respectively. Roman authors referred to them as "lumbricus teres", in view of their fancied resemblance to the common earthworm, and to disti nguish them from "lumbricus latus" (the broad worm, i.e. tapeworm), and "ascaris" of the Greeks (which, confusingly , indicated the worm now known as Enterobius vermicularis ). At the beginning of the Christian era, Celsus (c.20 AD) wrote: Again, worms also occasionally take possession of the bowel, and these are discharged at one time from the lower bowels, or more nastily from the mouth; and we observe them sometimes to be flattened, which are the worse, at times to be rounded. 23

Galen (129-c.200 AD)42 and Alexander Trallianus (c.525-605 AD) knew that A. lumbricoides normally inhabited the upper part of the small intestin e 469

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whereas tapeworms extended over a considerable length of the bowel, an d E. vermicularis was thought to be seated chiefly in the rectum. This parasit e was also the first human helminth recorded in the Chinese literature, bein g mentioned in the work, Nei Chung, which was probably written about 300 200 BC59. It was not until the late seventeenth century, however, that investigator s began to pay much attention to the details of the anatomical structure of these parasites. The first person to publish such an account (1683) was the English don, Edward Tyson; he clearly distinguished A. lumbricoides (which he called "lumbricus teres") from the earthworm. Having observed that they were about a foot in length, he wrote: They are about the bigness of a wheat straw, or a goose quill, their colour white....I did not observe those feet, or asperities on the annuli, as in the earthworm. At both extremes they grow narrow. Their mouth is composed of three lips....The anus is a transverse slit a little below the extreme point of the tail. 133

On dissecting the parasite, Tyson found a large, spiral muscle layer under the skin, a copious body fluid, a straight intestine, and genital parts which largely filled the body cavity. He recognized that the sexes were separate, an d described the appearance of the male and female reproductive organs . Moreover, he discovered the eggs of Ascaris: I opened the cornua uteri and found them turgid with a milky juice, having placed a little of it upon a microscope. I plainly perceived 'twas nothing else but an infinite number of small eggs, tho' to the naked eye it appeared onely as a fluid body. These eggs when fresh, appeared....covered with an abundance of small asperities, but as they grew dry, their surface appeared smooth.133

In the following year, the Italian, Francisco Redi, also described the anatomy of this worm104, as did Vallisnieri in 1713. Although the latter commentato r illustrated both the male and female sexual organs, he misinterpreted hi s observation and thought that the female Ascaris was hermaphroditic and that the male worm belonged to a different species of helminth altogether 134. In the tenth edition of his Systema Naturae in 1758, Linnaeus designated this worm Ascaris lumbricoides 77. The generic name was taken from the Gree k word (ASKARIS, ASCARIS) meaning "worm". Leiper in 1926 73 claimed that the correct name was Stomachida lumbricoides (Linnaeus 1758) Perebroom 1780, on the ground that since Linnaeus had described Ascaris vermicularis first in his tenth edition of Systema Naturae in 1758, Enterobius vermicularis should have retained this designation. The first person t o subsequently use another name for A. lumbricoides was Perebroom who, in 1780, called it Stomachida. However, Stiles and Hassall had earlier argued that Bremser's removal in 1819 of Ascaris vermicularis to the genus Oxyuris of Rudolphi eliminated it and left the name open for Ascaris lumbricoides. In 1915, the International Commission on Zoological Nomenclature by Opinion 66 confirmed this view by ruling that lumbricoides was the type species of Ascaris 61. Perhaps fortunately, Leiper's assertions did not receive genera l

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acceptance and the name Ascaris lumbricoides retains official recognition.

ELUCIDATION OF THE MODE OF TRANSMISSION It was generally held for many centuries that A. lumbricoides, like other intestinal worms, arose by a proces s of spontaneous generation (see chapter 2). During the sixteenth and seventeenth centuries, however, a number o f observers came around to the view that these worms were viviparous, i.e. they brought forth smaller versions of themselves. Thus, Amatus Lusitanius told of a girl who voided a large worm and, when her father trod on it, other worm s escaped from its interior 3. Similarly, Felix Platter recounted the story of a boy who died and when his abdomen was opened, his intestines were stuffed with a great number of living worms which were in turn filled with other smalle r worms98. Dominicus Panarolus claimed that from two persons: flesh-coloured worms about 16 inches long were expelled. These worms bore many little worms in them and the little worms looked like so many little sticks of wood. These small worms were innumerable; they were slender and white, being about six inches long, and on being born they slithered like so many tiny serpents. 94

Tyson, however, being certain of his discovery of the eggs, was convinced that all this was nonsense: "Whatever is related of this nature, I cannot but think is a mistake....For they are not viviparous but oviparous as I have shewn" 133. It is possible, though, that Tyson may have thought erroneously that the whole cycle of reproduction and growth could occur within the same host, for he went on to say: their containing so vast a number of eggs in the cornua uteri, as I have expressed, does not sufficiently account for the prodigious quantity, that are sometimes observed to be bred in animal bodies.133

Alternatively, he may simply have meant that a vast number of eggs wer e available to contaminate the environment. In any event, the concept tha t Ascaris was viviparous died hard. More than a century after Tyson clearl y described the eggs, Church wrote: Everyone who has examined this worm attentively when newly discharged from the body must have observed an appearance like white threads, folded, as it were together about the middle of the worm. This substance has in general been supposed to the intestines of the worm filled with chyle....but the fact I am going to relate seems to prove beyond doubt that this white appearance is in reality the young worms nearly fit for exclusion from the parent.26

The "evidence" Church advanced was that when he put a roundworm passed by a child in a cup of water and spirit, it produced three worms about one inch long which were exactly like the parent worm. He then went on to speculat e that infection might be acquired by worms creeping into the mouth while a person lay asleep on the ground 26. By the middle of the nineteenth century, however, there could no longer be any doubt that transmission depended upon eggs being excreted in the faeces,

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and that worms developed from them. At tention turned, therefore, to discerning the way in which this occurred. In particular, the question arose as to whether or not an intermediate host was involved in this process. Initially, development within the egg was examined. The first person to study this aspect was Gros in Moscow in 1849. He put moistened eggs into an incubator at a temperature of 15-16 oC and found that they began to develop within 24 hours, but require d four months to reach a perfect state o f larval development 53. Richter in Dresden made similar observations and showed that eggs remained alive for up t o eleven months. He placed unsegmented A. lumbricoides eggs in water on 15 November 1854 but did not examine them again until 15 October 1855, a t which time he found living larvae within the egg shells although none of them had hatched108. Similarly, Leuckart found that larvae remained motile within the egg shells for six months and showed them to the Congress of Germa n naturalists in 1857 74. Furthermore, Leuckart found that the period necessary for the development of the larvae was variable and was dependent upon th e temperature. These processes were reinvestigated by Davaine in 1859. He found tha t development of larvae took four to six months or even more to be completed, and reported at that time that they remained alive for more than one year 31. Subsequently, he discovered that larvae were still viable five years afte r collection32. Davaine also ascertained that incubation of eggs in gastric juice in vitro did not dissolve the egg shell and permit escape of the enclosed larva. He therefore performed an experiment in which he introduced two small fabri c containers, one containing embryonated A. lumbricoides eggs, and the other holding unembryonated ova, into the stomach of a dog. The flasks wer e recovered from the faeces two days later and the contents examined. In th e latter flask, unembryonated eggs were found, while in the former container , only a few free larvae could be detected. Davaine interpreted these results as indicating that: the egg shell is not dissolved by the intestinal juices because undivided eggs were found intact in the flasks but the eggs are sufficiently softened so that the embryos within, activated by the heat of the intestines, could pierce it and escape. 32

In October 1861, Davaine gave 300-400 A. lumbricoides eggs to a cow but could find no worms in the intestines four months later; he concluded that the cow was not a susceptible host to this parasite. In October 1862, he fed large numbers of eggs which had been kept viable for five months to a rat. Whe n Davaine killed the animal twelve hours later, he found large numbers of intact eggs in the stomach and the upper small bowel, but in the more distal parts of the small intestine, he discovered liberated larvae and larvae that were in the process of hatching through a small pore in the shell. In a subsequen t experiment upon another rat, he found that these freed larvae were expelled in the faeces. Davaine summarized his findings: eggs of....A. lumbricoides develop outside the body of man, but the embryo only hatches when it is brought into the intestine by food or drink. Two conditions are

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doubtless necessary for this hatching: the softening of the shell by intestinal juices and the activity of the embryo under the influence of heat of about 40 oC. In whichever animal supplies these conditions, the egg hatches if it remains in the intestine long enough; however, the embryo does not linger if the animal is not of the kind where the worm can (sic) acquire its final form.32

Although Davaine thought that transmission was direct, a number of authors after him believed that an intermediate host was probably necessary. Negative results with direct feeding experiments were obtained by Mosler in 1860 . Mosler first swallowed A. lumbricoides eggs himself, but a patent infection, as assessed by the subsequent administration of anthelmintics, failed to develop. He then fed mature eggs to a number of c hildren, initially in small numbers, but later gave several dozen ova to each child. No worms were ever evacuated after anthelmintic therapy, but in one or two children, fever with dyspnoea occurred a few days after administration of the eggs 85. Similarly, Leuckart in 1867 failed to achieve patent infections in dogs, rabbits, pigs and mice fed wit h embryonated eggs. Likewise, he failed to infect a horse directly with eggs of A. megalocephala (= Parascaris equorum), a dog with those of A. marginata (= Toxocara canis), and a cat with eggs of A. mystax (= Toxocara mystax = T. cati), all of these ascarids being natural parasites of these hosts. These findings convinced Leuckart that there must be intermediate hosts for this group o f parasites. In support of such an hypothesis, he noted that A. acus, which was found as an encysted larva in Leuciscus alburnus, occurred in the adult form in the pike, and that a larval Ascaris encysted in the muscles of a mole , continued to develop when administered to a buzzard. Finally, Leuckar t considered that Davaine's experiment with rats indicated that the rat was th e intermediate host, and the free larvae excreted in the rat's faeces would mature after subsequent ingestion by humans 75. Others took up similar ideas. Fo r example, von Linstow (1886), believed that a garden myriapod, Iulus guttulatus, was the vector. He suggested that these creatures ingested Ascaris eggs in human excrement deposited in the garden, the eggs then hatched and the larvae encysted in their organs. The myriapods then parasitized variou s fruits and were eaten accidentally by humans 78. On the other hand, experiments with other ascarids suggested that no intermediate host was necessary. In 1868, Unterberger showed that A. maculosa (= Heterakis maculosa = Ascaridia columbae) of the pigeon developed directly, and Henry (1873) found that A. mystax of the cat and dog were transmitted in a similar fashion. In 1879, Battista Grassi in Italy undertook an experiment in an attempt to settle the matter. On 20 July 1879, he ingested about 10 0 embryonated eggs of A. lumbricoides that had been obtained the precedin g October from the large intestine o f a cadaver and that had been cultivated since that time. On 21 August 1879 (22 days later ), he claimed to have found Ascaris eggs in his faeces, thus indicating that direct infection had occurred 51. This report must be viewed with some circumspection, however, in view of th e unusually short incubation period that he indicated. A few years later ,

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Calandruccio repeated this experiment. He swallowed a large number o f embryonated eggs but was not able to infect himself. He had more success , however, with a seven year ol d boy who had been infected naturally previously but had then been cured. At the end of September 1886, he gave 150 eggs in a pill to the lad. He found no eggs in the faeces over the next 20 days, s o abandoned the search until the end of November when he found the faeces to be full of Ascaris ova. At the beginning of January, without having had an y overt symptoms or signs of helminthiasis, the boy expelled 143 ascarids about 20cm in length. As discussed in chapter 18 concerning a similar study with the transmission of Trichuris trichiura, Grassi published the results of thi s experiment under his own name 52, without giving due acknowledgement t o Calandruccio. Similar experiments by a number of subsequent investigators confirmed the result obtained by Calandruccio. Lutz in Brazil in 1887 infected a 32 year old woman with 96 embryonated eggs over a period of one month. A few day s later, she developed a severe bronchitis accompanied by a remittent fever . When she was later given an anthelmintic, she passed 35 adult Ascaris 80. Epstein in Germany then infected three children experimentally by feedin g them with A. lumbricoides ova on 28 January 1891. Two of the three children remained in hospital and systemati c examination of their faeces for nearly three months failed to reveal any Ascaris eggs. On 24 April (86 days after infection), however, microscopical examination showed great numbers of ova in the stools of both children. The subsequent administration of santonin expelled 2 2 Ascaris from one child and 72 worms from the other. Moreover, Epstei n became infected accidentally during the course of his experiments 37. Finally, Koino infected himself successfully with A. lumbricoides in 1922 (see next section).

DISCOVERY OF MIGRATION OF LARVAE WITHIN THE HOST When the development of the larva within the egg had been discovered, attention turned eventually to studyi ng the anatomy of the newly-liberated larvae, the most important studies in this regard being done by Hallez 54,55. However, uncertainty still surrounded the nature of the events occurring betwee n ingestion of the eggs and maturation of the worms. A number of observer s including, Heller, Leuckart, Grassi, Laennec, Küchenmeister and Vix had seen immature worms. For example, Heller in Erlangen in present-day Wes t Germany, had found 18 small worms between 2.75 and 13 mm in length in the small intestine of a madman; each head had the three characteristic lips but the sexes were indeterminate 56. It seemed clear, therefore, that growth an d maturation took place within the small intestine, but the details were unclear. In order to examine an analogous system, Leuckart studied the development of A. mystax in the cat. According to Blanchard, Leuckart found larvae 0.4 mm

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long in the stomach soon after ingestion. They stayed there until they wer e 1.5-2 mm in length, then passed into the intestine. When the worms ha d reached 2.8 mm in size, they moulted, losing their perforating tooth an d acquiring the three lips that were prominent in adult parasites. Blanchar d (1890) commented that it was likely that A. lumbricoides developed in the same manner in humans 12. On the other hand, Martin found that the larvae of the ascarids of the calf, pig, horse and dog only hatched when eggs reached the small intestine, as indeed Davaine had found in rats that had been given A. lumbricoides. No further significant advances were made until Francis Stewart, an Englishman working in Hong Kong, began to exp eriment with Ascaris in pigs in 1915. First, he fed large numbers of embryonated A. suum eggs to a pig on 13 occasions between 20 September and 6 December 1915. When the animal was killed on 15 December, only one small Ascaris was found. A second pig was given large numbers of mature A. lumbricoides ova between 27 September and 2 December 1915; its faeces were examined repeatedly until 17 April 1916 , but no eggs were found. Stewart interpreted these findings as indicating tha t direct infection did not occur, so he reverted to the modes of investigation used 50 years earlier by Davaine. On 6 April 1916, he fed mature A. lumbricoides ova to four rats. Faeces passed between six and 22 hours later contained free larvae of A. lumbricoides. Thereupon, Stewart gave A. suum ova three times to three of the rats and twice to the fourth rat which then received a second dose of A. lumbricoides ova. Two days after its final infection, the last rat died. At autopsy of this animal, the lungs appeared congested and microscopica l examination revealed numerous active larvae. A few larvae were also found in the liver. The other three rats seemed to have pneumonia, so one of them was killed and abundant larvae were again found in the lungs. Histologica l examination of the lungs of these rats r evealed larvae in the alveolar spaces and in the bronchi. The third rat was killed 12 days after the last infection, but no larvae were found. In order to determine whether larvae in the lungs of a ra t were capable of further development in another host, Stewart gave portions of infected lung to a pig. He killed the animal two weeks later but failed to fin d any ascarids. Nevertheless, he advanced some possible reasons to explain this negative finding and concluded: The life history of A. lumbricoides presents an alternation of hosts....When ripe eggs reach the alimentary canal of the rat....or mouse....they hatch. The larvae liberated enter the bodies of their host, a few only escaping in the faeces. Between four and six days after infection they are found in the blood vessels of the lungs and liver . . On the sixth day, they have passed from the blood vessels into the air vesicles of the lung causing haemorrhage into them....they are (then) found....in the bronchi....On the sixteenth day the host is free from parasites....It is obvious that the transfer of the parasite from the bronchi of the rat and mouse to the intestine of man and of the pig could be readily effected. The intermediate host might readily contaminate the food of the definitive host and the dust and earth of his surroundings. 115

Stewart's paper was published in the British Medical Journal of 1 July 1916 115.

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In the issue of the following week, a laudatory letter written by Ronald Ross, the discoverer of the life cycle of malaria, appeared: Will you allow me space to offer my warmest congratulations to Captain F.H. Stewart I.M.S., upon his work on the above subject [the life history of Ascaris lumbricoides], the most important medical work which has been done for a long time past. The mode of entry of Ascaris has perplexed everyone from the beginning of parasitology, because no intermediate host could be found, or even suggested, while direct infection seemed unlikely for many reasons, in spite of the alleged result of various experiments. That rats and mice are apparently the intermediate hosts will come as a great surprise to many, and will constitute a valuable addition to medical zoology. 109

No doubt with his own experie nce in mind of when he was ordered to abandon his malaria research at a critical stage in favour of studies on kala azar, Ross added: His paper is also another proof of the common observation that important discoveries must wait until the proper kind of worker comes along to tackle them. I hope sincerely that, in spite of the war, every facility will be given to Captain Stewart to complete his invaluable work.109

In fact, this was the first of a series of fragmented, confusing and contradictory reports which were spread over the next five years. Stewart at first placed an emphasis on his observation exactly the opposite to the correct state of affairs. However, an editorial in the British Medical Journal discussing Stewart's first paper made no reference to his theory that rats and mice were intermediat e hosts in the life cycle of A. lumbricoides and, no doubt with the experiments of Calandruccio and others in mind, suggested instead that the complete cycle of migration through the lungs and d evelopment within the one host might occur 5. There was, of course, precedent for this idea, for Looss had demonstrated ten years earlier a similar sequence of events in ancylostomiasis (see chapter 20). Nevertheless, Stewart was so upset that he wrote complaining that insufficient weight had been given to his experiments on pigs in which he failed to induce direct infection and he rejected as untenable the idea that Ascaris passes through the lungs of the same host as that in which it attains full maturity 116. It must be said in Stewart's defence, however, t hat these experiments were carried out under extremely difficult conditions during wartime. He himself was well aware of the deficiencies for he wrote in a footnote to one paper: The author regrets that he is obliged to publish incomplete work and pleads in excuse that he has been obliged to discontinue the research, not knowing when he will have an opportunity of resuming it.121

Although Stewart made a major contribution in discovering the systemi c migration of Ascaris larvae, subsequent events were to show that he was quite wrong in ascribing transmission to an intermediate host. In fact, he did not give up the idea of an intermediary role for rod ents for some time. He postulated that larvae might escape from the rodents in their saliva, and showed that larva e obtained from the lungs could survive for up to 24 hours on damp bread 117. He then repeated his attempts to transfer A. lumbricoides larvae to pigs; he fed infected rat and mouse lung to four pigs and recovered small numbers (1-15)

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of ascarids in three of them and no worms in the fourth pig. Although Stewart wrote that these experiments could hardly be considered very satisfactory, the fact that two control pigs had no worms, enabled him to cling to the belief: The experiments which have been conducted so far tend to prove that the larvae from the lungs of rodents can infect the pig, and it is probable that in nature infection in man and the pig takes place by food contaminated by rats and mice. 117

More enduring, however, were his studies of the migration of worms in mice. Stewart believed that A. lumbricoides larvae hatched when the eggs wer e ingested then either bored their way into the venules of the portal system o r ascended the bile duct. He found larvae in dilated hepatic capillaries between two and five days after infection following which they escaped through th e hepatic veins to the lungs where they were filtered out in the pulmonar y capillaries. They then passed together with effused blood into the alveola r spaces on the sixth day and the worms ascended the bronchial tree and reached the mouth by the eighth day117,119. Stewart found later, however, that the larvae in the mouth were swallowed subsequently and passed through the intestines to be excreted in the faeces 118,120. In 1917, Ransom and Foster in the United States repeated many of Stewart's experiments. They confirmed the systemic migration of A. suum larvae in rats and mice. They also attempted to infect pigs, and although they failed t o achieve patent infections, suggested, on very tenuous grounds, that this ma y have been due to the age of the animals rather than indicating that an inter mediate host was required 101. Nevertheless, Sadao Yoshida reported in 1918 that it was possible for infection to be acquired from larvae obtained from an intermediate host. He swallowed A. lumbricoides larvae taken from the lungs of a guinea pig, but at first had a negative result. He then ingested 50 large r larvae (1.65 mm long) recovered from the trachea of a guinea pig and foun d eggs in his faeces 75 days later 141. Meanwhile, because of repeated suggestions that no intermediate host was necessary and that migration and maturation occurred within the same host , Stewart undertook further experiments with A. suum infections in pigs. He showed that, in this host too, larvae migrated through the lungs with the pigs suffering from Ascaris pneumonia. However, he failed to find convincin g evidence of adult worms in the gut three to four weeks later and considered (in 1918) that while the matter was not yet fully resolved: "the evidence of these six experiments is opposed to the hypothesis of direct development without an intermediate host"121. Even so, he continued to be plagued with uncertainty. In 1919, Stewart reported the results of infecting two four-day-old pigs wit h 22,000 A. suum eggs. Large numbers of ascarids were seen in the intestines of one pig two weeks later, but none at all could be found in the other pig killed after another five days. A third pig, two months old, was given 50,000 eggs , and when killed 31 days later; no worms could be found. Stewart wrote with masterly understatement: "these experiments are very puzzling" 122. Later in that same year (1919), Ransom and Fos ter announced that A. lumbri-

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coides larvae migrated systemically in g uinea pigs and rabbits as they do in rats and mice. They also infected a goat twice with A. suum eggs. It died ten days later and numerous larvae, 1-2 mm long, were found in the lungs, trachea , oesophagus and stomach, and thousands of young ascarids, 10 mm in length, were seen in the small intestine. A lamb had also been fed with ova and killed 103 days later; 50 immature ascarids, 6-13 cm long, were recovered from the bowel. These results reinforced Ra nsom and Foster in their belief that infection was direct 102. Stewart later (1920) came round to this view when he found young worms in the small intestine of three pigs fed with A. suum eggs124, for he wrote in 1920: "It is extremely probable that the worm can undergo full development in one host alone - that is, man or the pig" 123. Final proof that this was indeed the case was provided by Shimesu Koin o (pen name Sui) in 1922. On 28 August, he ing ested 2,000 A. lumbricoides ova. A single larva was found in his sputum three days after infection, five on th e next day, and 178 on the fifth day. He was unable to collect any sputum on the succeeding two days because he was seriously ill but larvae were then found again for the next four days. Fifty days after ingestion of eggs, he took a n anthelmintic and recovered 667 immature A. lumbricoides. Thus, Koino proved that A. lumbricoides larvae both migrate through the lungs and develop within the intestine of the same human host 68. While it was now clear that systemic migrati on occurred and that worms matured in the one host, uncertainty remained about the precise route by whic h larvae reached the lungs after hatching in the gut. Yoshida (1918) claimed on the basis of his experiments that Ascaris larvae bored their way through th e intestinal wall into the peritoneal cavity, pierced the diaphragm, entered th e pleural space, then finally penetrated into the lungs from the surface, as ha d been shown with Paragonimus 142. This view was refuted by a number o f investigators who showed that larvae passed via the portal vein to the liver , then by the hepatic veins and inferior vena cava through the right heart to the pulmonary vasculature, or via the mesenteric lymphatics and the thoracic duct to the venous system, and that larvae in the viscera reached those location s 7 through the systemic circulation 7,40,86,87,100, although one of the authors considered that some larvae might also reach the liver via the peritoneal cavity. In addition, Ohba in 1925 showed that larvae could be excreted in the urin e during the migratory stage, with t he maximum output occurring five to six days after infection 88. In 1927, Fülleborn41 put all the known facts together and postulated that the reason why A. lumbricoides larvae could not settle in the gut initially wa s because this species may have originally re quired an intermediate host, as is the case with certain fish ascarids, and that later, the definitive host became th e intermediate host as well. Since Kondo 69 had shown under experimenta l conditions that artificially-liberated Ascaris larvae smeared on the ski n

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penetrated the integument then underwent migration, Fülleborn believed that in order for maturation to occur, larvae must first penetrate either the skin or gut wall, then pass to the lungs where they would be returned by the ciliate d epithelium to the oesophagus. Thus, it seemed that the definitive host could be infected not only by larvae which had penetrated its own intestine (the usua l case), but also (unusually) by eating an animal which contained larvae which had passed through that animal's lungs (as shown by the experiment o f Yoshida), or when such larvae penetrated the skin (as shown by Kondo' s experiment). Controversy has also surrounded the nature and timing of the moulting o f Ascaris larvae. In 1924, Asada reporte d that, shortly after hatching, the Ascaris larva moulted in the small intestine. He though t that a second ecdysis took place while the worms were in the airways, then two further moults occurred o n return of the worms to the intestine 8. In 1918, however, Yoshida ha d recognized that the first moult took place while the larvae was still within the egg shell141. For many years, it was accepted that the infective stage whic h emerged from the egg was a second stage larva. In 1968, Thust reported that the larva moulted twice while within the egg shell 131, although Maung believed that the second ecdysis might be completed during early migration 82. Recent studies in experimental animals have shown that the third moult occurs when the larva lies within the intestinal mucosa and is about 2 mm long. The worms then live free in the intestinal lumen and have a final moult three to four weeks after infection with egg production beginning eight to twelve weeks afte r infection. The adult worms live for between one and two years. Keller in 1931 showed that in a group of patients living in an are a unsuitable for transmission, and who did not receive treatment, the infections were eliminated spontaneously over a period of fifteen months 66. Similar observations on Japanese prisoner s suggested that the worms survived for an average of seventeen months (range 10-24) 58. Whether or not resistance to reinfection occurs is controversial though th e weight of evidence suggests that i t does not. Jung 64 believed that superinfection does not occur when eggs are newly ingested during the tenure of a curren t infection, but there have been litte data since to support or refute this view . Certainly, reinfection seems to occur easily following eradication of a prio r infection with anthelmintics. Otto and Cort in 1934 showed that reinfection was rapid, widespread and intensive after treatment of nearly 300 children wit h hexylresorcinol; eight months after treatment, 85% of the children wer e reinfected, and the mean number of Ascaris eggs per gram of faeces wa s 33,000 c.f. 23,000 before therapy 91. Similarly, a Japanese study showe d showed that reinfection appeared approximately two months after treatment 93, while another investigation in the Philippines indicated that 69% of childre n were reinfected after four months and 90% were infected eight and a hal f

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months after treatment 44.

RECOGNITION OF THE CLINICAL FEATURES The number of complaints that have been ascribed to Ascaris infection over the centuries is legion. Spontaneous passage of the worms was well-known an d Hippocrates wrote that this may be preceded by abdominal pain 57. Caelius Aurelianus (c.450 AD) believed that these worms may cause the gnashing of teeth by sleeping children, and that when large numbers were present, th e abdomen became hardened 10. Paulus Aegineta of Alexandria (c.640 AD) described in detail what he considered to be the clinical manifestations o f ascariasis: Those who have roundworms experience pain of the intestines and stomach, small dry tickling cough, and in some cases hiccough, sleep with palpitations and irregular startings; and some start from their sleep with a scream, and again fall over asleep. The pulse is unequal and the fever has irregular exacerbations, making its attacks with coldness of the joints, and coming on three and sometimes four times in the day or night. Children have mastication and projection of the tongue....and grinding of the teeth; they shut their eyes and wish to remain silent and are offended when disturbed. Their eyes appear bloody, their cheeks red, and again change to pale. But these things occur at intervals in a short time. Sometimes the worms crawling up to the stomach occasion nausea, gnawing pain, and anorexia....When forced to take food, they can scarcely swallow for nausea, or they vomit what they have taken, or their bowels are loose with corruption of the food, or are inflated like a bladder, but the rest of the body is wasted....But one must not expect to find all these symptoms in all cases, but certain ones, according to prevailing circumstances.1

According to Hoeppli, the Chinese physicians of around the third century AD considered that ascariasis altered the character of the pulse in various ways: A pulse felt at the upper Kuan portion to be under light tension and sliding in quality indicates that ascaris becomes active....A pulse felt....to be floating in quality indicates that the patient has stagnant heat in his stomach and will vomit ascaris. 59

Again, Hoeppli cites the following exchange: "What is the distinguishing feature of the pulse in a case of abdominal pain caused by worms?" somebody asked. The physician replied: "During the ordinary abdominal pain the pulse becomes feeble and thready. If, on the contrary, it is full and bounding, it indicates the sure presence of ascaris in the abdomen." 59

Such views changed little over the centuries. As late as 1829, the Englis h surgeon, William Rhind, gave a comprehensive and remarkable account of the symptoms and signs that were then believed to attend the presence of intestinal worms (both roundworms and tapeworms): The most general symptoms observable in those affected with worms are the following: - The appearance of the countenance is changed, it is generally very pale or of a leaden colour, with a red, circumscribed spot in one or both cheeks. The eyes lose their brilliance, the pupil is enlarged, and a blue rim is perceivable round the under eyelid. The nose is swelled and very generally the upper lip is somewhat

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tumified, and there is continual itching and irritation of both these. Sometimes, too, there is a bleeding from the nose. There is also headache, throbbing in the ears, a foul tongue, more saliva than natural in the mouth and the breath is very fetid especially early in the morning. The appetite is variable; sometimes it is quite gone and at other times it is voracious with a continual gnawing sensation in the stomach. There is also nausea and a desire to vomit; when this takes place, the fluid ejected is limpid like water. There are often violent gripings, and these are principally felt around the umbilical region. The urine is turbid and after it has deposited a sediment, it has the appearance of milk and water. The belly too is hard, and feels like a drum. There is a general emaciation of the body; the sleep is troubled and accompanied by grinding of teeth. The patient is generally lazy and indolent, sometimes in good and sometimes in irritable temper. Blindness, deafness, delirium, and even apopleptic and epileptic fits have been known to have their origin from these worms. The last and most decisive symptom observed is that in the matter vomited, but more generally in the alvine secretions, entire worms or portions of them are perceived. 107

Rhind did, however, add some caveats: It must be remarked that all the above symptoms are not always found in the same individual; nor do any of them, except the last, exclusively indicate the presence of worms. When these symptoms occur and cannot be attributed to any other cause, the strong presumption is that the cause is worms....At the same time, it may be mentioned that worms sometimes exist, and that in considerable quantities, without causing any inconvenience or bad symptom whatsoever. 107

The observation that worms may cause no i ll-effects had even led some observers such as Avicenna, Roeder er and Abildgaard to suggest that worms may not only be harmless, but may be very useful in the alimentary canal by consuming excessive nutrients and stimulating bowel movements. Rhind thought that this was fanciful and deprecated such ideas, saying: like all other diseases and all other evils which are incident to man, they are to be combated and warded off by the wisdom and foresight with which he is endowed for that purpose.107

In contrast to all-encompassing views of the symptomatology of Ascaris infection, such as espoused by Rhind, Küchenmeister was closer to the trut h when he wrote baldly in 1855: "as a general rule, the host and his guests agree very well together and give one another very little mutual trouble" 70. Küchenmeister did recognize, however, that these parasites could occasionally cause intestinal obstruction or rarely produce jaundice, pancreatitis or layryngea l spasm, and had been known to wander through intestinal fistulae. Even so, a wide range of clinic al manifestations of Ascaris infection was still accepted by many practitioners, and w as explained on the basis of two different mechanisms33. Firstly, gastrointestinal symptoms and signs were clearly local reactions consequent upon the presence of worms in the alimentary system. It was recognized that roundworms were u sually located in the small intestine but occasionally they were met with in the biliary system, mouth and pharynx, or respiratory system. Secondly, "ref lex irritation" or "sympathetic excitation" was held to account for the diverse non-gastrointestinal symptoms commonl y blamed upon intestinal helminthiasis. This vague concept seemed to man y

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observers to be the only reasonable explanation for the coincidence betwee n expulsion of intestinal helminths and resolution of the symptoms. Date in 1872 summed up the attitudes prevailing at the time: It has been the fashion of recent writers....to assert that worms, of themselves, never give rise to symptoms of any kind. This view, no doubt, is a reaction from the old notion which attributed to intestinal worms all sorts of extraordinary phenomena. The truth....seems to lie between the two extremes. I have repeatedly seen cases in which the expulsion of the worm has been followed by a relief of urgent symptoms so immediate and marked as to convince me that the worm itself was the cause of the mischief. . On the other hand, it cannot be denied that worms may and often do exist in the intestinal canal, even of delicate children, without giving rise to any special symptoms. It may be that reflex irritation is induced only in children of very excitable temperament, or in certain peculiar states either of the general nervous system or of the intestinal mucous membrane. Certainly the gravity of the symptoms does not appear to depend upon the number of worms, except in those rare cases where they have multiplied to such a degree as to cause obstruction of the bowel. 29

Debate continued until the turn of that century over the validity of the refle x irritation theory, but it gradually fell by the wayside. For example, it becam e accepted slowly that the passage of rou ndworms during an epileptic fit or in the course of a febrile episode was the consequence of an inhospitable milie u rather than the cause of those disturbances. The discovery by Stewart in the early twentieth century of the pulmonar y migration of Ascaris larvae caused a number of observers to look back in the literature and see evidence of pulmonary ascariasis in the patients of Mosler 85 and Lutz80 who developed respiratory symptoms shortly after the experimental ingestion of A. lumbricoides ova. This was confirmed in a dramatic fashion in 1922 by Koino, who recovered larvae from his sputum and described hi s symptoms and signs after ingestion of 2,000 such eggs: On the sixth day....there was fever followed by chills, headache was severe and respiration and pulse were increased. The face was flushed and I was thirsty. There was a heavy feeling over the chest....The temperature on the second day after the onset rose up to 39.8 and remained between 38.7 and 40.2. It began to come down by crisis on the seventh day and on the ninth day was normal. Respiration increased and became shallow. On the fifth and sixth days there was severe respiratory difficulty and the face was cyanotic. The number of respirations was from 56 to 58 per minute. From the seventh day on the number of respirations decreased....The cough increased with the rise of temperature....It came in paroxysms with intervals of two to five minutes at the height of the attacks....The amount of sputum increased with the increase of coughs. There was 35 cc. of sputum on the first day. On the fifth day up to 7 p.m. it was 155 cc. There was a large amount of output for the following few days. A noticeable thing was that sputum of the fifth and sixth day contained well-mixed blood. The eighth day on it decreased.... Appetite....was lost....There was severe lumbago on the third and fourth day and pains in the gastrocnemius muscles....As to the objective symptoms....the rales [moist sounds heard on auscultation of the lungs] and dullness increased day after day until breathing became difficult and weak. But when the crisis had begun, the rales and dullness gradually decreased....The liver....was enlarged to two finger's breadth below the costal margin

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on the right mammary line....On the twelfth day it was scarcely palpable. . The spleen was not palpable.68

This clinical picture was re-described in 1932 by Löffler who, in addition to recounting the clinical features noted by Koino, showed that transien t pulmonary opacities were present in chest radiographs and that there was an associated eosinophilia in the peripheral blood 79. Although Löffler's syndrome was caused commonly by migrating Ascaris larvae, it was recognized tha t migrating hookworm and Strongyloides larvae, as well as other agents, could also cause the syndrome. Similar effects were noted ten years later by Voge l and Minning in Germany who gave Ascaris ova to six volunteers 136, and then by Brudastov and colleagues in Russia who undertook experimental self infections16. In 1967, Gelpi and Mustafa found that outbreaks of acute respirator y infection recurring each spring among young local employees of an oi l company in Saudi Arabia were due to infection with A. lumbricoides; larvae were found in the sputum then eggs were recovered from the faeces two t o three months later 46. It was then realized that this presentation was mos t common in areas where transmission was seasonal, for Spillman 113 showed that pulmonary ascariasis was rare in areas where transmission was continuou s throughout the year. Because populations rarely have solitary A. lumbricoides infections, there have been few studies of the clinical manif estations of pure intestinal ascariasis, and it is probable that Küchenmeister's summation of the situation may years ago was fairly accurate. Nevertheless, small numbers of worms in ectopi c locations can cause significant and sometimes fatal disease. There have been hundreds of such reports in the literature of the twentieth century alone, bu t they represent a very small fraction of the total number of infected persons . Ascarides have on occasion caused obstructive jaundice, liver abscess , pancreatitis, appendicitis and respiratory obstruction, and have migrate d through intestinal perforations and fistulae, and out through the mouth and the nose. Of all the various complications, however, intestinal obstruction is th e most frequent. In a series of 202 cases who had either solitary ascariasis or light infections with Trichuris trichiura as well, Swartzwelder in New Orleans , USA, found in an uncontrolled and selected study that abdominal discomfort was the chief symptom, fever was quite often present, and that intestina l obstruction occurred in 18 patients 125. Although most individuals have only one or two worms, rare patients have vast numbers. An adult patient in Peiping, China presented with a perforated intestine; even though 1533 worms were removed from the peritoneal cavity at operation, he died subsequently and a further 445 worms were recovered at autopsy, bringing the total number to 1978 ascarids 60. Similarly, 1488 worms were removed from a patient in Malaysia110, 990 were recovered from a nine year old European girl and 899 from an eleven year old Hottentot in Sout h Africa76, and 693 worms were obtained from a two year old child with intestinal

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obstruction in East Africa 47. Argument over the contribution of ascariasis to malnutrition has raged fo r decades 112, but perhaps the first person to pay any serious attention to thi s subject was an English ship's surgeon, Percy Rendall, in 1892. He was i n charge of 557 Indian coolie emigrants on a voyage from Calcutta to Demerara. He weighed every person then administered santo nin to everyone and recovered 989 roundworms, but thought that many more had gone over the side of th e ship. He weighed his patients again two months later and found that there was a net increase of 2240 pounds in their weight and considered that: this result, though doubtless due to the generous dietary provided by the Colonial Governments in some part, may I think, be not unfairly attributed to the fact that this large number of roundworms had been expelled which would otherwise have caused grave interference with the digestive functions and prevented the due assimilation of food products.106

DEVELOPMENT OF DIAGNOSTIC METHODS A diagnosis of Ascaris infection has been made from time to time when adult worms are expelled spontaneously, usually in the faeces. The diagnosis i s normally made, however, by finding Ascaris eggs in the stools. Such ova i n faeces were first illustrated clea rly by Swayne in 1849, although he had no idea of their true nature, believing them possibly to be involved in the causation of cholera 126. Indeed, the Rev Mr Berkeley, in discussing the nature of thes e bodies, went so far as to remark that: "w e still remain to discover what they are, as it should seem that no ova of entozoa are known which can be reconcile d with them"11. In 1854, Wedl described the histological examination of a n intestinal concretion removed from an ingu inal abscess by H Ulrich. In addition to T. trichiura eggs which Wedl illustrated clearly, other bodies were present which he noted: "most nearly rese mbled those of Ascaris lumbricoides"137. The eye of faith is required, however, to recognize such an egg in the figure h e provided. The diagnosis of ascariasis by microscopical examination of th e faeces was first put on a sound basis in 1856 by the English physician, W H Ransom. Ransom described the case of a 12 year old girl who presented at the Nottingham General Hospital complaining of abdominal pain and giving a history of having passed two round worms after the administration of a n aperient. Examination of her stools revealed "very numerous ova of ascari s lumbricoides, the characters of which are well known and easil y recognisable"103. and Ransom provided clearcut illustrations of Ascaris ova. It is perhaps most remarkable that only seven years after an argument had raged in the columns of The Lancet and the London Medical Gazette, and the College of Physicians had been disposed to produce a report on the nature of thes e so-called "cholera bodies", that Ransom was able to write so facilely that the morphological characteristics of these eggs were well-known and were easily

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recognizable. In the following year, Davaine in France likewise demonstrated Ascaris eggs in the faeces of a child who ex pelled subsequently five or six adult worms30. The diagnosis of ascariasis turned out to be extremely easy, for it was found that female worms produced vast numbers of eggs. Brown and Cort calculated that approximately 200,000 ova were excreted in the faeces by each femal e worm every day15. This technique had been put to use to make retrospectiv e diagnoses of ancient Ascaris infections. For example, eggs have been found in human coproliths, dated 800-300 BC, recovered from a prehistoric salt mine in Austria9, and from the intestinal contents of a girl's body (600 BC) recovered from a peat bog in East Prussia 127. While most eggs are characteristic, variations occur and mistakes have been made in diagnosis. In 1922, Miura and Nishiuchi drew attention to the appearance of the not uncommon unfertilized eggs 83. Vegetable matter has bee n mistaken for Ascaris ova, perhaps the most famous example being the erroneous report by Tullis that 90% of asthmatics who lived in a non-endemic area in Canada had ascariasis 67,132. These roundworms are so large that they may be seen radiologically, particularly with contrast radiography. In 1922, Fr itz reported that X-ray examination had revealed ascarids wandering from the duodenum into the stomach 39. In the following year, Reiter described one patient in whom numerous roundworms were seen in the jejunum and ileum, and another in whom an Ascaris was seen lying coiled in the stomach 105. In 1924, Schinz reported that X-ray examination of a 40 year old woman after a bismuth meal revealed a "worm-like absence of shadow"111 and that roundworms were passed after anthelmintic therapy 111. Pulmonary ascariasis may be diagnosed by finding larvae in the sputum a s was shown by Koino 68. Many years later, Proffit and Walton indicated tha t ascariasis may also be diagnosed during the migratory phase by finding larvae in gastric aspirates 99. The immunological diagnosis of ascariasis has not proved to be particularly useful. Ghedini in 1907 described complement fixing antibodies in the serum of patients with Ascaris infection48, while skin reactivity in such patients was described by Brunner 18, and by Coventry and Taliaferro 27,

THE SEARCH FOR EFFECTIVE TREATMENT Over the centuries, a large number of agents has been used for the treatment of ascariasis. These comprised two major grou ps of compounds: purgatives which expelled worms by increasing peristalsis and stimulating intestinal secretion, and vermifuges, including substances of vegetable, animal or mineral origin, which poisoned the worms themse lves. Concerning purgatives, Elliotson in his lecture on worms in 1833 wrote that:

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As to getting rid of worms, in the first place, any brisk purgative may answer the purpose. A good dose of calomel and jalap is an old remedy and a very excellent one....(or) twelve grains of calomel and half a drachm of rhubarb. 36

With respect to destruction of roundworms, Elliotson advised that oil o f turpentine was one of the best remedies available: (it) should be given by the mouth and the dose then is from half an ounce to three ounces. It is best not to give it fast lest it should create sickness and be lost....The effect it generally produces is that of making the patient sick, purging him violently....and causing extreme vertigo.36

As the century progressed, this drug was replaced gradually in popularity by santonin, the active principle of semen-contra-vermes, so-called because of its vermifugal properties and its fanci ed resemblance to semen. The drug was prepared from the dried, unexpanded flower heads of the genus Artemisia, especially A. cina which is common in the Midd le East. Thus, Anderson (1864) wrote: The introduction of 'santoninum' into the British Pharmacopoeia was no more than was expected by those practitioners who have for several years been convinced of its efficiency, and especially of its superiority to all known anthelmintics in the treatment of roundworm.4

Because of its toxicity and non-uniformity in its therapeutic effectiveness , however, santonin fell into disuse as better drugs became available. Thes e agents included oil of chenopodium and its active principle, ascaridole , prepared from Chenopodium ambrosioides var. anthelminthicum, common in the United States of America, and thymol found in a large number of plants of the genera Thymus (thyme), Origanum and Carum (ajowa). Thus, Vervoort in 1913 compared oil of chenopodium, thymol, Eucalyptus oil and sundry other anthelmintics, and concluded that wormseed oil (oil of chenopodium) was a good anthelmintic in ascariasis, rather more expensive than thymol, bu t possessing the advantage of being able to be given in capsules 135. Another product active agains t Ascaris was helminal, a dried extract of a red alga, Digenea simplex 35, which had long been used as a popular vermifuge in Japan, the active principle of which was kainic acid. The anti- Ascaris properties of the alkylated phenol, hexylresorcinol, were first studied b y Lamson and colleagues in 1931 71 and this drug became popular for the treatment of ascariasis in the United States. Betanaphthol and carbon tetrachloride also enjoyed transient popularity with some practitioners. Following the use of piperazine in enterobiasis (see chapter 17), F ayard in a thesis presented in Paris in 1949 gave an account of its efficacy in some 2,000 patients with ascariasis; 70-95% of people passed roundworms on the second and third day afte r treatment, but stool examinations in order to assess the percentage of cures and the reductions in egg excretion were apparently not performed 38. The efficacy of the drug in its various forms was confirmed in many published studies , beginning in 1954 with those of Brown 14 and Brumpt and Ho-Thi-Sang17 . Meanwhile, the piperazine derivative, diethylcarbamazine, was shown b y

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Oliver-Gonzalez and colleagues in 1949 also to be effective 89. Bephenium hydroxynaphthoate, one of a new series of drugs first described in 1958, was shown in the same year by G oodwin and his colleagues during the course of a pilot study of its effectiveness against hookworm, to be active i n ascariasis50. In a follow-up study using varying doses of the drug, Jayewardene and her colleagues found that approximately 90% of patients had at least a n 80% reduction in eggs counts in the faeces 63. In 1962, Bui-Quoc-Hong an d co-workers reported that the benzimidazole compound, thiabendazole (se e chapter 21), cured 80% of patients with ascariasis 19. Nine years later, it was shown by several groups of investigators that the related compound , mebendazole (see chapter 3), was highly active against Ascaris lumbricoides 24. In 1966, Do Nascimento and colleagues indicated that a new compound , tetramisole, eliminated Ascaris infection in 80-90% of patients 34. Several years later, it was shown that the laevo-isomer of tetramisole, levamisole, was even more active than the racemate 130. Another new series of anthelmintics, the pyrante l compounds, was discovered in 1966. In 1970, pyrantel pamoate was found to be useful in the treatment of ascariasis by Amato Neto and colleagues 2. While the administration of anthelmintics is the almost universal method of treating ascariasis, one physical measure which enjoyed some transien t popularity in the Soviet Union must be mentioned. One to two litres of oxygen were given intermittently over ten minutes through a duodenal tube, then a magnesium sulphate aperient was given two hours later. Dead ascarids were then usually passed two to three days afterwards, and Talyzin (1954) wrote : "The above method is so simple and safe that it has often been used fo r outpatients, and large groups of people can be disinfested quickly" 129. Finally, surgery has been used for most of this century to treat certai n complications of ascariasis, such as intestinal and biliary obstruction b y roundworms.

UNDERSTANDING THE EPIDEMIOLOGY Comprehension of the factors controlling the distribution and prevalence o f ascariasis dawned only slowly over t he seventy years between the studies in the middle of the nineteenth century by Gros, Davaine and others on the development of the egg, and the general acceptance at the end of World War I tha t transmission was direct. Considerable uncertainty surrounded the roles of pigs and the pig ascarid in the epidemiology of human ascariasis for some time (see Ascaris suum). It transpired eventually that although pigs may be susceptible to infection with A. lumbricoides, and despite the experimental infection o f various subhuman primates with A. lumbricoides 90, humans are the most

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important host of A. lumbricoides and the major determinant of th e epidemiology of this infection. A number of investigators demonstrated that larval development within the egg occurred at a faster rate in warmer temperatures, and that moist, shad y locations facilitated such development 13,101. It was shown that maximu m transmission took place when the soil was composed of clay or fine silt, fo r these materials provided a light covering to Ascaris eggs after rains, thus protecting them from dessication but leaving them near the surface where they were more likely to be ingested. Furthermore, the ova were found to b e relatively resistant to low temperatures, dessication, various chemicals an d putrefaction28,141. Under certain conditions, they may remain dormant for years, thus permitting reactivation of infection upon the return of favourabl e environmental circumstances. Consequently, it was apparent that transmission was dependent upon frequent contamination of the soil with faeces, favourable climatic and soil factors, and ingestion of contaminated eggs in various vehicles 92,138,139. The precise nature and importance of these various determinants was found to vary from region to region. In some areas, promiscuous defaecation by small children was the main source of contamination138, while in other areas, the use of human night soil as a fertilizer in vegetable gardens was a major factor 140. In his review of the modes of infection, Lane (1934) indicated that the most common means o f transmission were consumption of eggs adhering to vegetables or other food, the drinking of contaminated water, and ingestion of infected soil by children. Of possible but unproven significance were inhalation of airborne eggs an d percutaneous infection by liberated larvae 72. Under adverse conditions , breakdown of sanitary measures may result in an increased incidence o f ascariasis, such as occurred in Germany after World War II, probably as a result of eating vegetables and ground-fruit on land irrigated with untreate d waste water 45.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Many years ago, Chandler wrote that A. lumbricoides has been one of Man's most faithful and constant companions from time immemorial, and has clung to mankind through the stone, copper and iron ages up to the present day. He went on to predict that modern plumbing would eventually dissolve th e partnership25. The financial, technical, and educational difficulties in providing effective waste disposal systems in most endemic areas, however, ar e enormous, and the words Lane wrote fifty years ago are just as apposite today: Sewered privies cleanly kept are sure safeguards for the user. But to devise privies of demonstrable effectiveness and inoffensiveness, to provide them for millions of people of poor means, and to alter the habits of these so that they religiously use and clean them, is a task which will not be completed within the lifetime of any of us. 72

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The problem is compounded in communities were human nightsoil is used as a fertilizer. The difficulties in such a situation are almost insuperable fo r composting and the fashioning of faecal "bricks" 62 are ineffective in destroying the parasites. Under such circumstances, reliance must be placed upon thor ough cooking of the vegetables, but this is of little relevance in the case o f vegetables such as lettuces and ground-fruits such as strawberries which ar e eaten raw. Mass treatment has been tried on a limited scale in selected localities, bu t administration of anthelmintics has to be repeated frequently because of th e persistence of viable ova in the environment. Such measures reduced th e prevalence of ascariasis from 60% to 1.9% in one area of Japan over a period 20 years84, and similar results were obtained in another study in the Philip pines20. Unfortunately, such measures remain beyond the financial resources of many countries that host endemic ascariasis.

OTHER SPECIES OF ASCARIS A. SUUM This parasite was so named by Goeze in 1782 49, but has also been referred to frequently in the older literature as A. suilla, a designation given by Dujardin in 1845. Confusion has reigned for many years as to the relationship between A. lumbricoides and A. suum. Various investigators could not discern an y morphological differences between the two form s until Sprent (1952) described alterations in the labial denticles 114. While many workers have confirmed and extended Sprent's observations, others have found them to be inconsistent, and sometimes individual worms could not be differentiated reliably from on e another. Similarly, differences of opinion have occurred over chromosoma l numbers and biochemical and immunological characteristics. The sam e problem has bedevilled using physiological differences in the infectivity o f roundworms derived from humans or pigs for the opposite host as a distinguishing feature. In 1925, Payne and her colleagues infected five young pigs with embryonated Ascaris eggs of human origin; all anima ls suffered respiratory disturbances, but no adult worms were recovered from the gut 96. On the other hand, Galvi n (1968) infected successfully pigs with A. lumbricoides ova, but the percentage of ova which matured and the duration of infection were reduced when compared with pigs infected with A. suum 43. Koino in 1922 gave 500 A. suum ova to his brother and produced a severe respiratory disease. He failed to find Ascaris larvae in the sputum or evidence of intestinal infection, and contrasted t his with the results of infection of himself with A. lumbricoides:

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The pig Ascaris can not parasitise till adult worms in human. Therefore although morphologically they are the same, they are entirely different. If there is a strain of pig Ascaris which can parasitise in human, it must be a deviated strain. Human body is not a good host for pig Ascaris.68

Similarly, Payne and her colleagues gav e A. suum ova to two human volunteers but failed to produce patent infections 96. On the other hand, Takata claimed to infect successfully 7 of 17 human volunteers who swallowed 2-25 A. suum eggs, but the prepatent period in many of th em was extraordinarily short (25-29 days)128. Lýsek recovered mature worms from the gastrointestinal tract afte r administering A. suum eggs to himself 81. Finally, four students in Montreal , Canada, swallowed unknowingly large numbers of eggs in food which had been contaminated maliciously. They all developed severe respiratory infections. In two of them, immature worms were passed in the stools four months afte r ingestion of eggs, but no worms were recovered following anthelmintic therapy seven months after ingestion 97. Epidemiological evidence suggests that ther e is not much cross-over between porcine and human ascarids. For example, Caldwell and Caldwell reported in 1926 that 45% of pigs in one region were infected with Ascaris c.f. only 1% of humans, despite apparently fa vourable conditions for infection of humans from that source22. Similar observations have been made since in other parts of the world. Thus, although the contribution of A. suum to human ascariasis cannot b e determined precisely, it would seem that A. suum is a possible, though not a major cause of this condition.

REFERENCES 1. AEGINETA P. De re medica. The seven books of Paulus Aegineta, translated by F Adams, The Sydenham Society, London, three volumes, 1844-1847 2. AMATO NETO V, LEVI GC, CAMPOS LL. Observaçoes sobre a atividad e anti-helmintica do pamoato de pirantel. I. Tratamento da ascaridiase. Revista do Instituto de Medicina Tropical de São Paulo 12: 207-210, 1970 3. AMATUS LUSITANIUS. Medici physici praestantissimi. Curationum medicinaliu m centuria quatuor etc, B Constantinus, Venetiis, pp 645, 1557 4. ANDERSON W. On santonine: with especial reference to its use in the round an d thread-worm. British Medical Journal i: 443-445, 1864 5. ANONYMOUS. The life history of Ascaris lumbricoides . British Medical Journal ii: 23, 1916 6. ARISTOTLE. Opera omnia, graece et latine, cum indice nominum et rerum absolutissimo, F Dübner, E Heitz et UC Bussemaker (Editors), Didot, Parisiis, five volumes, 1848-1874 7. ASADA J. (Experimentelle Unt ersuchung ueber die Entwicklung und Infektionswege von Ascaris lumbricoides.) Tokyo Iji Shinshi pp 161-168, 218-223, 1921. In Japanese . Abstracted in Tropical Diseases Bulletin 21: 568-569, 1924 8. ASADA J. (On the development of ascarid larvae in the body of the host. Especially on the desquamation of the ascarid larvae and the nourishing substances for the ascari d larvae.) Tokyo Iji Shinshi No 2366, pp 812-815, 1924. In Japanese. Astracted in Japan Medical World 4: 179, 1924

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9. ASPÖCK H, FLAMM H, PICHER O. Darmparasiten in menschlichen Exkrementen aus prähistorischen Salzbergwerken der Hallstatt-Kultur. Zentralblatt für Bakteriologie , Abteilung Originale 223: 549-558, 1973 10. AURELIANUS C. On acute and on chron ic diseases, translated by IE Drabkin, University of Chicago Press, Chicago, pp 1019, 1950 11. BERKELEY MJ. On the larger cell s observed in cholera evacuations by JG Swayne Esq., M.D., Dr. Budd, and others. London Medical Gazette 44: 1035-1037, 1849 12. BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes pp 1691, 1885-1890 13. BROWN HW. A quantitative study of the influence of oxygen and temperature on th e embryonic development of the eggs of the pig ascarid ( Ascaris suum Goeze). Journal of Parasitology 14: 141-160, 1928 14. BROWN HW. The treatment of Ascaris lumbricoides infections with piperazine. Journal of Pediatrics 45: 419-424, 1954 15. BROWN HW, CORT WW. The egg production of Ascaris lumbricoides . Journal of Parasitology 14: 88-90, 1927 16. BRUDADASTOV AN, LEMELEV VR, KHOLMUKHAMEDOV SK, KRASNONOS LN. (Clinical picture of the migration phase of ascariasis in self-infection.) Meditsinskaya Parazitologiya i Parazitarn e Bolenzni 40: 165-168, 1971. In Russian 17. BRUMPT L, HO THI SANG. Traitement de l'ascaridose et de l'oxyurose par les dérivés de la pipérazine. Bulletin de la Société de Pathologie Exotique 47: 817-822, 1954 18. BRUNNER M. Immunological studies in human parasitic infestation. Journal o f Immunology 15: 83-101, 1928 19. BUI QUOC HONG, BUI HOI, TRAN LU Y, TANG NHIEP, NGUYEN VAN DICH, VY DINH MINH. Activité anthelminthique du 2(4' thiazolyl) benzimidazole che z l'homme. Chemotherapia 5: 326-331, 1962 20. CABRERA BD, ARAMBULO PR, PORTILLO GP. As cariasis control and/or eradication in a rural community in the Phili ppines. Southeast Asian Journal of Tropical Medicine and Public Health 6: 510-518, 1975 21. CAIUS PLINIUS SECUNDUS. Hist oria naturalis, translated by J Bostock and HT Riley, Bohn's Classical Library, London, six volumes, 1855-1857 22. CALDWELL FC, CALDWELL EL. Are Ascaris lumbricoides and Ascaris suilla identical? Journal of Parasitology 13: 141-145, 1926 23. CELSUS AC. De medicina, translated by WG Spencer, Loeb Classical Library , Heinemann, London, three volumes, 1948-1953 24. CHAIA G, CUNHA A S. Therapeutic action of mebendazole (R-17.635) against human helminthiasis. Folha Médica 63: 843-852, 1971 25. CHANDLER AC. Animal parasites and human disease, third edition, John Wiley an d Sons, New York, pp 573, 1926 26. CHURCH J. Remarks on the Ascaris lumbricoides . Memoirs of the Medical Society of London 2: 63-67, 1788 27. COVENTRY FA, TALIAFERRO WH. Hypersensitivity to helminth proteins. I . Cutaneous tests with proteins of ascaris, hookworm and trichuris in Honduras. Journal of Preventive Medicine 2: 273-288, 1928 28 CRAM EB. The influence of low temperatures and disinfectants on the eggs of Ascaris lumbricoides. Journal of Agricultural Research 27: 167-175, 1924 29. DATE W. Intestinal worms. Lancet i: 145-146, 184-185, 1872 30. DAVAINE C. Sur le diagnostic de la présence des vers dans l'intestin par l'inspectio n microscopiques des matierès expulsées. Comptes Rendus des Séances et Mémoires de la Société de Biologie, second series, 4: 188-189, 1857 31. DAVAINE C. Recherches sur le développement et la propagation du trichocéphale d e l'homme et de l'ascaride lombricoïde. Journal de Physiologie 2: 195-200, 1859 32. DAVAINE C. Nouvelles recherches sur le développement de la propagation de l'ascaride

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lombricoïde et du trichocéphale de l'homme. Comptes Rendus Hebdomadaires de s Séances de l'Académie des Sciences, third series, 4: 261-265, 1862. Translated in 65 DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et de s animaux domestiques, J-B Baillière et fils, Paris, pp 1003, 1877 DO NASCIMENTO OB, HALSMAN M , ORIA H, CAMPOS JV. Ensaio terapeutico na ascariase com doses unica de novo antihelmintico de sintese (tetramisole). Revista d o Instituto de Medicina Tropical de São Paulo 8: 143-147, 1966 EICKELBERG T. Zur Diagnose und Behandlung von Askaris-Erkankungen. Deutsch e medizinische Wochenschrift 49: 1020-1021, 1923 ELLIOTSON J. Lectures on the theory an d practice of medicine: worms. London Medical Gazette 12: 689-695, 1833 EPSTEIN A. Ueber die Uebertragung des menschlichen Spulwurme ( Ascaris lumbricoides). Eine klinisch-experimentalle Untersuchung. Jahrbuch für Kinderheilkunde und physische Erziehung 33: 287-301, 1892 FAYARD C. Ascaridiose et pipérazine, Thèse, Paris, 1949 FRITZ O. Ascariden des Magendarmtraktes in Röntgenbild. Fortschritte auf dem Gebiete der Roentgenstrahlen 29: 591-593, 1922 FÜLLEBORN F. Ueber die Wanderung von Askaris- und anderen Nematoden-larven im Körper und intrauterine Askarisinfektion. Archiv für Schiffs- und Tropen-Hygiene 25 : 146-149, 1921 FÜLLEBORN F. Ueber das Verhalten der Larven von Strongyloides stercoralis , Hakenwürmer und Ascaris lumbricoides im Körper des Wirtes und ein Versuch, e s biologisch zu deuten. Archiv für Schiffs- und Tropen-Hygiene, 31, No. 2: pp 56, 1927 GALENUS CC. Works of, In: Medicorum graecorum opera quae extant, edited by KG Kühn (Greek text with Latin translation), Leipzig, 20 volumes, 1821-1833 GALVIN TJ. Development of human and pig Ascaris in the pig and rabbit. Journal o f Parasitology 54: 1085-1091, 1968 GARCIA EG, CABRERA BD, CRUZ TA , JUECO NL. Reinfection rates of successfully treated cases of ascariasis. Journal of the Philippines Medical Association 37: 239-243, 1961 GÄRTNER H, MUTING L. Beitrag zur Verbreitung der Wurmkrankheiten. Deutsch e medizinische Wochenschrift 74: 881-883, 1949 GELPI AP, MUSTAFA A. Seasonal pneumonitis with eosinophilia. A study of larva l ascariasis in Saudi Arabs. American Journal of Tropical Medicine and Hygiene 16 : 646-657, 1967 GHANDI BP. Intestinal obstruction due to roundworm. East African Medical Journal 42: 124, 1965 GHEDINI G. Anticorpi elmintiaci nel siero di sangue di individui affetti da elmintiasi , anticorpi anchilostomiaci e ascaride. Cronac a della Clinica Medica di Genova 13: 58, 1907 GOEZE JAE. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper, PA Pape, Blankenburg, pp 471, 1782 GOODWIN LG, JAYEWARDENE G, STANDEN OD. Clinical trials with bephenium hydroxynapththoate (Alcopar) against hookworm in Ceylon. British Medical Journal ii : 1572, 1958 GRASSI B. Note intorno ad alcuni parassiti dell'uomo. III. Intorno all' Ascaris lumbricoides. Gazzetta degli Ospitali, Milano 2: 432, 1881 Also: Weiteres zur Frage der Ascarisentwickelung. Centralblatt für Bakteriologie und Parasitenkunde, Abteilun g originale 3: 748-749, 1888 GRASSI B. Trichocephalus und Ascarisentwicklung. Preliminarnote. Centralblatt fü r Bakteriologie und Parasitenkunde, Abteilung originale 1: 131-132, 1887 GROS G. Fragments d'helmin thologie et de physiologie microscopiques. Sur les lombrics cholériques. Bulletin de la Société Impériale des Naturalistes de Moscou 22: 549, 1849 HALLEZ P. Sur le développement des nématodes. Comptes Rendus Hebdomadaires des

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Séances de l'Académie des Sciences 101: 831, 1885 55. HALLEZ P. Nouvelles études sur l'embryogénie des nématodes. Comptes Rendu s Hebdomadaires des Séances de l'Académie des Sciences 104: 517, 1887 56. HELLER C. Ueber Ascaris lumbricoides. Sitzungsbericht der physiche-medische Societät in Erlangen 4: 71, 1872 57. HIPPOCRATES. Works of, transla ted by WH Jones and ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953 58. HOBO B. (Epidemiological studies on Ascaris infection among prisoners and the length of life of Ascaris lumbricoides in human host.) "Japanese Journal of the Nation's Health" 25: 1-14, 1956. In Japanese, with English summary. Abstracted in Tropical Disease s Bulletin 53: 1255, 1956 59. HOEPPLI R. Parasites and parasitic infection in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 60. HSU HF, FAN YC, TAN CC, CHIN KY. Two cases of heavy infection by Ascaris lumbricoides. Chinese Medical Journal 57: 168-175, 1940 61. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE . Nematode and Gordiacea names placed in the official list of generic names (Opinion 66), Smithsonian Institution Publication 2359, Washington D C, pp 171-176, 1915 62. ISHIKAWA S. On the fate of the ova of Ascaris in heaped manure mixed with huma n faeces, and the investigation of eggs adheri ng to vegetables. "Journal of Oriental Medicine" 11: 127-131, 1929. In Japanese. Abstracted in Tropical Diseases Bulletin 28: 225, 1931 63. JAYEWARDENE G, ISMAIL MM, WIJAYARATNAM Y. Bepheniu m hydroxynaphthoate in treatment of ascariasis. British Medical Journal ii: 268-271, 1960 64. JUNG RC. The predominance of single-brood infections in human ascariasis. Journal of Parasitology 40: 405-407, 1954 65. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 66. KELLER AE. Ascaris lumbricoides : loss of infestation without treatment. Journal of the American Medical Association 97: 1299-1300, 1931 67. KNIGHT R. Discussion of reference 132. Tropical Diseases Bulletin 67: 5355, 1970 68. KOINO S. Experimental infections on the human body with ascarides. Japan Medica l World 15: 317-320, 1922 69. KONDO K. (Experiments on the infection of Ascaris lumbricoides . I. Percutaneous infection.) Tokyo Iji Shinshi No 2181, pp 1123-1125, 1920. In Japanese. Abstracted in Tropical Diseases Bulletin 19: 233, 1922 70. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Mensche n vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung de r thierischen und pflanzischen Pa rasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to th e group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 71. LAMSON PD, CLADWELL EL, BROWN HW, WARD CB. Hexylresorcinol in th e treatment of human ascariasis. American Journal of Hygiene 13: 568-575, 1931 72. LANE C. The prevention of Ascaris infection: a critical review. Tropical Diseases Bulletin 31: 605-615, 1934 73. LEIPER RT. Discussion on the validity of certain generic names at present in use i n medical helminthology. Archiv für Schiffs- und Tropen-Hygiene 30: 484-491, 1926 74. LEUCKART R. Amtlicher Bericht uber die 33. Versammlung deutscher Naturforsche r und Aertze zu Bonn, 1857 75. LEUCKART R. Die menschlichen Paras iten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Nat urforscher und Aertze, C F Winter'sche Verlagshandlung, Leipzig, volume two, pp 882, 1867-1876 76. LEVIN JJ, PORTER A. Surgical and parasitological notes on four cases of intestina l

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obstruction due to accumulation of very large numbers of round worms. British Journal of Surgery 11: 432-438, 1924 77. LINNAEUS C. Systema naturae sive per regna triae naturae, secundum classes, ordines, genera , species, cum characteri bus, differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 78. von LINSTOW O. Ueber den Zwischenwirth von Ascaris lumbricoides L. Zoologischer Anzeiger 9: 525-528, 1886 79. LÖFFLER W. Zur Differential-Diagnose der Lungenfiltrierungen: uber fluchtig e SuccedanInfiltraten (mit Eosino philie). Beiträge zur Klinik Tuberkulose und specifischen TuberkuloseForschung 79: 368-382, 1932 80. LUTZ A. Zur Frage der Uebertragung des mensichlichen Spulworms. Weiter e Mittheilungen. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 3: 425-428, 1888 81. LÝSEK H. P ispevek k otázce patogenity škrkavky prase i pro lov ka. eskoslovenska Epidemiologie, Mikrobiologie, Imunologie 10: 134-136, 1961 82. MAUNG M. The occurrence of the second moult of Ascaris lumbricoides and Ascaris suum. International Journal for Parasitology 8: 371-378, 1978 83. MIURA K, NISHIUCHI K. Ueber befruchte und unbefruchtete Ascarideier i m menschlichen Kote. Centralblatt für Bakteriologie, Parasitenkunde un d Infektionskrankheiten, Abteilung originale 32: 637-641, 1902 84. MORISHITA K. Studies on the epidemiological aspects of ascariasis in Japan and basic knowledge concerning its control. In, Progress of medical parasitology in Japan, K Morishita, Y Komiya and H Matsubayashi (Editors), Meguro Parasitological Museum, Tokyo, volume 4, pp 3-153, 1972 85. MOSLER F. Ueber einen Fall von Helminthia sis. Archiv für pathologische Anatomie und Physiologie und für klinische Medizin (Virchow) 18: 242-250, 1860 86. NETTESHEIM W. Das Wandern der Spulwurmlarven in inneren Organen. Münchener medizinische Wochenschrift 69: 1304-1306, 1922 87. NISHIGORI M, OHBA T. (On the route of migration in the host's body taken by th e Ascaris.) Nissin Igaku 13: 13-16, 1924. In Japanese. Abstracted in Japan Medical World 4: 263, 1924 88. OHBA T. (Investigation on the presence of Ascaris-larvae in the urine during the initial stage of infection with Ascaris.) Taiwan Igakka Zasshi No 242, pp 465-469, 1925. I n Japanese, with English summary 89. OLIVER-GONZALEZ J, SANTIAGO-STEVENSON D , HEWITT RI. Treatment of six cases of ascariasis in man with 1-diethylcarbamyl 4-methylpiperazine hydrochloride . Southern Medical Journal 42: 65-66, 1949 90. ORIHEL TC. Primates as models for parasitological research. In, Medical Primatology, S Karger, Basel, pp 772-782, 1971 91. OTTO GF, CORT WW. Further studies on post-treatment reinfection with Ascaris in the United States. Journal of Parasitology 20: 245-247, 1934 92. OTTO GF, CORT WW, KELLER AE. Environmental studies of families in Tennessee infested with Ascaris, Trichuris and hookworm. American Journal of Hygiene 14 : 156-193, 1931 93. PAN C, RITCHIE LS, HUN TER GW. Reinfection and seasonal fluctuations of Ascaris lumbricoides among a group of children in an area where night soil is used. Journal of Parasitology 40: 603-608, 1954 94. PANAROLUS D. Iatrologismorum seu medicinalium observationum pentecosta e quinque etc., F Moneta, Romae, pp 445, 1652. Partly translated in 133 95. PAPYROS EBERS. Das hermetische Buch über die Arzneimittel alten Aegypter i n hieratischer Schrift. Herausgegeben, mit Inhaltsangabe und Einleitung versehen vo n Georg Ebers, Mit hieroglyphisch-lateinischem Glossar von Ludwig Stern, Leipzig, two volumes, 1875. The Papyrus Ebers, translated from the German version by CP Bryan,

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Geoffrey Bles, London, pp 167, 1930 96. PAYNE FK, ACKERT JE, HA RTMAN E. The question of the human and pig Ascaris. American Journal of Hygiene 5: 90-101, 1925 97. PHILLS JA, HARROLD AJ, WHITEMAN GV, PERELMUTTER L. Pulmonar y infiltrates, asthma and eosinophil ia due to Ascaris suum infestation in man. New England Journal of Medicine 286: 965-970, 1972 98. PLATTER F. (PLATERUS). Cited in 133 99. PROFFIT RD, WALTON BC. Ascaris pneumonia in a two-year-old girl. Diagnosis by gastric aspirate. New England Journal of Medicine 266: 931-934, 1962 100. RANSOM BH, CRAM EB. The course of migrat ion of Ascaris larvae. American Journal of Tropical Medicine 1: 129-156, 1921 101. RANSOM BH, FOSTER WD. Life history of Ascaris lumbricoides and related forms. Preliminary note. Journal of Agricultural Research 11: 395-398, 1917 102. RANSOM BH, FOSTER WD. R ecent discoveries concerning the life history of Ascaris lumbricoides. Journal of Parasitology 5: 93-99, 1919 103. RANSOM WH. On the diagnosis of, and treatment for, roundworm; and on th e occurrence of a new species of taenia in the human body. Medical Times and Gazette, new series, 12: 598-600, 1856 104. REDI F. Osservazione intorno agli animali viventi che si trovano negli animali viventi, Piero Matini, Firenze, pp 224, 1684 105. REITER J. Zum Röntgenologischen Nachweis von Askariden in Magendarmtrakt . Wiener klinische Wochenschrift 36: 592, 1923 106. RENDALL P. "Death from irritation of ascarides." Lancet ii: 1303, 1892 107. RHIND W. A treatise on the nature and cure of intestinal worms of the human body , Samuel Nighley, London, pp 153, 1829 108. RICHTER HE. Beobachtungen über die Eier der Eingeweidewürmer. Allgemein e Deutsche naturhistorische Zeitung (Sachse) 1: 1-5, 1856 109. ROSS R. The life-history of Ascaris lumbricoides . British Medical Journal ii: 5-7, 1916 110. RYRIE GA. Intestinal obstruction due to Ascaris infection. Malayan Medical Journal 3: 166-167, 1928 111. SCHINZ HR. Askariden in Röntgenbild. Deutschen Zeitschrift für Chirurgie 184 : 105-109, 1924 112. SCHULTZ MG. Ascariasis: nutritional implications. Reviews of Infectious Diseases 4: 815-819, 1982 113. SPILLMAN R. Pulmonary ascariasis in tropical communities. American Journal o f Tropical Medicine and Hygiene 24: 791-800, 1975 114. SPRENT JF. The dentigerous ridges of the human and pig Ascaris. Transactions of the Royal Society of Tropical Medicine and Hygiene 46: 378, 1952 115. STEWART FH. On the life-history of Ascaris lumbricoides . British Medical Journal ii: 5-7, 1916 116. STEWART FH. The life history of Ascaris lumbricoides. British Medical Journal ii: 474, 1916 117. STEWART FH. Further experiments on Ascaris infection. British Medical Journal ii : 486-488, 1916 118. STEWART FH. On the life history of Ascaris lumbricoides . British Medical Journal ii: 753-754, 1916 119. STEWART FH. On the development of Ascaris lumbricoides Lin. and Ascaris suilla Duj. in the rat and mouse. Parasitology 9: 213-227, 1917 120. STEWART FH. On the development of Ascaris lumbricoides and Ascaris mystax in the mouse. Part II. Parasitology 10: 189-196, 1918 121. STEWART FH. On the life history of Ascaris lumbricoides L. Part III. Parasitology 10: 197-205, 1918 122. STEWART FH. Recent experiments on the life history of Ascaris lumbricoides . British

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Medical Journal i: 102, 1919 123. STEWART FH. Life-history of Ascaris lumbricoides . British Medical Journal ii : 818-819, 1920 124. STEWART FH. On the life history of Ascaris lumbricoides . Part V. Parasitology 13 : 37-47, 1921 125. SWARTZWELDER JC. Clinical ascariasis. An analysis of two hundred and two cases. American Journal of Diseases of Children 72: 172-180, 1946 126. SWAYNE JG. Observations on the report of the College of Physicians relative to th e organic bodies discovered in the evacuati ons of cholera patients. Lancet ii: 530-532, 1849 127. SZIDAT L. Über die Erhaltungsfähgkeit von Helmintheneiern in Vor- un d Frühgeschichtlichen Moorleichen. Zeitschrift für Parasitenkunde 13: 265, 1944 128. TAKATA I. Experimental infection of man with Ascaris of man and pig. Kitasat o Archives of Experimental Medicine 23: 49-59, 1951 129. TALYZIN FF. The oxygen treatment of ascariasis. Lancet ii: 314-315, 1954 130. THIENPONT D, BRUGMANS J, ABADI K, TANAMAL S. Tetramisole in th e treatment of nematode infestations in man. American Journal of Tropical Medicine and Hygiene 18: 520-525, 1969 131. THUST R. Submikroskopische Untersuch ungen über die Morphogenese des Integuments von Ascaris lumbricoides L. Zeitschrift für wissenschaftliche Zoologie 178: 1-39, 1968 132. TULLIS DC. Bronchial asthma associated with intestinal parasites. New England Journal of Medicine 282: 370-372, 1970 133. TYSON E. Lumbricus teres, or some anatomical observations on the round worm bred in human bodies. Philosophical Transactions of the Royal Society 13: 153-161, 1683 134. VALLISNIERI A. Nuovo osserva zioni ed esperienze intorno all'ovaja scoperta ne' vermi tondi dell'uomo, nomo e de' vitelli con varie lettre spettanti all storia medica e naturale, G Manfrè, Padova, pp 184, 1713 135. VERVOORT H. Oleum chenopodii anthelmintici, een Wormmiddel tegen Ankylostomum en Ascaris. Geneeskundig Tijdschrift voor Nederlandsch-Indië 53: 435-445, 1913 136. VOGEL H, MINNING W. Beiträge zur Klinik der Lungen-Ascariasis und zur Frage der flüchtigen eosinophilen Lungeninfiltrate. Beiträge zur Klinik der Tuberkulose un d spezifischen Tuberkulose-Forschung 98: 620-654, 1942 137. WEDL C. Grundzuge der pathologischen Histol ogie, Carl Gerold & Sohn, Wien, pp 825, 1854. Rudiments of pathological histology, translated by G Busk, The Sydenha m Society, London, pp 637, 1855 138. WINFIELD GF. Studies on the control o f fecal-borne disease in North China. III. Family environmental factors affecting the spread of Ascaris lumbricoides in a rural population. Chinese Medical Journal 51: 643-658, 1937 139. WINFIELD GF, CHIN TH. Studies on the control of fecal-borne diseases in Nort h China. VI. The epidemiology of Ascaris lumbricoides in an urban population. Chinese Medical Journal 54: 233-254, 1938 140. YOSESATA M, SUMI I. (Helminth eggs on vegetables in Mukden.) "Journal of Oriental Medicine" 16: 493-506, 1932. In Japanese. Abstracted in Tropical Diseases Bulletin 29: 739, 1932 141. YOSHIDA S (T). On the development of Ascaris lumbricoides L. Verhandlungen der japanischen pathologischen Gesellschaft zu Tokyo 8: 160-162, 1918. Also (same title), Journal of Parasitology 5: 105-115, 1919 142. YOSHIDA S (T). On the migrating course of ascarid larvae in the body of the host . Journal of Parasitology 6: 9-17, 1919. Original reports in Japanese in Tokyo Iji Shinshi No. 2066, pp 555-561; No. 2072, pp 867-872, 1918

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Table 19.1. Landmarks in ascariasis ___________________________________________________________________ BC

Adult worms have been known since ancient times and various anthelmintics have been employed c.170 AD Galen knew that adult worms normally inhabited the upper small intestine 1683 Tyson described the anatomy of the worm and clearly distinguished it from the earthworm. He discovered the eggs 1849 Gros found that eggs took several months to embryonate 1856 Ransom showed that ascariasis could be diagnosed by finding eggs in the faeces 1862 Davaine showed that eggs remained viable for up to five years 1862 Davaine discovered that when embryonated eggs were fed to rats, larvae were liberated in the small intestine then were passed in the faeces 1879 Grassi swallowed embryonated eggs and claimed to find evidence of a patent infection 22 days later 1886 Calandruccio gave 150 eggs to a boy and recovered 143 worms after anthelmintic administration three months later 1916 Stewart found that larvae liberated from eggs in the intestines of rats underwent systemic migration through the lungs then returned to the gut 1922 Koino infected himself with 2,000 eggs, recovered larvae from his sputum several days after infection, then recovered 667 immature worms from his intestines after anthelmintic administration 50 days after infection 1949 Fayard reported that piperazine was a useful treatment 1958 Bephenium was shown by Goodwin and colleagues to be useful for treatment 1962 Bui Quoc Hong and co-workers showed that thiabendazole was an effective treatment 1966 Tetramisole was demonstrated by Do Nascimento and colleagues to be efficacious 1969 Thienpont and colleagues showed that levamisole was even more effective than tetramisole 1970 Amato Neto and co-workers indicated that pyrantel was active 1973 Mebendazole was shown by a number of investigators to be useful in ascariasis __________________________________________________________________

Chapter 20

Ancylostoma duodenale, Necator americanus and HOOKWORM DISEASE

SYNOPSIS Common name: hookworm, causing hookworm disease Major synonyms: 1. Ancylostoma duodenale: Agchylostoma duodenale, Anchylostomum duodenale, Ankylostoma duodenale, Dochmius ankylostomum, Sclerostoma duodenale, Uncinaria duodenale 2. Ancylostoma ceylanicum: A. braziliense 3. Necator americanus: Uncinaria americana Distribution: widespread, especially in the tropics and subtropics Life cycle: The adult worms, about 1 cm long, live attached by the mouth to the small intestinal mucosa. Eggs are passed in the faeces then hatch and moult twice in the soil over two weeks or so to become infective (filariform) larvae. These penetrate the intact skin and pass via the bloodstream to the lungs where they enter the alveolar spaces, ascend the airways to the pharynx, and are swallowed and pass to the small intestine where they mature over 1-2 months Definitive host: A. duodenale, N. americanus - humans A. ceylanicum - dogs, cats, humans Major clinical features: dermatitis, pulmonary infiltrates with eosinophilia, indigestion, iron deficiency anaemia Diagnosis: finding eggs in faeces Treatment: bephenium, mebendazole, pyrantel, thiabendazole; blood transfusion if necessary

DISCOVERY OF THE ADULT WORM In May 1838, while dissecting the body of a peasant woman who had died of pulmonary infarction in the Maggiore Hospital in Milan, the Italian doctor, Angelo Dubini, encountered "a little worm in the small intestine, in the midst of much gray mucus....this worm impressed me as having really distinct generic characteristics" 70. Dubini did not publish news of this discovery, however, until he came across the parasite again four and a half years later. In November 1842, Dubini found another example of this peculiar worm in the jejunum of an old lady who had suffered with dropsy (oedema). Both of these parasites, and the specimen he found in a third patient in the following month, were all

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female worms. On 15 December 1842, Dubini found a dozen worms in the first part of the jejunum of a woman who had died from a chest abscess, and this time, male helminths were present. The parasites were so frequent, that in the course of 100 autopsies, he encountered them in more than twenty cadavers. Dubini described the worms as being: somewhat curved in on themselves....about four and one half lines [= 1 cm] in length, transparent in the anterior, and marked by wavy yellow brown or red stripes in the posterior three quarters. A black spherical dot marks the boundary between the transparent and colored parts. Posteriorly, the female has a blunt tail which is slightly curved.70

Dubini recognized that the worms were nematodes, for they were cylindrical in shape, elastic, possessed a complete intestinal tract with a mouth at one end and an anus at the other, and were unisexual. There were a number of characteristics, however, which he felt justified the erection of a new genus in which to place this worm. He described the salient features: Head not distinct from body; round mouth furnished with four hooks folded back towards the center and situated above conical eminences which project from the interior of the pharynx; esophagus enlarged at the bottom like a club and distinct from the spherical, blackish stomach; blunt tail in the female, spread out like a fan in the male; a single central penis in which are inserted two small vas deferens.70

Dubini named the genus Agchylostoma, being a mistransliteration of the Greek words (AGCHYLOS i.e. ANCHYLOS because before [CH] should be transliterated as "N" and not "G") and µ (STOMA), meaning "curved" and "mouth", respectively. Dubini thought that was the Greek word for "hook" and intended the name to reflect the hooked shape of the body of the parasite and its prominent mouth. In addition, he gave it the specific epithet, duodenale, to indicate its common location in the intestine. Dubini considered the reasons why the worm, despite its moderate size, had not been discovered earlier. Until a short period before his own era, it had not been the general practice to open the bowel at autopsy, and the worm was so small that there would have been no chance of feeling it through the intestinal wall when squeezing the gut. When it became common to open the intestines and examine the mucosa (particularly in patients with typhoid fever and tuberculosis), the usual procedure was to wash out the intestinal lumen with large volumes of water which would probably have carried away many worms. Finally, the worms were ordinarily embedded in somewhat opaque mucus which made it extremely difficult to visualize them. Dubini's discovery was confirmed several years later in Egypt by the German 31 physician, Pruner (1846) 171, then by the latter's compatriots, Bilharz and 92 Griesinger , also in Egypt. In 1865, Wucherer found the parasite in Brazil204, then the worm was found subsequently in many countries. A number of studies were then made of the anatomy of the worm, the most complete and extensive being those of Looss in Cairo141. Confusion and controversy reigned over the proper name of the worm. In addition to Dubini's name of Agchylostoma duodenale, it was called Ancylo-

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stoma duodenale by Creplin (1845) 60, Anchylostomum duodenale by Diesing (1849-1851), Ancylostomum duodenale by Küchenmeister (1855), and Ankylostoma duodenale by Blanchard (1885-1890), and renamed Strongylus quadridentatus by von Siebold (1851), Dochmius ankylostomum by Molin (1860), Sclerostoma duodenale by Cobbold (1864), and Uncinaria duodenale by Railliet (1885), amongst other names. With the acceptance of the International Rules of Zoological Nomenclature (see chapter 1), it was clear that by the law of priority, Dubini's name should stand. Considerable argument took place, however, over the relative merits of Agchylostoma, Anchylostoma, Ankylostoma and Ancylostoma. By Opinion 66 in February 1915, the International Commission on Zoological Nomenclature settled the matter by declaring that the valid name of the genus was Ancylostoma, with duodenale being the type species105.

DIFFERENTIATION OF NECATOR ANCYLOSTOMA DUODENALE

AMERICANUS

FROM

In 1868, Camuset appreciated that the hookworm found in South America was distinct from A. duodenale seen in Europe and Africa and indicated clearly the differential characteristics. This information was buried in a thesis52, however, and was not generally known until Leger drew attention to it in 1921125. Likewise, Adolfo Lutz in 1888 noted some differences between the Brazilian hookworm and the European form, but did not classify the former as a new species143. In 1901, Dr AJ Smith in Galveston, Texas, USA, recognized that the worms expelled by a patient from a plantation in southern Mexico were not the same as Dubini's A. duodenale but thought that they might be identical with Uncinaria stenocephala of dogs189. Smith sent specimens to CW Stiles in Washingtom as did Drs CA Claytor in Washington, DC, and BK Ashford in Puerto Rico. Stiles described a number of morphological differences between this parasite and classical A. duodenale (which, following Railliet, he called Uncinaria duodenalis), including replacement of the hook-like teeth in the mouth by semilunar plates, the location of the vulva, and appearance of the caudal bursa of male worms. In addition, he thought that the eggs of the American worm were slightly larger. Stiles concluded that: These parasites differ from all of the members of the genus Uncinaria which I can find recorded, and on that account, I propose to base a new species, Uncinaria americana, upon them.192

In 1903, Stiles suggested splitting up the genus Uncinaria (i.e. Ancylostoma) and placed the American hookworm in the subgenus, Necator 193. He elevated this subgenus to generic status in 1906194. The name meant "the killer" and was derived from the Latin word "neco", meaning "to kill". In 1915, the International Commission on Zoological Nomenclature in Opinion 66 declared that the official name for the parasite was Necator americanus 105.

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DIFFERENTIATION OF ANCYLOSTOMA CEYLANICUM FROM A. DUODENALE In 1910, Dr Gomes de Faria recorded the occurrence of a new species of hookworm, which he named Ancylostomum braziliense, in the intestines of cats and dogs at Manguinhos, Brazil73. In the following year, Looss described another hookworm which he named Agchylostoma ceylanicum; this parasite had been recovered from a civet cat and sent to him by Willey in Ceylon142. Shortly thereafter (1913), Major Clayton Lane of the Indian Medical Service examined stools of prisoners in a gaol in India and in three cases found hookworms which did not conform to the ordinary type of parasite (A. duodenale). Closer examination revealed that they were A. ceylanicum 116. Later in the same year, Leiper expressed an opinion that A. ceylanicum was identical with A. braziliense 133, with which view Lane later concurred 118. Since de Faria had described the parasite first, this name held general sway. In 1951, however, Biocca reviewed the relationship between A. braziliense and A. ceylanicum and differentiated the two species on morphological grounds32. This distinction was then confirmed by Rep and his colleagues in cross-breeding experiments in 1968173.

ELUCIDATION OF THE MODE OF TRANSMISSION STUDIES

OF

THE

DEVELOPMENT

OF

LARVAE

IN

THE

EXTERNAL

ENVIRONMENT

Dubini made little mention of hookworm ova other than to say that the elliptical eggs could be seen in the oviduct of female worms, and to provide a rudimentary drawing of them in situ 70. Not much attention was paid to the eggs over the next twenty years, and Wucherer in 1866 wrote "Nothing is known about the way in which the eggs or embryos of Ancylostoma are introduced into the human body and under what conditions they exist outside it"204. In view of the unavailability of A. duodenale in Germany at the time, Rudolf Leuckart, in the same year that Wucherer wrote those words, made some observations on the related hookworm of dogs, Dochmius trigonocephalus (now called Uncinaria stenocephala) in order to study any developments which may occur within the egg. He found that when the eggs were placed in damp earth or mud, the segmented embryo formed a larva which hatched after three or four days. The larvae moulted after a further three days, then a second moult at the end of another week coincided with a marked change in the internal organization of the worms, and they were no longer able to feed. Leuckart supposed that these forms, which resembled Rhabditis (a free-living worm), must enter some intermediate host, but preliminary experiments were

Hookworm Disease

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negative. He therefore introduced some of these third-stage larvae in muddy water directly into the gastrointestinal tract of some dogs. Leuckart found that they grew for eight days then moulted. Another moult took place and he recovered mature worms three weeks after infection. This convincing experiment led Leuckart to surmise that A. duodenale of humans would have a similar development and infection must be acquired by drinking free-living larvae in dirty water134. This finding stimulated Wucherer to make similar observations on human hookworms. He placed eggs in a damp place and found that larvae developed within 24 hours, then escaped from the egg shell in the same fashion as the dog hookworm. The larvae increased in size and cast off their cuticles once or twice, but then died. Unfortunately, Wucherer was unable to pursue these investigations any further as he had insufficient laboratory resources at his disposal. The next significant studies were not made until 1878 when the Italians, Giovanni Battista Grassi, Corrado Parona and Ernesto Parona studied the development of hookworm eggs of human origin. They observed the repeated segmentation of the embryo within the egg shell, and found that when the larva had reached a length approximately three times that of the egg, it pierced the shell. They then observed moulting of the parasite: This larva will gradually increase in size, becoming quite long and undergoing at least two moults; that is, it will shed its skin at least twice....However, as of today, we are unable to say what happens afterward.90

Grassi and his colleagues found that the best medium for the development of the larvae was the faeces itself, and that all stages of development were hastened by increased temperatures. Shortly thereafter, their compatriot, Eduardo Perroncito in Turin, used eggs obtained from the faeces of miners infected while building the St. Gothard's tunnel to study further the extracorporeal development of hookworms. Perroncito found that the larvae hatched from the egg shells asynchronously, beginning a day or so after incubation. He described the anatomy of the larva in detail, then recorded the progessive changes which occurred in the internal organization of the growing worm. He failed to recognize the first moult and misinterpreted the second moult as cyst formation or encapsulation: Whilst the pharynx is greatly modified, the skin separates a substance chitinoid (?) glassy, transparent, which in a very short time is condensed, and forms a capsule which encloses the living larva. This is seen to move freely in its capsule or cyst, which completely repeats its shape.166

Perroncito considered that the capsule provided some resistance to dessication and postulated that the "cysts" might be transported by the wind as well as in water then produce infection when ingested in contaminated food or water. Further, he believed that the cyst became calcified and that the larva was liberated by the hydrochloric acid of the gastric juice: After from one to two days, [the larva's] skin separates from the salts of chalk (particularly from the carbonate of chalk)....and becomes one with the capsule. Thus,

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this always becomes more rigid and friable.166

Perroncito's conclusions were repudiated a few years later (1886) by Schulthess in Germany who correctly interpreted the "cyst formation" as representing merely a phase in ecdysis and dismissed the calcification as being a process of degeneration 184. These phenomena were also investigated by Leichtenstern who misguidedly tried to support Perroncito's views with regard to cyst formation, although he did not agree with the concept of calcification. Like Perroncito, Leichtenstern denied that moulting of larvae occurred128. Ten years later, Arthur Looss in Egypt re-examined the development of larvae and confirmed, although he does not appear to have been aware of it at the time, the observations and interpretations of Schulthess. Looss watched the development and hatching of the larva, then found that at the prevailing temperature (27oC), a moult occurred after two to three days. After five days, changes in the internal morphology of the larva began to take place, particularly in the mouth, buccal cavity and oesophagus. A second moult then occurred, but the old cuticle was usually retained: the body membrane is seen to consist of two layers, the outer one of which begins to detach itself more and more from the body until it finally loses connection with it completely and covers it all around with an exceptionally thin and delicate chitinous coat....the body....seems to contract a little in length so that the old skin extends to a degree over head and tail....In the great majority of cases they do not cast off the outer chitinous skin.136

These larvae were non-feeding, infective forms and ripe for transfer. Looss, like Schulthess, realized that it was this process that Perroncito and others had called "encystment" and was nothing more than an ordinary shedding process except that the old coat was not cast off completely. Looss was able to keep such larvae alive for 10-20 days in water and confirmed that they could not withstand dessication. Looss began the paper alluded to above by saying that very little was known about the life history of A. duodenale. This statement was made despite the numerous investigations of Perroncito, Parona, Grassi, Lutz, Leichtenstern and others, but he did acknowledge that all the pertinent literature was not available to him. This did not save him, however, from a savage attack by Leichtenstern who charged that Looss's paper was nothing more than a re-hash of the known facts, combined with a curious ignorance of, if not intentional disregard for, the literature129,130. To this, Looss replied vigorously, saying that for one such as him incarcerated in Egypt and denied the scientific aids and libraries to which those in Europe were accustomed, he had one of two choices; either he worked for his own pleasure and kept all his discoveries to himself, or he published them, whether the form was perfect, as could rightfully be expected in the centres of scientific life, or not. He chose the latter course and wrote: It is my intention to contribute to the improvement of our knowledge as far as I am able, and it is my conviction that the merits of prior authors will prevail in any scientific question, regardless of whether they are or are not cited in every later work.138

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In any case, Looss was not convinced that everything had indeed been clarified about the life cycle. He then claimed that in eight months he had advanced knowledge further than Leichtenstern had done over many years, and went on to justify this assertion by describing the percutaneous penetration of infective larvae138 (see later). Another blind alley also bedevilled a proper understanding of the in vitro development of hookworms for over thirty years. In 1886, Leichtenstern first put forward the proposition that hookworms underwent heterogony, i.e. larvae developed outside the human body into a generation of sexual animals which in their turn produced offspring. Such a phenomenon had been described with Strongyloides stercoralis (see chapter 21). Leichtenstern wrote: By observing suitable culture methods....a freeliving, sexually mature rhabditis form, reproducing itself through unlimited generations, was successfully cultivated from the egg and larva of ankylostoma; a form which is essentially distinct form the parasitic ankylostoma....I foresee that my observations, being that of an 'outsider' will not at once be accepted by zoologists, but rather be received with careful reserve and incredulity.126

Nevertheless, Leichtenstern wrote categorically: "I am in a position entirely to dispose of all such doubts and objections" 126. He then went on to canvass the possibilities that these freeliving worms might be identical with either freeliving nematodes which frequently occur in decaying matter, or may be S. stercoralis which was sometimes found in association with hookworms in the intestines. Later that year, however, Leichtenstern retracted these statements when further experiments convinced him of his error127. Many years later, Looss remarked somewhat pontifically: Supreme personal confidence in his method of research, and neglect inspired by this confidence of the biological probabilities pointed out by specialists on the subject, were the reasons which made it possible that Leichtenstern was deceived. It is fortunate in the interests of science that he was soon convinced himself that he was in the wrong; for where personal convictions play the most prominent part it is not always easy for impersonal reason brought forward by others, to gain a hearing.142

Ironically, the same trap was to befall Looss with his insistence that the transmission of schistosomiasis was direct, yet, unlike Leichtenstern, Looss in that instance remained obdurate. Although the question of the existence or non-existence of heterogony in A. duodenale was settled rapidly as far as the German literature was concerned by the recantation of Leichtenstern, the same did not apply to English investigators. In 1889-1890 and quite independently of Leichtenstern, Captain GM Giles of the Indian Medical Service in Assam made observations during the course of an investigation into the aetiology of kala azar and beri beri which caused him to claim that heterogony occurred with hookworm83. Giles's views were soon opposed by Macdonald who repeated the experiments but failed to verify the findings; he believed that Giles had inadvertently cultured S. stercoralis 145. This view was echoed by Kynsey112 then Sonsino suggested that Giles may have cultured freeliving nematodes. On the other hand, Giles was

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supported by Sandwith in Egypt who claimed to have raised heterogonic hookworms. The subject was raised again when Giles re-asserted his views at the annual meetings of the British Medical Association in 189984 and 190085. A few years later, he was supported by Ozzard who wrote in 1902: During the last two years I have been able to completely confirm the experiments of Giles. That this is an example of dimorphism or heterogenesis I have not the slightest doubt.160

Ozzard reiterated these views in 1909 and wrote that it was absurd to describe the freeliving adult worms as S. stercoralis 161. This immediately brought forth a response from Leiper criticizing Ozzard's assertions 132. Finally, and at great length, Looss in 1911 examined the pitfalls into which previous workers had fallen. He noted that the proponents of heterogony had looked at the first and last stages of development only, and had failed to follow carefully the evolution of individual worms. Nor had sufficient attention been paid to differentiating between first-stage larvae of Strongyloides and hookworms. Furthermore, Looss was convinced that the facts had been made to fit the theory rather than vice versa. He was in no doubt that the various workers had been dealing with S. stercoralis or a nonparasitic, freeliving nematode and pleaded: "It is much to be desired that the legend of heterogony of the ankylostomes should at last definitively disappear from scientific literature" 142. It did.

PROOF OF THE ORAL ROUTE OF INFECTION The first persons to attempt to transmit human hookworm infection experimentally were Grassi and an unnamed colleague. Grassi swallowed a large pill laden with segmenting hookworm eggs; after 45 days of observation, no symptoms attributable to hookworm infection had appeared and no eggs were found in the faeces. Likewise, his colleague, who wished to remain anonymous, consumed some faeces loaded with A. duodenale rhabditiform larvae, again without effect. They also fed a large quantity of faeces full of eggs to a dog, but it eliminated many of them unchanged or nearly unchanged on the following day90. Why these investigators should have swallowed eggs or first-stage larvae when they knew that larvae underwent further development in vitro is unclear. Perhaps, as Looss has surmised142, they wished to counteract the suggestion of Sangalli that eggs developed directly into adults without passing out of the body179. It was in this paper too, that Grassi and his colleagues postulated that Filaria sanguinis hominis (i.e. the microfilaria of Wuchereria bancrofti) might be an ancylostome larva circulating in the bloodstream. The suggestion was based upon the geographical coexistence of filariasis and hookworm infection, the fact that the adult filaria was not known to them, and the statement by Bilharz that he sometimes found female worms in the intestinal submucosa. The idea was negated rapidly, however, when the adult filarial worm was found

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by Bancroft (see chapter 23). It was not until twenty years after Leuckart's demonstration of the oral transmission of Dochmius trigonocephalus of the dog that it was shown that a similar mode of infection could occur with A. duodenale. In 1886, Leichtenstern undertook feeding experiments with human volunteers and found ova in the faeces four to five weeks after ingestion of larvae that had undergone the morphological changes, which have just been described, during in vitro cultivation 127. In 1897, Looss attempted to repeat Leichtenstern's experiment by infecting experimental animals orally with A. duodenale. At first, all the animals vomited the infected worms. He then overcame this problem by cleaning his preparations and exposed a number of species of animals, including monkeys, dogs and cats, to this parasite. He had the best results with newly-weaned animals, but even then, most of the larvae passed directly through the gastrointestinal tract without settling. In older animals, this was the inevitable result. In those cases where helminths did persist in the gut, however, the worms did not complete their development and failed to produce fertilized ova. Looss did not deny that oral transmission of hookworm infection could take place, but concluded that these hosts were insusceptible to infection with hookworm recovered from humans137. Confirmation of this mode of infection was provided, however, when Joyeux in 1912 reported that he had infected monkeys (Cercopithecus patas) by causing them to swallow N. americanus infective larvae. The first monkey died 37 days after infection, and many worms were found attached to the small bowel mucosa which was congested and contained numerous haemorrhages. The second animal died several days later and harboured small numbers of male and female adult worms106. DISCOVERY OF THE PERCUTANEOUS ROUTE OF INFECTION In 1898, Arthur Looss reported that infective hookworm larvae penetrated the intact skin. This was a momentous discovery, for it was the first time that the percutaneous penetration of any worm was shown. The discovery itself was serendipitous. Looss had attempted to infect himself experimentally with Strongyloides stercoralis, and on examining his faeces, was surprised to find numerous Ancylostoma eggs. He reflected, therefore, on how this might have occurred. He had never had any misgivings about allowing water containing hookworms to settle on his hands, although he had ensured that they had been kept away from his mouth. The matter remained inexplicable to him until he had another experience: A drop of water with a high larva content fell on my hand one day and rolled off. I paid no attention to this moist spot which dried itself after a few minutes. But at the same time I felt there an intense burning....and the spot became extremely red. What

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was the meaning of this? The cause could only be the Ancylostoma larva.138

Looss then repeated the process with water alone, but had no repetition of the reaction. Thereupon, he applied some more larvae to the skin: The reddening of the skin and the burning sensation started exactly as before. I then scraped off the last moisture residue from the epidermis....The Ancylostoma larvae previously present in such abundance had disappeared except for a few very indolent ones; in their place among the scraped-off epidermal cells were found numerous empty worm skins! The larvae themselves could only have penetrated the skin.138

In fact, his hand was so swollen the next day that he thought it best to ask for medical help. Two or three months later, he noted a considerable increase in the number of hookworm eggs in his stools138. This assertion by Looss that hookworm larvae penetrated the skin was met with hostile criticism from a number of quarters, so much so that he determined to say nothing more on the subject till he could prove his point. The most telling argument against his hypothesis was that he could have acquired the infection naturally as he lived in an endemic area. This necessitated morphological confirmation by Looss of penetration of the skin by larvae. First, he tried to infect skin removed from a cadaver and heated to 37oC; this was unsuccessful. Next, with the cooperation of his colleague Maddern, who was professor of surgery at Kasr-el-Aini Hospital in Cairo, he extended his observations by infecting a 13 year old boy who was about to have his leg amputated. One hour before operation, a drop of fluid containing many larvae was spread out on the skin. Immediately following removal of the leg at operation, a section of skin was excised and histological sections were prepared. Looss found that the larvae entered the skin and that they did this via the hair follicles: Inside the hair follicles the larvae crowded toward the hair papilla. When particularly numerous in the same follicle, they completely destroyed the outer root sheath. Having reached the hair papilla they left the follicles to penetrate the adjacent tissue of the cutis vera.139

and concluded "That actual penetration of the Ancylostoma larvae into the skin does occur can now be looked upon as unassailable" 139. Looss's colleague, FM Sandwith, professor of medicine at the same hospital, later in the year (1901), presented Looss's observations to the annual meeting of the British Medical Association 177. (This caused some confusion and Sandwith later had to specifically emphasize that it was Looss's and not his own research to which he was alluding178.) In the ensuing discussion, GM Giles, despite being opposed to Looss in the matter of heterogonic development of hookworm, supported ardently the latter in this respect, and remarked that he had examined Looss's histological sections when in Cairo a short while before86. Patrick Manson, on the other hand, was somewhat more cynical: I would deprecate premature interpretation of the fact as indicating a phase in the normal life-history of the parasite or as a method of infection....Before the fact can be accepted as more than a curiosity, further experiments....should be carried out.147

In view of the continued scepticism, Looss persuaded an hospital attendant

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to volunteer for an experimental infection. The subject's faeces were examined daily for six weeks and were found to be free of hookworm ova. A drop of culture containing infective larvae of A. duodenale was then placed on his forearm. The first egg was found in his faeces 71 days later, and every stool for the next month was positive142. Looss's hypothesis soon received independent confirmation from another source. In 1901, Charles Bentley, a medical officer to the Empire of India and Ceylon Tea Company in Assam, India, began to investigate the cause of a condition variously called "ground-itch", "pani-ghao", "water-itch" and "coolie-itch", which was prevalent in the tea gardens of the Indian subcontinent and in sugar plantations in the West Indies. This illness was characterized by a vesicular dermatitis of the feet which occurred epidemically in workers during the rainy season. In 1901, Dalgetty had suggested that the affliction might be caused by an acarus (mite)62. In order to verify this suggestion, Bentley took some soil from a known infective area, moistened it, and applied it to the arm for six hours; the typical eruption resulted. Microscopical examination of the used soil and an unused aliquot of the same material failed to reveal any acari, but disclosed the presence of A. duodenale larvae, minutes leeches, small earthworms, rotifers, various protozoa, fungi and bacteria. In order to exclude sensitization to a chemical, a portion of the soil was sterilized by heating and the experiment repeated; no eruption resulted. Bentley then examined soil from a non-infective area and found only earthworms, leeches and protozoa, so he concluded that either the hookworm, a fungus, or a bacterium was responsible. He then scraped the skin of patients with early cases of ground itch and found empty hookworm sheaths on the surface. His next procedure was to culture soil with or without faeces containing hookworm ova for a week, take two samples from each culture, then kill the hookworm larvae in one sample from each culture by gentle drying. On application of these four specimens to the skin, only the one containing living hookworm larvae caused ground itch. Microscopical examination of that specimen failed to reveal any larvae and Bentley concluded: Apparently, therefore, the living larvae had entered the skin, and their entry had been followed by lesions similar in every particular to those found associated with the condition known as water-sore.28

Bentley then went on to consider the rarity of ground itch among the general rural population and suggested that this reflected a different method of disposal of human excreta, and postulated that the severe inflammation in ground itch might be due to bacteria associated with passage of the hookworm larvae28. In the years following these observations, patent infections were produced percutaneously with a variety of species of hookworms. Austregesilo reported that he had infected two students (presumably with N. americanus); eggs appeared in the faeces 67 or more days later21. Caldwell recorded the accidental infection of a laboratory worker with N. americanus. Fluid containing larvae

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was spilt upon the hand and produced immediate itching. The following day, the area was grossly inflamed. After two days, axillary lymphadenitis was present, then marked bronchitis succeeded on the third day. The stools became positive 38 days after infection51. In 1933, Maplestone reported the successful experimental infection of humans with A. ceylanicum 148. Thus, there was no doubt that infection could be acquired percutaneously. The next question concerned the relative importance of the oral and percutaneous routes in human hookworm infection. Peiper in German East Africa (1912) conducted a careful series of studies and concluded that although a small proportion of infections may be acquired orally, either by drinking contaminated water or by consumption of contaminated, raw vegetables, the usual mode of infection was undoubtedly by way of the skin, with larvae being either brushed off damp grass or taken up from infected soil by the feet165. Finally, two other routes of infection have been suggested. In 1917, Howard reported the discovery of ova in the stool of an infant only 14 days old102, then de Langen found them in the faeces of a six day old infant122. The only possible explanation other than that unclean habits on the part of an infected mother may have introduced ova into the mouth, and that these passed through the gastrointestinal tract unchanged, was that prenatal, transplacental infection had occurred. More recently, it has been suggested that hookworm larvae may be transmitted in breast milk.

DETERMINATION OF THE ROUTE OF MIGRATION OF LARVAE Having proven to his own satisfaction, if not to everyone else's, that larvae penetrated the skin, Looss then turned his attention to examining the course of migrating larvae within the body, and in the process of defining this remarkable pathway, proved the truth of his theory beyond any doubt. For these experiments, Looss used dogs and infected them with the hookworm, A. caninum, which was able to complete its development in that host. First, he infected some puppies percutaneously, and when they died nine days later, found immature ancylostomes in the small intestine. He then infected a group of puppies and killed them at various times after infection. Looss showed that larvae entered the lymphatics in the subcutaneous tissues and passed via the draining lymph nodes to the bloodstream, or else entered the veins and were carried through the right heart to the lungs. He found larvae both in the pulmonary capillaries and in the alveolar air spaces, although he did not see a worm precisely in the act of escaping from a capillary to an alveolus. The larvae then migrated quickly upwards along the surface of the bronchiolar, bronchial and tracheal epithelium, then passed through the larynx to the oesophagus. During their migration through the respiratory tree, Looss noted that the larvae began to grow and became prepared for the third ecdysis,

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although that event did not take place until the worms had reached the intestines. He then repeated this experiment with A. duodenale in dogs, and found that the larvae penetrated the skin and passed to the lungs, but that in their ascent of the airways, they grew less rapidly and that no trace of the provisional mouth-capsule, which normally appeared prior to moulting, was present. Furthermore, most of the larvae made their way into the tracheal mucosa and very few reached the gut; those that did were passed in the faeces. Looss presented his findings to the International Congress of Zoology in Berne in 1904 and published his results in detail in the following year141. Looss's observations were soon confirmed by other workers. Fritz Schaudinn of the German Imperial Board of Health infected monkeys with hookworm larvae percutaneously. The first animal died 13 days later and 36 worms were found in the small bowel. A second monkey was infected on 11, 29 and 30 June 1904, then killed six hours after the last infection; worms were found in the skin, heart, lungs and intestine181. In the following year, Lambinet produced patent infections in dogs given A. caninum orally, percutaneously and subcutaneously; he found that most of those given orally or subcutaneously matured but that a proportion of those given percutaneously perished in the process113. In 1914, Friedrich Fülleborn reported an extensive series of investigations on the migration of S. stercoralis and Ancylostoma in dogs. Fülleborn interrupted the tracheo-oesophageal route by tracheotomy or oesophagotomy in order to see whether this route was essential for the maturation of worms in the gut. When the former operation was performed and a dog was then infected percutaneously, larvae were found in the tracheal mucus 2-6 days later, but a few eggs were seen in the faeces. When another dog underwent the latter operation and was then infected subcutaneously, no hookworms developed in the gut. Consequently, Fülleborn concluded that the vast majority of larvae followed the pulmonary circuit78. Soon afterwards, Miyagawa (1916) investigated the migratory route of A. caninum larvae in dogs and confirmed the pulmonary-oesophageal route after percutaneous infection. In addition, he showed that some of the larvae given orally also followed this pathway after boring through the oesophageal or gastric mucosa151. On the other hand, Yokogawa and Oiso repeated this experiment with tracheotomized dogs some ten years later, and concluded that the pulmonary route was not necessary for maturation 207. Nevertheless, both Fülleborn 79 and Okada158 introduced A. caninum larvae into isolated loops of small intestine and found mature worms in the normal bowel, thus indicating that systemic migration must have occurred. The question remains incompletely resolved, and the behaviour of A. duodenale and N. americanus in humans after oral infection is unknown. What is clear is that worms mature in the gut two to three months after infection. A number of studies have been carried out on the persistence of

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hookworms under conditions in which reinfection is not possible. These investigations have shown that the life span of hookworms is generally one to two years, with 50-70% of worms being lost in one year, although a few parasites seem to persist for many years55,149. Stoll, in a small series of patients, calculated that each female N. americanus produced some 9,000 eggs per day197, while Hill in a much larger series, concluded that the figure was closer to 2,500 ova per female worm per day99.

CORRELATION OF INFECTION WITH PATHOLOGY In the first four patients found by Dubini, all the worms were located in the intestinal mucus. In the next positive cadaver that he dissected (on 1 January 1845), however, he saw that "Two of them (the worms) were firmly attached by their heads to the mucosa, and the mucosa was specked with small red dots"70. Subsequently, Dubini found hookworms in many patients, either in a free state, or sucking onto the intestinal mucosa. As a result of his accumulated observations during many post-mortem examinations, he reached the following conclusions about the worms: - their exclusive habitat is the duodenum and the beginnings of the jejunum. - the mucosa, to which the worms sometimes adhere by their oral cavity, may appear to be normal or else slaty, greatly specked with black or red, or also simply hypervascular. - the variety of illnesses from which these people died does not permit us to establish a relationship between the affliction and the presence of these worms70

Although he did not realize their significance, Dubini made two observations necessary for a proper understanding of the pathogenesis of hookworm disease - the attachment of worms to the small intestinal mucosa by their mouth and the small haemorrhages around worms. The person who was able to herald the pathological importance of hookworm infection was Wilhelm Griesinger while working in Cairo. Many patients in Griesinger's clinic suffered from severe anaemia, the syndrome being labelled by Griesinger and his colleagues as Egyptian chlorosis. He sought the aetiology of this condition without success for several months. During one of his last autopsies (17 April 1852) before his return to Germany, much light was shed on the matter. A twenty year old soldier died, apparently from diarrhoea. At autopsy, all the organs were extremely anaemic, the heart was dilated and the lungs were markedly oedematous. When Griesinger examined the intestines, however, he found that: the duodenum, the whole jejunum and even the upper half of the ileum were completely filled with fresh, red, partly coagulated blood. Thousands of ancylostomes were hanging in the mucosa of the small intestine, each with its own small petechia resembling the bite of a leech.92

He concluded, therefore:

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It was clear that in every respect the deceased belonged to the 'chlorotics', and had bled to death. Since then I have become convinced that the 'Egyptian chlorosis' is an entozoal disease, above all an ancylostomiasis.92

Griesinger postulated that the daily loss of blood in the gastrointestinal tract must result in anaemia. He asserted that such haemorrhage need not be visible macroscopically, since not only did bleeding come from the upper small bowel, but the faeces of Egyptians were copious and mushy as they consumed large quantities of bread. Rather, he believed that the continuous extraction of blood for their own sustenance by hundreds or thousands of hookworms over the years would be sufficient to account for the development of anaemia. Griesinger left Egypt shortly thereafter and was unable to prove his views statistically, but had no doubt that subsequent investigators would confirm his hypothesis92. In fact, his colleague, Theodor Bilharz, who carried on this work, came to the same conclusions and published his observations 31 two years before Griesinger's paper appeared. Despite these tantalizing suggestions, little further attention was paid to the subject until Otto Wucherer in Brazil recognized the same phenomenon. In December 1865, he was called to see a slave in a sugar mill who was grossly oedematous and markedly anaemic. The patient died within 24 hours and at autopsy, Wucherer found many hookworms and the same features that Griesinger had described. In order to ensure that the association was not coincidental, Wucherer made post-mortem examinations on twelve persons with other diseases and failed to find any hookworms. Furthermore, since he found subsequently the parasites in the bodies of five more patients who had this syndrome (which he called hypoaemia or tropical chlorosis), he was convinced of a causal relationship between the two events204,206. The publication of Wucherer's findings led J R de Moura in Rio de Janeiro to examine the bodies of patients with tropical chlorosis and he also found hookworms in 91 them153 . Subsequently, Grenet in the French colony of Comoros (1867) , Camuset in French Guiana (1868) 52, and Kérangel in the French colony of Cayenne (1868) 108 confirmed Wucherer's observations. The findings of Wucherer and de Moura were discussed at the Academy in Rio de Janeiro and the general opinion was reached that hookworms were not a primary and necessary cause of tropical anaemia, but rather a cooperating agent in its production (cited in206). In his turn, Wucherer protested against this view205. Thus was born a controversy which was to persist for decades. There were two great questions: (1) did hookworm infection cause disease at all?; and (2) how many worms were necessary to cause illness? In 1878, Sangalli179 in Italy, like Dubini, cast doubt on the idea that hookworms caused any significant disease when he showed that autopsy examinations in the University of Pavia revealed that half of the cadavers were infected with hookworm, but that the symptoms and signs of disease did not by any means appear to be as serious as might have been inferred from previous descriptions, particularly those of Griesinger and Bilharz.

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The potential importance of hookworm infection was brought home to many European doctors, however, by the outbreak of hookworm disease which occurred during the building of the St. Gothard tunnel, a railway tunnel in the Swiss Alps which was opened in 188347,48,164. At the beginning of 1880, a large number of workmen, mainly from Piedmont, returned home ill. Despite their evacuation from the tunnel, the condition of many patients worsened and several died. In February 1880, one of these persons died in hospital in Turin from what had been labelled "pernicious anaemia". A post-mortem examination by Francisco-Vittoria Colomiatti, professor of pathology at the University, disclosed some 1500 ancylostomes in the small bowel. Considerable argument at both medical and political levels then ensued as to whether the St. Gothard anaemia was due to ancylostomiasis or to poor hygienic conditions, particularly bad air, poor light and unsuitable food. Some investigators, such as Bozzolo and Pagliani, supported the latter view, at least initially41. The former view eventually prevailed, however, particularly as a result of the work of Eduardo Perroncito who found large numbers of hookworm eggs in the faeces of many patients, and showed that they responded to treatment with anthelmintics 57,167,168 The confusion over the role of hookworms in the genesis of disease is further illustrated by the following sample of views expressed over the next few years. In 1882, JF McConnell reported for the first time that hookworms were present in India, and noted that anaemia was present in only 40% of these patients. He made no reference to the worm burden, but wrote: "My opinion is that their presence is to be regarded in the majority of cases as purely accidental, and their relation to any special disease a coincidence" 144. Similarly, Attygale in Ceylon in 1888, could not find ancylostomes in half of his patients with anaemia. Furthermore, he realized that hookworms could not reproduce in the bowel and presumed that the worm burden depended upon the number of eggs ingested, so asked the question: Might it not also be considered with greater reason that whatever induced the disease [i.e. anaemia]....in cases in which the anchylostoma was absent, was also the cause [when they were present], and that the presence of anchylostoma in these cases was of no more import in its causation that that of the lumbrici found in common with it in a large number of cases?17

Sonsino (1890) forthrightly denied any connection between hookworm infection and severe illness of the type described by Griesinger when he wrote: I think the so-called African cachexia and Griesinger's Egyptian chlorosis cannot rightly be identified with ankylostomiasis, inasmuch as they are the combined result of different morbid conditions into which frequently, but not constantly, ankylostomiasis enters as an element.190

In like manner, Dobson in India (1893) examined the stools of 1,249 persons, most of them healthy coolies en route to work from various parts of India on the Assam tea plantations. He found hookworms in 76% of these individuals, with numbers varying from very few to hundreds. Moreover, it sometimes happened that a person with very few worms was in very bad health whereas some

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persons in whom there was a great abundance of parasites were robust and healthy. Furthermore, in 15 cases of kala azar (which some persons had postulated was caused by hookworm infection), there were only 0-36 hookworms, so Dobson concluded that hookworms had no great influence as a factor in the genesis of disease, whether it be the "beri-beri of Assam" or anything else69. Such views were echoed by Williams203 and by Zinn and Jacoby208. On the other hand, Kynsey in Ceylon (1887) 112 and Giles in Assam (1890) 83 were both convinced that the so-called "beriberi" of Ceylon and Assam or "kala azar" of Assam were due to ancylostomiasis. This occasioned some confusion, for "beriberi" was a rather elastic term including a number of entities such as wet beriberi (cardiac failure) and dry beriberi (peripheral neuropathy) that are now recognized as being due to thiamine deficiency, and kala azar is the name now given to the disease caused by infection with Leishmania donovani. Nevertheless, the disease then called beriberi in Assam and Ceylon was of the wet variety in both cases and may well have been related to ancylostomiasis in the form of marked hookworm-induced anaemia and consequent congestive cardiac failure. An anonymous commentator in the British Medical Journal came very close to the truth when he remarked in 1893: In the healthy and robust native, with a liberal physiological margin to draw on, a few hundreds of minute nematodes in the alimentary canal may be a circumstance of little importance; but when the native has been half starved all his life, and is further reduced by actual famine, by malaria, dyspepsia, enteritis, overwork, and other conditions tending to diminish the amount of aliment absorbed, while at the same time they tend to increase waste and destruction - in these conditions a daily steady drain of blood by a swarm of anchylostomata, though it may after all be but a small one, may prove to be the last straw which breaks the camel's back, the final factor which determines the starting of the vicious pathological circle.7

Two events in particular which occurred around the turn of the century did much to convince the sceptics that hookworm infection sometimes culminated in serious disease. The first of these was the spread of ancylostomiasis from the St. Gothard's tunnel and elsewhere to the rest of Europe. Miners and expatriates returning from the tropics carried hookworms with them to the congenial surroundings of the brickfields of Austria, Hungary and Germany, and to the coalmines of France, Belgium and England, where the parasites flourished in the warm, damp, insanitary conditions underground8,77,159. This epidemic confirmed the pathogenicity of the parasite, for many people developed severe anaemia, and it stimulated many investigations into the habits of the larvae, the genesis of anaemia, and means of prevention. The second series of observations emanated from the Western Hemisphere. In August 1899, a hurricane wreaked havoc in Puerto Rico. Bailey K Ashford of the United States Army was put in charge of a temporary hospital to deal with the thousands of sick, homeless, starving peasants who were mountain dwellers of Spanish descent. When they were fed on the nourishing diet of the

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American soldier, they developed diarrhoea. When they left camp and returned to their normal, bulky diet, the diarrhoea resolved but the anaemia with which they were also afflicted did not. A search for malarial parasites as a cause of the anaemia revealed the presence of a blood eosinophilia which in turn stimulated inspection of the faeces for hookworm eggs. These were found in abundance and on 24 November 1899, Ashford in Ponce sent a telegram to the chief surgeon in San Juan: "Have this day proven the cause of many pernicious, progressive anemias of this island to be due to Ankylostoma duodenale. 15 Ashford"14. He published his findings in the following year . Several years later, Ashford headed a commission for the study and treatment of anaemia; his earlier belief that hookworm infection was a major cause of disease was confirmed fully16. As a result of these and other observations, the tide of opinion began to turn, with Baker (1903) writing: I firmly believe that ankylostomiasis is productive, both directly and indirectly, of far greater mortality than the vast majority of medical men have any conception of. The large number of deaths ascribed to unknown causes, the heavy mortality attributed to general dropsy and debility, and the great loss of life occurring among paupers found dying the streets of tropical towns, I am convinced, were in the past and are today in no small measure due to ankylostomiasis. There are few things more remarkable in the whole history of tropical medicine than the failure to realize and the reluctance to admit, on the part of many medical men, the injurious tendency of an invasion of the body by the parasite which gives rise to ankylostomiasis.25

Similarly, Boycott (1911) said in his Milroy lectures: Taking the world as a whole, with the possible exception of the malarial organisms, ankylostoma is, I suppose, responsible for more unhappiness and inefficiency than any other parasite, and for the most part indirectly for no inconsiderable number of deaths. Practically all tropical countries are permeated with the worm, and in places where the conditions for its propogation are favourable it may reduce four-fifths of the population to a continual state of chronic ill-health which is only terminated by the premature decease, commonly with some secondary infection.37

Around this time, however, the pendulum began to swing even further away from the point at which it had at one time stood. Far from saying that hookworms were never pathogenic, some authors began to claim that hookworms always caused disease, even when the worm burden was small. This was brought about by observations flowing from the campaign to control hookworm in the southern USA just before World War I. It seemed that hookworm carriers, i.e. those with hookworm infection but with no apparent ill-effects from the infection, improved in health and energy after treatment. This was interpreted as an indication that they were not simply carriers, but that their general ineptitude, which had been put down to laziness, carelessness, or race, was in fact due to hookworm infection. Thus, Stiles in 1914 was induced to write: There still exist a number of persons who believe that light infections are of no clinical importance....The view that infection with less than 100 or 50 worms is clinically

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unimportant is negatived by the fact that treatment of such cases has resulted in the children in question having made greater improvement in certain respects, in a given time, than has a control group of children who did not show hookworm infection and a control group of children who did have the infection but were not treated.195

This view was echoed by Lane (1918). He quoted passages from the Reports of the Rockefeller Sanitary Commission which, he believed, demonstrated that the officials of the Commission began with the premise that light infections were of little moment to the host, yet finished thoroughly convinced that even very mild infections constituted a grave handicap. Similarly, he quoted letters from managers of tea estates in Darjeeling, India, where there was widespread but moderate hookworm infection, who were pleased with the effects of anthelmintic treatment on the health of their labourers. This stimulated Lane to write: "We seem then to have no option but to conclude that light infections are of clinical moment to the individuals concerned"117. Lane later indicated that the practical import of this view was that the only safe course was to regard no infection as clinically unimportant until such time as the dividing line between hookworm infection and hookworm disease had been defined scientifically 120. As late as 1935, he proclaimed: "the host's interests demands complete deworming"121. Stiles in the USA and Lane in the United Kingdom were the most ardent, prolific and persuasive writers on this subject, expounding the view either that light infections were important, or that, at the very least, it was not proven that they were unimportant. Not everyone accepted this belief, however, Boycott in 1911 drew a distinction between Ancylostoma infection and ancylostomiasis, defining any individual who harboured parasites in his intestines but without having any symptoms or signs of the infection as a "worm-carrier" and as the subject of hookworm infection, whereas those infected persons who had dyspepsia or anaemia as a consequence of that infection were deemed to suffer from ancylostomiasis37. Similarly, Gordon in 1925 reported that his studies of West African males revealed no effect by hookworm infection on haemoglobin level, physique or mental alertness, and recommended that the effects of hookworm infection on a particular population should be assessed by correlating pathogenic effects with intensity of infection before embarking upon mass treatment89. This information caused Harold Scott in his review of the paper to write: This article is of great interest and serves as a refreshing counterblast to exaggerated records of the dire evils of hookworm infection....(which have been recorded as ranging from) rheumatism to nyctolopia [night blindness].185

This idea was taken further by Smillie and Augustine (1926) in the USA who divided children up into groups on the basis of hookworm numbers. They found that no adverse effects upon clinical status or haemoglobin level were seen when less than 100 worms were present, and more than 500 worms were required for the full clinical disorder to be produced187. When they analysed changes three months after treatment, they discerned no effects of this

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intervention in children who had less than 25 worms, an improvement in haemoglobin concentration only in those with 25-100 worms, and enhanced gains in height, weight and haemoglobin level in those who had more than 100 worms188. In the same vein and as a result of his own investigations in Argentina, Fülleborn declared: One becomes more and more convinced I think, that in the past the damage caused by a slight hookworm infection has often been overestimated, at least as far as Necator is concerned.80

Also in 1929, Chandler reviewed the evidence. He noted that the difficulty with the early Rockefeller reports was that they grouped all grades of infection together, so that improved health and efficiency in a small number of heavily infected individuals might be sufficient to provide the observed improvement in the group as a whole. He remarked, however, that more recently, incidence data had been supplemented with information on the intensity of infection, which brought him to hold the opposite conclusion to Stiles and write: Recent investigations have, fortunately, made the opinion that any hookworm infestation, however light, is harmful, practically untenable. No doubt even a single hookworm does some injury to its host, but this injury, in a normal individual, is so easily compensated that it is of little or no consequence.56

It was only with the elucidation of the pathogenesis of hookworm anaemia, as described in the next section, that the controversy was resolved, with the view being generally upheld that heavy worm burdens were usually required for the production of anaemia.

DETERMINATION OF THE PATHOGENESIS OF HOOKWORM ANAEMIA Amongst those who accepted that hookworms might cause anaemia, the question arose as to how the anaemia was produced. The first and most obvious way, as reported by Griesinger, was as a consequence of massive bleeding into the gut. At one time, it was thought that only a few worms were necessary, for it had been shown that when hookworms moved, they left wounds behind them which continued to bleed, and this led one anonymous reviewer to write in 1889: "Hence it is easy to understand how a very few may cause fatal anaemia"6. An alternative possibility was canvassed by Rake in 1894: Is the anaemia the result of a simple drain of blood from the gut by worms, or is it, as William Hunter contends, the result of excess blood destruction in the portal circulation effected by the action of certain poisonous agents absorbed from the gut through breaches made by the worms?172

The likely importance of this latter mechanism seemed to be heightened when the authoritative and prestigious Looss declared that the epithelial cells of the small bowel rather than blood provided the food supply of hookworms 140. Before any proper understanding of hookworm anaemia could be gained, however, the condition had to be differentiated from idiopathic pernicious

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anaemia. One of the first persons to investigate hookworm anaemia in detail was Arthur Boycott who studied miners in Cornwall infected with hookworm. He recognized (1907) that the degree of anaemia was in general proportional to the number of worms present, although he qualified this statement by saying that exceptions occurred, and suggested that the frequency with which further infections were acquired may be a more important factor. This latter comment was based largely upon the improvement often seen when patients were removed from an endemic location, thus allowing worms to be expelled gradually and haemoglobin concentrations restored. The importance of this observation was that the natural history of hookworm anaemia was clearly different from the progressive downhill course of pernicious anaemia. So was the appearance of the blood film. Boycott emphasized that in hookworm anaemia the red cells were microcytic and that the colour index fell (i.e. they were hypochromic), whereas in pernicious anaemia the erythrocytes were macrocytic and the colour index was normal36. Nevertheless, Boycott was puzzled by the mechanism by which the anaemia was produced, for he did not believe it was due to gastrointestinal haemorrhage, and considered that the haemolysin and anticoagulant factor which had been found in hookworms a short while before by Loeb and Smith135 were of no great import. Experimental studies by Huart in Leiden, Holland104 and by Fülleborn and Kikuth in Hamburg, Germany81 in 1919 using dogs infected with A. caninum and A. braziliense, however, re-emphasized the role of gastrointestinal haemorrhage in the genesis of hookworm anaemia, and failed to identify a place for haemolysis in the production of the anaemia. The processes by which haemorrhage occurred were observed in vivo by Wells, who watched the behaviour of A. caninum in the opened intestine of anaesthetized dogs. Worms moved around on the mucosa for hours, but eventually attached themselves to the bases of some villi. The vessels of the villi became distended, blood appeared in the mouth of the worm, and the oesophageal muscles pumped blood through the gut at the rate of 2-4 pulsations per second. Wells calculated that each A. caninum wasted nearly 0.84 ml of blood a day201. The importance of gastrointestinal blood loss was then underlined by three studies reported in 1934. Biggam and Ghalioungui in Egypt found that oral iron corrected hookworm anaemia, even when the patient was still harbouring worms, but that removal of the worms alone produced little or no change in the blood picture30. Rhoads and Castle showed in a study of 150 patients with hookworm anaemia in Puerto Rico, that either the intramuscular injection of erythrocytes or the oral administration of iron, but not liver extract (rich in vitamin B12), stimulated red cell production and a rise in haemoglobin concentration. They concluded that since deficient diets were the rule, and as gastric hypochlorhydria was present frequently, it seemed likely that dietary deficiency and gastrointestinal disturbances were of major aetiological significance 174. The role of iron deficiency in the genesis of this anaemia was also supported by Cruz in Argentina; he observed that a rich meat diet or the

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administration of large doses of iron prevented the appearance of anaemia61. Similarly, Napier and his colleagues in India a few years later considered that even a heavy load of worms did not produce anaemia unless the diet was deficient in iron. Further, they showed that a return of haemoglobin level to normal could be achieved with iron alone, but that this was not maintained unless the worms were removed by anthelmintic therapy156. In the same manner, Andrews in the southern USA concluded that hookworm disease was more likely and more severe when worm burdens were high and protein consumption was low3. Thus, the pendulum began to swing once more, and it became generally accepted that the likelihood of anaemia was directly proportional to the worm burden and inversely proportional to the iron and protein intake in the diet. By the same token, growing children and menstruating or pregnant women were more likely to develop disease with a lower worm burden by virtue of increased demands upon, or losses of, these nutrients. In 1957, Roche and his colleagues quantified gastrointestinal blood loss in human hookworm infection by labelling erythrocytes with radioactive chromium then measuring the radioactivity subsequently lost in the faeces. They calculated that approximately 0.03 ml blood was lost per day for each N. americanus, but that 0.2 ml was lost for every A. duodenale 175. In most people with a normal or highly nutritious diet, therefore, there was little probability of a significant fall in haemoglobin concentration. More than 2,000 eggs per gram of faeces were necessary before anaemia was seen in Venezuela123, anaemia was not seen unless egg counts were greater than 1,000 per gram in the Gambia199, and considerably higher counts were required in Nigerians who had a much higher daily intake of iron87. This realization led to an increased emphasis on hookworm disease and less on hookworm infection, and the arguments which had been raised over the efficiencies of various concentration techniques for the diagnosis of hookworm infection (see later) became less relevant. As a parenthetical postscript, it may be remarked that blood-letting activities of hookworms have even been made use of therapeutically in the treatment of polycythaemia rubra vera45,71.

RECOGNITION OF THE CLINICAL FEATURES Classical descriptions of illnesses that were possibly or probably a consequence of hookworm infection were described long before the worms themselves were recognized. Attempts have been made to find evidence of hookworm disease in the Egyptian Papyrus Ebers (c.1550 BC)162, particularly in the - - disease which was said to be a chronic disorder of the gastrointestinal tract followed by a disturbance of the circulatory system182, although more modern opinion favours its association with schistosomiasis101,169. Nevertheless, Ebell expressed the opinion in his translation of the Papyrus Ebers that the anaemia mentioned

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in association with the worm was probably hookworm anaemia72. Hippocrates (c.460-375 BC) may have been dealing with hookworm infection when he spoke of pallor in people who ate dirt100. In 50 BC, Lucretius wrote of the pallor of those who worked in mines. Khalil109 has claimed that Avicenna (981-1037 AD) referred to hookworms, although this view is not now generally accepted101. Various accounts emanating from Central and South America are consistent with a diagnosis of hookworm disease, as in the following extract from a book by an anonymous author who was apparently a doctor and a planter: When a negro is languid and listless, and so much indisposed to motion as to require to be impelled to it by threats, when he is short-breathed and unable to ascend a hill without stopping, his efforts for that purpose being accompanied with a throbbing of the temples and a violent palpitation of the heart; when he complains of giddiness, his lips being pale and his tongue white, you may know him to labour under that disorder which the French call mal d'estomac and the English after them by the same name or 'dirt-eating' from the propensity which there is in that case to eat chalk or clay or some other kind of dirty substance....This disorder which as I observed is very common in West Indies estates is also one of the most obstinate and troublesome that negroes are afflicted with. It disables them from effective labour for a considerable time, sometimes for years, and often terminates in dropsy.5

As mentioned earlier, Griesinger in Egypt was familiar with the syndrome of Egyptian chlorosis before he discovered its relation to hookworm infection. He wrote that the symptoms and signs of this affliction were simply those of anaemia: The milder stages are characterized by pallor of the skin and the mucosa....a tendency to palpitations, a prolonged tachycardia, and slight fatigue on exertion....(In) the chronic form....the patients....develop edema in the lower extremities, the eyelids and other parts; their skin....becomes a dirty pale yellow, yellow or green-white....At the same time it becomes very withered, flabby, cool, dry and scaly; the conjunctiva is blue-white, and the lips and all visible mucous membranes are a deathly pale. Marked generalized weakness and fatigue....makes the patient very indolent and apathetic....Palpitations corresponding to the heart beat, the intensity of which we have never seen before, persist in many patients....The pulse is very rapid and weak. In all the larger arteries one hears a blowing sound....Patients often suffer from vertigo....Dyspnea occurs after a few steps ....The overall condition of the patient must be viewed as a state of advanced anemia or fluid retention.92

Clearly, in these patients, the anaemia had become so intense that marked features of congestive cardiac failure had supervened. The same clinical manifestations were then described by Wucherer204,206, de Moura153 and others in South and Central America. In 1878, Grassi and his colleagues in Italy published clinical notes on patients with hookworm infection, a number of whom were anaemic90. Similarly, the clinical features of anaemia in association with ancylostomiasis were highlighted in miners working in the St. Gothard Tunnel in 188047,57, and islanders living on Puerto Rico15. Thus, it was recognized that the clinical features of severe hookworm disease were those of marked anaemia produced by the mechanisms discussed earlier.

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While the clinical features of gross hookworm anaemia were clear, the other manifestations of infection were rather more obscure. Dermatitis (ground itch - see section on the proof of the percutaneous route of infection) was only observed sometimes. Migration through the lungs was thought to produce cough, wheezes and hoarseness in some patients10. Conflicting accounts were published on growth retardation and mental sluggishness 89,187,188,200. The gastrointestinal symptoms were also difficult to define because concurrent infections with other gastrointestinal pathogens was so common. Experimental infection with sole hookworm infections, however, provided some useful information. Brumpt infected patients with hypertension or polycythaemia with about 400 hookworm larvae and noted an initial dermatitis, subsequent upper respiratory symptoms (but no indication of Löffler's syndrome), then indigestion and diarrhoea. The abdominal discomfort soon cleared up but the diarrhoea sometimes persisted for a month45. Similarly, experimental infection with A. ceylanicum indicated temporary, but severe, indigestion, flatulence and abdominal distension 202.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of ancylostomiasis was first made only post-mortem. Wucherer in 1866 posed the question as to whether it might not be possible to determine the presence of hookworms during life in order to distinguish hookworm anaemia from the anaemia of "malarial cachexia". He found, however, that thus far he had not been able to locate adult worms in the faeces, even after the use of anthelmintics, and remarked further: "this diagnostic tool, even if it were reliable, would not be used very frequently by our colleagues" 204. It is surprising that neither Wucherer nor any of his contemporaries paid any attention to looking for hookworm eggs in the faeces, since Ransom (1856) and Davaine (1857) had shown the value of this diagnostic technique in ascariasis, trichuriasis and taeniasis, and Davaine had publicized it widely in his textbook of 186066. It was not until 1878 that the Italian parasitologists, GB Grassi, Corrado Parona and Ernesto Parona reported that: the diagnosis of Ancylostoma is very easy. To do this rapidly, it suffices to examine a little feces or vomit, diluted with any medium, at the microscopic magnification of at least 90 diameters. If the material is fresh, only Ancylostoma ova undergoing segmentation will be found; if it is stale, embryos and larvae will also be found.90

Grassi and his colleagues proved the diagnosis in several of their cases by the administration of anthelmintics and the recovery of adult worms; in one patient, an estimated 440 worms were found in the faeces90. This method of diagnosis was likewise taken up with success two years later by Perroncito when he diagnosed Ancylostoma infection in St. Gothard tunnel miners presenting to Concato's clinic57. As the technique became more widely used, it was realized that simple faecal

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smears did not always detect light infections. The forceful opinions expressed by some that light infections were of clinical significance generated intensive efforts, particularly in the first third of this century, to develop concentration techniques in order to permit detection of such infections. The various tests designed up to about 1930 have been reviewed by Lane120, who himself devoted many years to the problem. Later concentration techniques have been described in chapter 9. In addition, Harada and Mori in 1955 described a completely new method of cultivating hookworm larvae on moistened filter paper which they believed was considerably more efficient than flotation methods for detecting infection96. Quantitative techniques have permitted counting of the number of eggs in the faeces and this has been widely accepted as providing an index of the worm burden, although there have been a few vocal opponents of this view121. The identification of hookworm eggs in the faeces has been used in recent times to confirm the antiquity of hookworm infection, although this test is not able to differentiate between the species of hookworms. Hookworm eggs have been seen in human faeces in Brazil dating from 430-3490 BP74. A number of efforts have been made to develop immunological tests for the diagnosis of hookworm infection. Ghedini (1907) found complement fixing antibodies in the serum of patients with hookworm infection82. Pirie and colleagues in 1929 reported a skin test for the diagnosis of hookworm infection170. Such efforts, however, have been largely unrewarding as the diagnosis is made relatively easily by parasitological methods except in prepatent infections, and immunodiagnosis gives no indication of the worm burden. Similarly, the blood eosinophilia in hookworm infection, first described by Müller and Rieder in 1891154, is nonspecific and is merely a pointer to the possible presence of infection. The diagnosis is sometimes suggested by radiography. Krause and Crilly reported that barium meal examination revealed alterations in the small bowel mucosal outline which they called a "deficiency pattern"111. Finally, as sophisticated gastrointestinal endoscopic facilities become more widely available, someone in the near future will undoubtedly report the diagnosis of hookworm infection by the observation of adult worms during duodenoscopy.

THE SEARCH FOR EFFECTIVE TREATMENT As early as 1866, Wucherer in Brazil reported that latex d'higueron, an extract of the figs, Ficus laurifolia and F. glabrata, was effective in the treatment of hookworm infection204. Indeed, because of its effectiveness and local availability, this drug at one time became the basis of a hookworm control campaign in Venezuela 152. The preparation was not generally obtainable in Europe, however, and Grassi and his colleagues in Italy treated their patients with a

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combination of santonin, calomel, jalap and sugar with a modicum of success90. Interest in the treatment of hookworm infection was stimulated by the outbreak of ancylostomiasis in miners working in the St. Gothard tunnel around 1880. Perroncito in Turin26,167, then Ernesto Parona at Varese43,163 , Italy, claimed that the well-known remedy for tapeworm infection, filix mas (oleoresin of Aspidium, male fern) prepared from the powdered rhizomes of the fern, Dryopteris filix mas and related species) had antihookworm properties. Perroncito showed that an extract of filix mas killed larvae in vitro within five to ten minutes, then reported that he had reduced hookworm numbers in two patients by repeated administration of the drug167. Meanwhile, Camillo Bozzolo investigated the properties of thymol which is prepared from a large number of plants of the genera Thyme, Origanum and Carum. He had used it in 1879 in one patient with ancylostomiasis without effect38. The St. Gothard epidemic provided him with an opportunity to re-evaluate the drug more intensively. He increased the dosage and in 1881 claimed to have cured six patients39,40 with the consequence that the drug became very popular for the next several decades. Although there were claims from time to time that the drug was toxic and could be fatal, these were not accepted by Lane in his review of antihookworm agents in 1935121. Eucalyptus oil was a popular remedy for a time, but a number of investigators found it to be ineffective. Chloroform had been shown in 1885 to be active against tapeworms when used in combination with a purgative which caused passage of the anaesthetized worms27. Consequently, Herman in 1905 introduced a mixture of eucalyptus oil and chloroform for hookworm infection97 and this enjoyed transient fashionableness. Betanaphthol, a synthetic organic compound, was used by Bentley in 190429. Unfortunately, it sometimes caused haemolysis or nephritis, and occasionally death, and eventually fell into disrepute. Oil of chenopodium (American wormseed oil), prepared from Chenopodium ambrosioides var. anthelminthicum, an indigenous plant in the USA, had been a common household remedy for ascariasis in that country for many years. Baumler (1881) and Breton (1905) had tried it without success for ancylostomiasis, but then Bruning began to use it successfully in 190946. Subsequently, Schüffner in the Dutch East Indies (Indonesia) reported that it was more effective than thymol, betanaphthol or eucalyptus oil. He found that following a single treatment, oil of chenopodium eliminated 92% of hookworms, thymol dislodged 83%, betanaphthol expelled 64%, and eucalyptuschloroform-castor oil mixture removed 38% of worms, while male fern came a poor last183. Some 300,000 patients were treated with various remedies by the Puerto Rico Commission on hookworm, and an analysis of the results revealed that male fern was ineffective, eucalyptus was nauseating, and that thymol and betanaphthol were about equally efficacious16. All of these drugs, and many more, were investigated by Caius and Mhaskar in a major series of studies

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carried out in India50. Mhaskar in 1922 reviewed the results and concluded that of 54 substances investigated, oil of chenopodium, thymol and betanaphthol were the most effective drugs150. It was at this juncture that a new drug, carbon tetrachloride, was introduced. In 1921, MC Hall of the US Bureau of Animal Industry published a paper indicating that this agent was a useful anthelmintic in animals93. He then swallowed some of the chemical himself without ill-effect, and suggested its use in human hookworm infection94. A number of reports soon followed showing that it was effective in human ancylostomiasis 24,124,157. Considerable differences of opinion then ensued over the safety of the drug. Being aware that prolonged use of fat solvents such as carbon tetrachloride, chloroform and tetrachloroethane could cause severe liver disease, Nicholls and Hampton gave carbon tetrachloride twice to a condemned murderer then examined the organs after execution one to three weeks later. No signs of degeneration were found and they concluded that when given in a single dose, carbon tetrachloride was safe157. The drug became used widely and was employed with apparently few side-effects by some workers. For example, Bishop administered the drug to 25,000 cases in Trinidad and Tobago with little report of illness33, while Khalil claimed only one fatal result in 150,000 treatments 110. Nevertheless, these reports must be viewed with some circumspection, since there may have been a considerable latent period between the ingestion of carbon tetrachloride and the appearance of liver failure which may have obscured the relationship between the two events. On the other hand, some workers had sad experiences. For example, Straub and Kouwenaar had 16 deaths and gave up using the 155 drug198, while Nag reported three deaths in 289 children . With great indignation, Lane (1930) condemned its use, particularly in mass treatment campaigns where it had often not been shown that a particular individual was infected: For carbon tetrachloride....the fatal dose is [he should have said 'may be'] 1.5 c.cm.; while the dose advised as effective is 3 c.c., or twice the fatal dose. This advised dose has naturally killed a varying proportion of those who have taken it. Further, it has been freely administered without troubling to discover whether any particular recipient was infected, in which case it remains unknown whether the individuals so sacrificed should have been treated at all.119

Carbon tetrachloride was soon followed by its relative, tetrachlorethylene. This drug was introduced by Hall and Shillinger in 192595, and its effectiveness was confirmed by Schapiro and Stoll two years later180. The advantage of tetrachlorethylene over carbon tetrachloride was highlighted when Lamson and his colleagues in 1929 showed in experimental dogs that the hepatic necrosis evident after the latter drug was administered was absent when tetrachlorethylene was used115. In 1931, the same group of workers reported that hexylresorcinol, an alkylated derivative of phenol and related to thymol, was effective in ancylostomiasis 114, but this drug did not find a major place in treatment.

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The merits and demerits of the various anthelmintics known at this time led to contrasting views on the drug of choice in the treatment of hookworm infection. Lane (1935) damned carbon tetrachloride and extolled the virtues of thymol121, while Andrews (1942) espoused carbon tetrachloride and relegated tetrachlorethylene as being less effective3. The next major advance did not take place until 1958. In that year, it was shown that a new series of quaternary ammonium compounds was active against a broad range of nematodes parasitic in laboratory and domestic animals58. Goodwin and his colleagues then showed in a trial in Ceylon that one of these agents, bephenium hydroxynaphthoate, was active in human hookworm infection. The drug was shown to have an effectiveness comparable with that of tetrachlorethylene. Furthermore, it had the added advantages of less toxicity and some activity against Ascaris lumbricoides 88. In 1961, Brown and his colleagues described a new benzimidazole derivative, thiabendazole44, then a number of authors showed that it eliminated most nematodes from the intestines of sheep, pigs and horses. In the following year, Bui Quoc Huong and colleagues reported that thiabendazole cured 85% of humans infected with hookworm49, then many subsequent workers confirmed the effectiveness of the drug. In 1966, Austin and his colleagues discovered a new series of broad spectrum anthelmintics. One of these, pyrantel pamoate was active against mature and immature nematodes in animals20. Several years later, pyrantel embonate was shown to be effective in human ancylostomiasis, with 84% of patients being cured68. These findings were then confirmed by many other workers. Finally, Chaia and Cunha in 1971 showed that mebendazole, another benzimidazole derivative, was also very effective in hookworm infection54. The discovery and use of agents directed specifically against hookworms has not been the only way in which the problem of hookworm anaemia has been approached. As long ago as 1866, and before the mechanism of hookworm anaemia was defined and the biochemistry of anaemia due to blood loss was understood, Wucherer remarked that patients seemed to do better with the combined use of iron preparations and anthelmintics than when anthelmintics alone were given. In 1914, Day reviewed his experience in treating over 300 patients with gross hookworm anaemia (the average haemoglobin concentration was only 22% of normal), and showed that the addition of iron preparations hastened the recovery from anaemia after anthelmintic administration 67. As has already been indicated in the review of the pathogenesis of hookworm anaemia, many subsequent studies confirmed the value of treating hookworm anaemia with iron as well as giving anthelmintic therapy30,61,156,174. More recently, Topley concluded that although all hookworms should ideally be eliminated, this was most desirable in the most anaemic patients, and that for less severely affected persons, particularly men, iron therapy alone was often adequate. An anonymous writer in The Lancet concurred with this view:

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Ferrous sulphate is cheap, and now that iron-deficiency has been shown to be the commonest cause of anaemia among these people, whether from hookworm disease in men, or other causes in women, there seems every reason for training auxiliaries to test for it, keep records, and distribute tablets. Patients with severe anaemia, and those who did not respond to treatment, could be referred for more definitive treatment. The final answer to the problem of hookworm disease probably lies in environmental measures, but the use of oral iron could increase the economic potential of many populations.13

Such comments as this would have sent shudders up the spine of Stiles and of Lane, even if they did not cause them to turn in their graves, but they serve to exemplify how far conceptions concerning the management of hookworm infection and disease have swung.

UNDERSTANDING THE EPIDEMIOLOGY Both A. duodenale and N. americanus are disseminated widely throughout the tropical world, but their origins are uncertain. It was at first thought that A. duodenale emanated from the Old World and that N. americanus was indigenous to the Western Hemisphere. In 1905, Looss examined some hookworms obtained from six Central African pygmies and found that they were N. americanus. This observation led him to suggest that N. americanus may have been carried to the Americas from Africa by negro slaves140. Leiper (1907) confirmed Looss's observations, finding N. americanus not only over wide areas of Africa apart from Egypt, but also in specimens emanating from the Indian subcontinent131 and from Australia. Furthermore, Soper (1927) believed that A. duodenale had a much longer history in Central and South America than had been thought and suggested that, in addition to being brought over by the early Spaniards, the parasite may have been indigenous to the Indian race191. The longstanding presence of A. duodenale in South America was supported when an apparent A. duodenale was found in the small intestine of a mummified body discovered in Peru and dating from about 900 AD2. An understanding of the epidemiology of hookworm infection was largely incomprehensible until the percutaneous mode of infection was discovered by Looss around the turn of the present century. Thus, all sorts of inexplicable difficulties arose when attempts were made to explain the presence of ancylostomiasis in the St. Gothard tunnel. For example, Bozzolo and Pagliani postulated that impurities in the water used for drinking in the galleries contributed to the spread of hookworm ova, but Lombard, a staunch opponent of the parasitic theory of miner's anaemia, was able to counter with the reply that a perfectly safe supply of water was piped in164. Nevertheless, the recurrence of anaemia in miners stimulated interest in observing the habits of hookworm larvae and determining the factors which inhibited or enhanced their development. This interest was heightened enormously when the percutaneous

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route of infection was proven, as this would assist in the development of effective control measures. The optimal conditions of temperature, humidity and oxygen tension necessary for development of larvae were defined, and the actions of various larvicides such as salt, carbolic acid, and izal were investigated 22,23,35,77. Similarly, this new understanding of the mode of transmission improved ideas about the spread of infection in endemic areas. Stiles (1915) realized that ancylostomiasis was entirely due to bad sanitation and considered its prevalence as an index of the sanitation in the district where it occurred. In an investigation of hookworm infection in schoolchildren in the USA, he found that those children who came from sewered homes were relatively protected, but that those who lived in houses where there was a privy were more subject to infection. Further, Stiles believed that privies were not only inefficient, but may have positively evil effects because they concentrated contaminated faeces in focal areas rather than allowing them to be dispersed widely, thus reducing the chances of infection: "a privy has a radius of influence in every direction of the compass"196. This concept was confirmed by Baermann working in Indonesia (1917). He developed a novel method (the Baermann technique) for recovering larvae from soil samples, and found that hookworm larvae were not diffused over wide areas, but were concentrated in the neighbourhood of latrines and in constantly damp soil around water storage vessels. Baermann observed that hookworm larvae wandered from earth into water, moving in loose earth at the rate of 1 cm per minute. He found that larvae in shaded, moist areas under plants or grass survived for at least a month22,23. These observations were then confirmed and extended by Cort and Payne in Trinidad using Baermann's apparatus. They also found heavy soil infection around "natural latrines" but little evidence of contamination in houses59. Augustine then showed that larvae could migrate laterally for only several centimetres 18, and tended to remain in the upper regions of the soil, creeping up vegetation, decaying wood and other objects as far as the film of moisture allowed19. Progressive understanding of all these facts led to the evolution of better preventive and control measures.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The first major attempts to control ancylostomiasis were undertaken in infected mines in Europe. A combination of approaches was tried. In 1904, laws were passed in Belgium compelling the installation of surface waste disposal systems in mines near Liège, sanitary buckets below ground, periodic examination and treatment of infected men, and instruction in the principles of personal prophylaxis. Ten years later, the percentage of infected miners had fallen from 23% to less than 2%, and hookworm disease was abolished146. Similar

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principles were adopted in mines in other parts of Europe. Salt was one of the first chemicals suggested for the control of transmission. In 1880, Perroncito showed that salt was toxic to Ancylostoma larvae. This idea was reinforced when it was discovered that miners working in salty mines in Poland, France and Cornwall were protected from infection. Scattering of salt around mines was recommended 9, but perhaps because of its simplicity, it was not received with much enthusiasm. The value of the measure was forgotten and was rediscovered by WO Fischer working in gold mines in the Rand, South Africa76. Weekly disinfection with salt around underground latrines was adopted and infected miners were given anthelmintics with excellent results12. While methods such as these were successful in localized areas such as mines, completely different approaches were needed in the massive endemic areas of the tropics. The first region in which major attempts at control were initiated was the island of Puerto Rico into which the large resources of the United States government were thrown. A commission headed by BK Ashford was set up in 1904; it embarked upon the study and treatment of hookworm disease with considerable reward. Encouraged by Ashford's success, and stimulated by increasing reports of hookworm infection in the southern United States itself, Charles Stiles persuaded John D Rockefeller to finance the organization of a Sanitary Commission to eradicate hookworm disease in that area. In 1909, Rockefeller gave a million dollars to a Commission of thirteen leading educators, physicians and business men to be used during the next five years to work towards the eradication of hookworm. The twin planks upon which the campaign was to be based were the installation of sanitary privies for all people in infected areas and by the treatment of every infected person. During the first five years, 1.25 million people were examined and over 690,000 were found to be infected. These people were treated, either by local practitioners working in cooperation with the Commission, or by temporary dispensaries set up especially for that purpose. The Commission believed that hookworm produced vast suffering, partial inhibition of physical and mental growth, great loss of life, and decreased economic efficiency. The "lazy niggers" and "poor white trash" of the South were found in reality to be the unsuspecting victims of this insidious infection which sapped their strength and vitality. The results of the campaign were eulogized: The witnessing by the people of the transformation from invalidism, blighted ambition, misery and poverty to health, happiness and productive activity does the teaching which excites them to action.75

Because of these efforts, there was a noticeable improvement in living conditions, together with the awakening of an intelligent public interest in hygiene and sanitation34,53. These results encouraged Rockefeller to consider an extension of the work and scope of the Commission to outside of the USA. In 1913, The Rockefeller

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Foundation was formed and its International Health Commission, later International Health Board, undertook to become involved in hookworm control campaigns in other countries. This extension was first begun in 1914 in certain countries of the British Empire where the stability of government and the official use of English facilitated work. The first countries to be tackled were some of the West Indian islands, British Guiana, Egypt, Ceylon and Malaya. The Commission then moved into Central American countries, Brazil and China, until by the middle of the 1920's, campaigns were being carried out on a more or less extensive scale in the majority of infected countries in the world. The Foundation worked through, and cooperated with, governmental bodies in the countries concerned, and began on a small scale in order to develop the most appropriate strategy for that country. Two basic approaches were adopted. The "Dispensary Method" consisted of the examination and treatment of people who presented themselves, together with surveys of infection and sanitation. This was replaced progressively, however, by the "Intensive Method" whereby a defined area was examined systematically, the whole population was tested, all those found infected were treated, and attempts were made to improve general sanitation103. This was in turn modified at times, with some members of the Board, such as Darling, urging mass treatment of heavily infected populations without first verifying the diagnosis in individual persons. Further, Darling asserted that it was sufficient to remove most of the worms from a patient, without wasting time, funds, or generating toxicity by attempting to achieve total eradication 64,65. Unfortunately, and as many anticipated, evidence began to accumulate that hookworm infection reappeared in populations which had undergone mass treatment, albeit at lower intensities of infection, at least initially98,186. The logical inference was that mass treatment had to be accompanied by effective sanitary measures: Mass treatment without coincidental soil sanitation is likened to bailing a sieve-bottomed boat, universal use of a sanitary latrine constituting the only hope of eradicating the infection.11

The validity of proper sanitary measures had been well shown in several studies. Perhaps the most impressive of these was that of Baermann who built well-constructed, ventilated, clean latrines in the Dutch East Indies, and whose use was supervised. The overall mortality (to which hookworm was thought to be a major contributor) fell over ten years from 40 per thousand to 4 per thousand of population 23. The use of footwear and other agents to protect the skin as a prophylactic against hookworm infection has given conflicting results. Manson in 1904 recalled how a West Indian sugar planter had his coolies dip their feet in a mineral oil tar coated with sand, but Dalgetty pointed out the difficulties of such arrangements 63. Investigations in later years showed that hookworm larvae easily penetrated wet canvas footwear, and most observers were not impressed with the results of wearing the shoes that were commonly available in most

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endemic areas. Abdallah, however, did claim that the prevalence of infection was diminished in a village where a cheap kind of footwear made from old rubber tyres was used when compared with a neighbouring village in which this was not the practice1. Despite the vast efforts put into the control of hookworm infection in the early parts of this century, it still remains a major problem. Universal, effective sanitary systems which are actually used would eliminate the scourge, but this seems unlikely in the foreseeable future. The only other prospect, as yet dim, is the development and deployment of a powerful and durable vaccine.

REFERENCES 1. ABDALLAH A. Epidemiology of ankylostomiasis in Egypt. Journal of the Ministry of Health, Cairo 1: 4-12, 1959 2. ALLISON MJ, PEZZIA A, HASEGAWA I, GERSZTEN E. A case of hookworm infestation in Precolumbian America. American Journal of Physical Anthropology 41: 103-106, 1974 3. ANDREWS J. Modern views on the treatment and prevention of hookworm disease. Annals of Internal Medicine 17: 891-901, 1942 4. ANDREWS J. New methods of hookworm disease investigation and control. American Journal of Public Health 32: 282-288, 1942 5. ANONYMOUS. On the management of Negro slaves. Cited in 42 6. ANONYMOUS. Death from Ankylostomum duodenale in Australia. British Medical Journal 1: 792, 1889 7. ANONYMOUS. Indian helminthology. British Medical Journal ii: 807-808, 1893 8. ANONYMOUS. Ankylostomiasis among miners. Lancet i: 1883, 1903 9. ANONYMOUS. The prophylaxis of ankylostomiasis. British Medical Journal ii: 1418, 1905 10. ANONYMOUS. (Hookworm as a cause of respiratory disturbances.) Nippon Biseibutsugakkai Zasshi No. 1, 1918. Abstracted in Tropical Diseases Bulletin 15: 224, 1920 11. ANONYMOUS. Hookworm infection in the Straits settlements. Lancet ii: 1301, 1928 12. ANONYMOUS. Hookworms in gold-mines. Lancet i: 1400-1401, 1934 13. ANONYMOUS. Iron and hookworms. Lancet i: 766, 1969 14. ASHFORD BK. Cited in 120. 15. ASHFORD BK. Ankylostomiasis in Puerto Rico. New York Medical Journal 71: 552-556, 1900 16. ASHFORD BK, GUTIERREZ-IGARAVÍDEZ P. Uncinariasis (hookworm disease) in Porto Rico; a medical and economic problem. United States 61st Congress, third session, Senate Document 808, Government Printing Office, Washington, pp 335, 1911 17. ATTYGALE. Anchylostomiasis. British medical Journal i: 1387-1388, 1888 18. AUGUSTINE DL. Experiments on the migration of hookworm larvae in soils. American Journal of Hygiene 2: 162-171, 1922 19. AUGUSTINE DL. On the position of infective larvae in the soil. American Journal of Hygiene 2: 172-176, 1922 20. AUSTIN WC, COURTNEY W, DANILEWICZ JC, MORGAN DH. Pyrantel tartrate, a new anthelmintic effective against infections of domestic animals. Nature 212: 1272-1274, 1966 21. AUSTREGESILO A. Infestation de l'ankylostomiase par la peau. Archivos Brasileiros de

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Medicina 4: 27-33, 1914 22. BAERMANN G. Ueber ankylostomiasis, deren Ausbreitungsbedingungen durch die Bodeninfektion und deren Bakaempfung. Geneeskundig Tijdschrift voor Nederlandsch-Indië 57: 579-669, 1917 23. BAERMANN G. Eine einfache Methode zur Auffindung von Ankylostomum (Nematoden) Larven in Erdproben. Mededeelingen uit het Geneeskundig Laboratorium te Weltevreden, Feestbundel, Batavia, pp 41-47, 1917. Abstracted in Tropical Diseases Bulletin 12: 181, 1918 24. BAIS WJ. Tetrachloorkoolstof als mijnwormmiddel. Geneesundig Tijdschrift voor Nederlandsch-Indië 62: 381-391, 1922 25. BAKER O. On ankylostomiasis. British Medical Journal i: 718-720, 1903 26. BELLONI L. Dalla scoperta dell'Ankylostoma duodenale all vittoria dull'anemia dei minatori. Minerva Medica 57: 3215-3223, 1966 27. BENNETT WH. The treatment of Taenia by chloroform. Medical Record, New York, 28: 319-320, 1885 28. BENTLEY CA. On the causal relationship between "ground-itch" or "pani-ghao" and the presence of the larvae of Ankylostoma duodenale in the soil. British Medical Journal i: 190-193, 1902 29. BENTLEY CA. Some notes on ankylostomiasis in Assam. Indian Medical Gazette 39: 135-136, 1904 30. BIGGAM AG, GHALIOUNGUI P. Ancylostoma anaemia and its treatment by iron. Lancet ii: 299-304, 1924 31. BILHARZ T, von SIEBOLD C. Ein Beitrag zur Helminthographia humana, aus brieflichen Mittheilungen des Dr. Bilharz in Cairo, nebst Bemerkungen von Prof. C. Th. v. Siebold in Breslau, Zeitschrift für wissenschaftliche Zoologie 4: 53-76, 1852. Partly translated in 107 32. BIOCCA E. On Ancylostoma braziliense (de Faria, 1910) and its morphological differentiation from A. ceylanicum (Looss, 1911). Journal of Helminthology 25: 1-10, 1951 33. BISHOP H. Notes on the use of carbon tetrachloride (CCl4) in Trinidad and Tobago. Journal of the Port-of-Spain Medical Society, pp 21-24, 1924 34. BOCCACCIO M. Ground itch and dew poison. The Rockefeller Sanitary Commission 1909-1914. Journal of the History of Medicine and Allied Sciences 27:30-53, 1972 35. BOYCOTT AE. Ankylostomiasis. Transactions of the Epidemiological Society of London, new series, 24: 113-142, 1905 36. BOYCOTT AE. Anaemia in ankylostomiasis. British Medical Journal ii: 1318-1320, 1907 37. BOYCOTT AE. The Milroy lectures on Ankylostoma infection. Lancet i: 717-721, 783-790, 859864, 1911 38. BOZZOLO C. L'anchilostomiasi e l'anemia che ne conseguita (anchilostoanemia). Giornale Internazionale delle Scienze Mediche, new series, 1: 1054-1069, 1245-1253, 1879 39. BOZZOLO C. Di un'altra sostanza attiva contra l'anchilostoma Dubini. Giornale della Reale Accademia di Medicina di Torino, third series, 26: 66-67, 1881 40. BOZZOLO C. Ampia casistica terapeutica a favore des timolo fu prodotta da Grazieda B. II. Timolo nella cura dell'anchilostomanemia. Giornale della Reale Accademia di Medicina di Torino, third series, 30: 821-855, 1882 41. BOZZOLO C, PAGLIANI L. Lettera da Airolo. La Perseveranza, 9 March 1880. Cited in 168 42. BRANCH CW. Notes on Uncinaria and other intestinal parasites in the West Indies. Journal of Tropical Medicine and Hygiene 8: 261, 1905 43. BRONDA F. Ernesto Parona e la scoperta dell'anchilostoma duodenale. Minerva Medica 57: 3245-3249, 1966 44. BROWN HD, MATZUK AT, ILVES IR, PETERSON CH, HARRIS SA, SARETT LH, EGERTON JR, YAKSTIS JS, CAMPBELL WC, CUCKLER AC. Antiparasitic drugs. IV. 2-(4'-thiazolyl)-benzimidazole,a new anthelmintic. Journal of the American Chemical Society 83: 1764-1765, 1961 45. BRUMPT LC. Déductions cliniquées tirées de cinquante cas d'ankylostomiase provoquée. Annales de Parasitologie Humaine et Comparée 27: 237-249, 1952 46. BRUNING H. Zur Frage der Helminthiasis-Therapie in den Tropen. Archiv für Schiffs und Tropen-Hygiene 14: 733-738, 1910

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47. BUGNION E. On the epidemic caused by Ankylostomum among the workmen in the St. Gothard tunnel. British Medical Journal i: 382, 1881 48. BUGNION E. L'ankylostome duodénal et l'anémie du Saint-Gothard. Revue Médicale de la Suisse Romande 1:269-289, 405-440, 1881 49. BUI QUOC HONG, BUU HOI, TRAN LU Y, TANG NHIEP, NGUYEN VAN DICH, VU DINH MINH. Activité anthelminthique du 2(4' thiazolyl) benzimidazole chez l'homme. Chemotherapia 5: 326-331, 1962 50. CAIUS JF, MHASKAR KS. The correlation between the chemical composition of anthelmintics and their therapeutic values in connection with the hookworm enquiry in the Madras Presidency. Indian Journal of Medical Research 7: 429-463, 1919; 7: 570-609, 1920; 8: 125-130, 372-394, 1920; 9: 35-55, 191-209, 1921; 10: 343-360, 1922 51. CALDWELL FC. An accidental infection with Uncinaria. Parasitology 14: 51-52, 1922 52. CAMUSET L. De l'anémie tropicale observée à la Guyane française, Thèse de Montpellier, pp 50, 1868 53. CASSEDY JH. The "germ of laziness" in the South, 1900-1915: Charles Wardell Stiles and Progressive Paradox. Bulletin of the History of Medicine 45: 159-169, 1971 54. CHAIA G, CUNHA CA. Therapeutic action of mebendazole (R-17.635) against human helminthiasis. Folha Médica 63: 843-852, 1971 55. CHANDLER AC. The rate of loss of hookworms in the absence of reinfections. Indian Journal of Medical Research 13: 625-634, 1926 56. CHANDLER AC. Hookworm disease. Its distribution, biology, epidemiology, pathology, diagnosis, treatment and control, MacMillan and Co., London, pp 494, 1929 57. CONCATO L, PERRONCITO E. Sull'anchilostomiasi. Osservatore, Torino 16: 144, 1880. Also, Sur l'anchylostomiase. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 90: 619-620, 1880 58. COPP FC, STANDEN OD, SCARNELL J, RAWES DA, BURROWS RB. A new series of anthelmintics. Nature 181: 183, 1958 59. CORT WW, PAYNE GC. An epidemiologic study of hookworm disease in a cacao estate. American Journal of Hygiene 2: 149-161, 1922 60. CREPLIN FC. Nachträge zu Gurlt's Verzeichniss der Thiere, bei welchen Entozoen gefunden worden sind. Archiv für Naturgeschichte 11J, 1: 325-330, 1845 61. CRUZ WO. Pathogenesis of anaemia in hookworm disease. Parasite carriers. Relationship between the activity of the helminth and iron deficiency in the genesis of disease. Memorias do Instituto Oswaldo Cruz 28: 391-486, 1934 62. DALGETTY AB. Water-itch; or, sore feet of coolies. Journal of Tropical Medicine and Hygiene 4: 73-77, 1901 63. DALGETTY AB. The prevention of ankylostomiasis. British Medical Journal i: 17, 1905 64. DARLING ST. Suggestions for the mass treatment of hookworm infection. Lancet ii: 69-72, 1920 65. DARLING ST. The hookworm index and mass treatment. American Journal of Medicine 2: 397-447, 1922 66. DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques, J-B Baillière et fils, Paris, pp 838, 1860 67. DAY HB, FERGUSON AR. The treatment of Ankylostoma anaemia. Lancet i: 82-87, 1914 68. DESOWITZ RS, BELL T, WILLIAMS J, CARDINES R, TAMARUA M. Anthelmintic activity of pyrantel pamoate. American Journal of Tropical Medicine and Hygiene 19: 775-778, 1970 69. DOBSON EF. Notes regarding the prevalence of Dochmius duodenalis. Indian Medical Gazette 27: 354-357, 1892; 28: 1-4, 40-43, 68-72, 1893 70. DUBINI A. Nuovo verme intestinal umano (Agchylostoma duodenale) costituente un sesto genere dei nematoidea proprii dell'uomo. Annali Universali di Medicina 106: 5-13, 1843. Translated in 107 71. DUVOIR M, BRUMPT LC. Le traitement des polyglobulies par l'ankylostomose provoquée (apropos de cinq cas). Annales de Parasitologie Humaine et Comparée 20: 1-2, 35-42, 1944-1945 72. EBBELL B. The Papyrus Ebers, the greatest Egyptian medical document, translated by B

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Ebbell, Levin and Munksgaard, Copenhagen, pp 135, 1937 73. de FARIA G. Contribução para a sistematica helmintolojica brazileira. III. Ancylostomum braziliense n. sp. parazito dos gatos e câia. Memorias do Instituto Oswaldo Cruz 2: 286-293, 1910 74. FERREIRA LF, de ARAÚJO AJ, CONFALONÍERI UE. The finding of eggs and larvae of parasitic helminths in archaeological material from Unai, Minas Gerais, Brazil. Transactions of the Royal Society of Tropical Medicine and Hygiene 74: 798-800, 1980 75. FERRELL JA. Methods for the eradication of hookworm disease. American Journal of Public Health 3: 492-493, 1913 76. FISCHER WO. Über eine Methode zum Abtöten von Hakenwurmlarven in Boden. Archiv fur Schiffs- und Tropen-Hygiene 32: 164-175, 1928 77. FRANÇOIS E. Anémie des Mineurs: Étiologie, séméiologie, prophylaxie, organisation médicale, A. Maloine, Paris, pp 110, 1906 78. FÜLLEBORN F. Untersuchungen über den Infektionsweg bei Strongyloides und Ankylostomum und die Biologie dieser Parasiten. Archiv für Schiffs- und Tropen-Hygiene 18: 26-80, 1914 79. FÜLLEBORN F. Ueber das Verhalten der Hakenwurmlarven bei der Infektion per os. Archiv für Schiffs- und Tropen-Hygiene 30: 638-653, 1926 80. FÜLLEBORN F. Epidemiological observations on hookworm infection. Discussion of the question of immunity and specific reactions of the host in helminthic infections. British Medical Journal i: 755-759, 1929 81. FÜLLEBORN F, KIKUTH W. Wie entseht die Anämie bei Hakenwurminfektion. Archiv für Schiffs- und Tropen-Hygiene 33: 171-186, 1929 82. GHEDINI G. Anticorpi elmintiaci nel siero de sangue di individui affetti da elmintiasis, anticorpi anchilostomiaci e ascaride. III. nota. Gazetta degl'Ospedali e della Cliniche 28: 476, 1907 83. GILES GM. A report of an investigation into the causes of the diseases known in Assam as kala-azar and beri beri, Assam Secretariat Press, Shillong, pp 156, 1890 84. GILES GM. The life-history of the free stage of Ankylostoma duodenale. British Medical Journal ii: 660, 1899 85. GILES GM. A discussion on ankylostomiasis. British Medical Journal ii: 539-541, 1900 86. GILES GM. Discussion of 177. British Medical Journal ii: 691, 1901 87. GILLES HM, WATSON-WILLIAMS EJ, BALL PA. Hookworm infection and anaemia. An epidemiological, clinical and laboratory study. Quarterly Journal of Medicine 33: 1-24, 1964 88. GOODWIN LG, JAYEWARDENE LG, STANDEN OD. Clinical trials with bephenium hydroxynaphthoate against hookworm in Ceylon. British Medical Journal ii: 1572-1576, 1958 89. GORDON RM. The effect of ancylostome, ascaris and trichuris infections on the health of the West African native. Annals of Tropical Medicine and Parasitology 19: 429-460, 1925 90. GRASSI GB, PARONA C, PARONA E. Intorno all'Anchilostoma duodenale (Dubini). Gazzetta Medica Italiana Lombardia 38: 193-196, 1878. Translated in 107 91. GRENET AL. Présence de l'ankylostome duodénal sur un sujet mort à Mayotte de cachexie aqueuse ou malcouer. Archives de Médecine Navale 8: 70-72, 1867 92. GRIESINGER W. Klinische und anatomische Beobachtungen über die Krankheiten von Egypten. Archiv für Physiologie Heilkunde 13: 528-575, 1854. Partly translated in 107 93. HALL MC. Carbon tetrachloride for the removal of parasitic worms, especially hookworms. Journal of Agricultural Research 21: 157-175, 1921 94. HALL MC. The use of carbon tetrachloride for the removal of hookworms. Journal of the American Medical Association 77: 1641-1643, 1921 95. HALL MC, SHILLINGER J. Tetrachlorethylene, a new anthelmintic. American Journal of Tropical Medicine 5: 229-237, 1925 96. HARADA Y, MORI O. A new method for culturing hookworm. Yonago Acta Medica 1: 177-179, 1955 97. HERMAN M. Le traitement de l'anchylostomasie par l'essence d'eucalyptus associée au chloroforme et à l'huile de ricin. Bulletin de l'Académie Royale de Médecine de Belgique,

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fourth series, 19: 144-155, 1905. 98. HILL RB. Hookworm reinfestation in sanitated and unsanitated areas. Southern Medical Journal 18: 665-668, 1925 99. HILL RB. The estimation of the number of hookworms harbored, by the use of the dilution egg count method. American Journal of Hygiene 6: Supplement, pp 19-41, 1926 100. HIPPOCRATES Works of, translated by WH Jones & ET Whithington, Loeb Classical Library, Heinemann, London, four volumes, 1948-1953. 101. HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 102. HOWARD HH. Prenatal hookworm infection. Southern Medical Journal 10: 793-795, 1917 103. HOWARD HH. The control of hookworm disease by the intensive method. The Rockefeller Foundation, Publication No. 8, International Health Board, New York City, pp 189, 1919 104. HUART AJ. On the causes of anaemia in ankylostomiasis. Acta Leidensia (Scholae Medicae Tropicae) 4: 48-109, 1929 105. INTERNATIONALCOMMISSION ON ZOOLOGICAL NOMENCLATURE. Nematode and Gordiacea names placed in the official list of generic names (Opinion 66), Smithsonian Institution Publication 2359, Washington, DC, pp 171-176, 1915 106. JOYEUX C. Le Necator americanus en Haute-Guinée. Notes d'epidémiologie. Bulletins de la Société de Pathologie Exotique et de ses Filiales 10: 843-846, 1912 107. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 108. KÉRANGEL R. L'ankylostome duodénal observé à Cayenne. Archives de Médecine Navale 10: 311-322, 1868 109. KHALIL M. An early contribution to medical helminthology translated from the writings of the Arabian physician Ibn Sina (Avicenna) with a short biography. Journal of Tropical Medicine and Hygiene 25: 65-67, 1922 110. KHALIL M. Note on the toxicity of carbon tetrachloride in the treatment of ankylostomiasis. Lancet i: 547-548, 1926 111. KRAUSE GR, CRILLY JA. Roentgenologic changes in the small intestine in the presence of hookworm. American Journal of Roentgenology and Radium Therapy 49: 719-730, 1943 112. KYNSEY WR. Report on anaemia or beri-beri of Ceylon, Colombo, pp 56, 1887. Cited in British Medical Journal ii: 1205, 1892 113. LAMBINET J. Recherches sur le mode d'infection de l'organisme animal par les larves de l'anchylostomes.Bulletin de l'Académie Royale de Médecine de Belgique, fourth series, 19: 56-75, 1905 114. LAMSON PD, BROWN HW, ROBBINS BH, WARD CB. Field treatment of ascariasis, ancylostomiasis and trichuriasis with hexylresorcinol. American Journal of Hygiene 13: 803-822, 1931 115. LAMSON PD, ROBBINS BH, WARD CB. The pharmacology and toxicology of tetrachlorethylene. American Journal of Hygiene 9: 430-444, 1929 116. LANE C. Agchylostoma ceylanicum, a new human parasite. Indian Medical Gazette 48: 217-218, 1913 117. LANE C. Final report on the ankylostome enquiry in the Darjeeling District of India. Indian Journal of Medical Research 6: 1-25, 1918 118. LANE C. Ancylostoma braziliense. Annals of Tropical Medicine and Parasitology 16: 347-352, 1922 119. LANE C. Fatal and medicinal doses. Lancet i: 1317, 1930 120. LANE C. Hookworm infection, Oxford University Press, London, pp 319, 1932 121. LANE C. The appraisement of hookworm-killing drugs. Lancet i: 1459-1464, 1935 122. de LANGEN CD. Prenatal infection by ankylostoma. Mededeelingen van den Burgerlijken Geneeskundigen Dienst in Nederlandsch-Indië pp 275-277, 1923 123. LAYRISSE M, ROCHE M. The relationship between anemia and hookworm infection. Results of surveys of a rural Venezuelan population. American Journal of Hygiene 79: 279-301, 1964 124. LEACH CN. Carbon tetrachloride in the treatment of hookworm disease. Journal of the American Medical Association 78: 1789-1790, 1922

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125. LEGER M. À propos de Necator americanus, Stiles 1902. Bulletins de la Société de Pathologie Exotique et des ses Filiales 14: 159-161, 1921 126. LEICHTENSTERN O. Zur Entwickelungsgeschichte von Ankylostoma duodenale. Vorläufige Mittheilung. Centralblatt für klinische Medicin 7: 132-133, 1886. Partly translated in 142 127. LEICHTENSTERNO. Fütterungsversuche mit Ankylostomalarven. Eine neue Rhabditisart in den Fäces von Ziegelarbeitern: Berichtigung. Centralblatt für klinische Medicin 7: 673-675, 1886 128. LEICHTENSTERN O. Einiges über Ankylostoma duodenale. Deutsche medicinische Wochenschfrift 13: 565-568, 594-596, 620-623, 645-647, 669-672, 691-694, 712-715, 1887 129. LEICHTENSTERN O. Ueber Ankylostoma duodenale. Wiener klinische Rundschau 12: 361-363, 377-378, 393-395, 412-414, 428-429, 1898 130. LEICHTENSTERNO M. Die Lebensgeschichte des Ankylostoma duodenale. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 24: 974-980, 1898 131. LEIPER RT. The distribution of the "American" hookworm. British Medical Journal i: 683, 1907 132. LEIPER RT. The alleged heterogenesis of Ankylostoma duodenale. British Medical Journal ii: 1332, 1909 133. LEIPER RT. The apparent identity of Agchylostoma ceylanicum (Looss, 1911) and Agchylostoma braziliense (Faria, 1910). Journal of Tropical Medicine and Hygiene 16: 334-335, 1913 134. LEUCKART R. Zur Entwicklungsgeschicht der Nematoden. Archiv für wissenschaftliche Heilkunde, Leipzig, new series, 2: 235-250, 1866 135. LOEB L, SMITH AJ. The presence of a substance inhibiting the coagulation of the blood in Ankylostoma (with discussion). Proceedings of the Pathological Society of Philadelphia, new series, 7: 173-178, 1904 136. LOOSS A. Notizen zur Helminthologie Egyptens. I. Die Lebensgeschichte des Anchylostomum duodenale (Dub.). Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 20: 865-870, 1896. Translated in 107 137. LOOSS A. Notizen zur Helminthologie Egyptens. II. Die Uebertragung der Larven (Anchylostomum duodenale). Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 21: 913-917, 1897. Translated in 107 138. LOOSS A. Zur Lebensgeschichte des Ankylostoma duodenale. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 24: 441-449, 483-488, 1898. Partly translated in 107 139. LOOSS A. Ueber das Eindrigen der Ankylostomalarven in die menschliche Haut. Centralblatt für Bakteriologie und Parasitenkunde, Abteilung originale 29: 733-739, 1901. Partly translated in 107 140. LOOSS A. Note on intestinal worms found in African pygmies. Lancet ii: 430-431, 1905 141. LOOSS A. The anatomy and life-history of Agchylostoma duodenale (Dub.). A monograph. Part I. The anatomy of the adult worm. Translated from the German by M Bernhard, Records of the School of Medicine, Egyptian Ministry of Education, National Printing Department, Cairo, 3: 1-159, 1905 142. LOOSS A. The anatomy and life history of Agchylostoma duodenale Dub. A monograph. Part II. The development in the free state. Translated from the German by M Bernhard, Records of the School of Medicine, Egyptian Ministry of Education 4: 163-613, 1911. Pp 252-277 reprinted in the Journal of Tropical Medicine and Hygiene 15: 155-157, 171-174, 182-185, 199-201, 235-238, 1912; Abstracted in Journal of the Royal Army Medical Corps 19: 42-55, 1912 143. LUTZ A. Ueber Ankylostoma duodenale und ankylostomiasis. Sammlung klinischer Vorträge in Verbindung mit Deutschen Klinikern 9: 2295-2350, 2467-2506, 1885. Translated in Gazeta Medica da Bahia, third series, 5: 487-496, 541-544; 6: 60-65, 113-124, 157-166, 254-264, 1888 144. McCONNELL JF. On Dochmius duodenalis (Sclerostoma vel Anchylostoma duodenale) as a human parasite in India. Lancet ii: 96-97, 1882

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145. MacDONALD JD. First Indian Medical Congress, 1890. Cited in 176 146. MALVOZ E. Dix années de lutte contre l'ankylostomasie des mineurs. Bulletin de l'Académie Royale de Médecine de Belgique, series 4, 27: 264-278, 1913 147. MANSON P. Discussion of 177, British Medical Journal ii: 691, 1901 148. MAPLESTONE PA. Creeping eruption produced by hookworm larvae. Indian Medical Gazette 68: 251-256, 1933 149. MHASKAR KS. Hookworm infection and sanitation. Indian Journal of Medical Research 8: 398-406, 1920 150. MHASKAR KS. Mass treatment of hookworm infection. Indian Medical Gazette 57: 208-210, 1922 151. MIYAGAWA Y. Ueber den Wanderungsweg der Ankylostoma duodenale innerhalb des Wirtes bein Oralinfektion und ueber ihren Hauptinfektionsmodus. Mittheilungen aus der medicinischen Facultät der kaiserlich-japanischen Universität zu Tokyo 15: 411-452, 1916 152. MOUAT-BIGGS CE. The treatment of ankylostomiasis in Venezuela. Transactions of the Royal Society of Tropical Medicine and Hygiene 8: 216, 1915 153. de MOURA JR. Note sobre um caso de hypoemia intertropical terminado pela morte; autopsia e verificação da existencia de entozoarios da especie - Anchylostomum duodenale. Gazeta Medica da Bahia 1: 122-125, 136-138, 1866 154. MÜLLER H F, RIEDER H. Ueber Vorkommen und klinische Bedeutung der eosinophilen Zellen, Erlich im circulirenden Blute des Menschen. Deutsches Archiv für klinische Medizin 48: 96-121, 1891 155. NAG SC. Notes on the use of carbon tetrachloride. Indian Medical Gazette 64: 683, 1929 156. NAPIER LE, DAS GUPTA CR, MAJUMDAR DN. The treatment of hookworm anaemia. Indian Medical Gazette 76: 1-11, 1941 157. NICHOLLS L, HAMPTON GG. Treatment of human hookworm infection with carbon tetrachloride. British Medical Journal ii: 8-11, 1922 158. OKADA R. Experimental studies on the oral and percutaneous infection of Anchylostoma caninum. Fourth report. Japanese Journal of Experimental Medicine 9: 269-280, 1931 159. OLIVER T. Ankylostomiasis in Westphalia, Hungary and Cornwall. Lancet ii: 1635-1637, 1904 160. OZZARD AT. Life history of the Ankylostoma duodenale. Journal of Tropical Medicine and Hygiene 5: 273-274, 1902 161. OZZARD AT. Life-history of Ankylostoma duodenale. British Medical Journal ii: 779-780, 1909 162. PAPYROS EBERS. Das hermetische Buch über die Arzeneimittel der alten Aegypter in hieratischer Schrift. Herausgegeben, mit Inhaltsangabe und Einleitung versehen von Georg Ebers. Mit hieroglyphisch-lateinischem Glossar von Ludwig Stern, W Engelmann, Leipzig, two volumes, 1875. The Papyrus Ebers, translated from the German version by CP Bryan, Geoffrey Bles, London, pp 167, 1930 163. PARONA E. L'estratto etereo di felce maschio e l'anchilostomiasi die minatori del Gottardo. Osservatore, Torino, 17: 19-49, 1881 164. PEDUZZI R, PIFFARETTI JC. Ancylostoma duodenale and the Saint Gothard anaemia. British Medical Journal ii: 1942-1945, 1983 165. PEIPER O. Über den Infektionmodus der Ankylostomiasis in Deutsch-Ostafrika. Archiv für Schiffs- und Tropen-Hygiene 16: 537-570, 1912 166. PERRONCITO E. Helminthological observations upon the endemic disease developed among the labourers in the Tunnel of Mount St. Gothard. Journal of the Quekett Microscopical Club 6: 141-148, 1880. Also, Observations helminthologiques et recherches experimentelles sur la maladie des ouvriers du Saint-Gothard. Comptes Rendus Hebdomadaires des Séances de la Académie des Sciences 90: 1373-1375, 1880 167. PERRONCITO E. On the action of chemical agents and medicinal substances on the larvae of Dochmius duodenalis and Anguillulae; including therapeutical considerations relative to the cure of patients from Mount St. Gothard. Veterinarian 53: 824-828, 1880 168. PERRONCITO E. La malattia dei minatori dal S. Gottardo al Sempione: una questione risolta, Carlo Pasta, Torino, pp 335, 1910 169. PFISTER F. Über die - - -Krankheit der Papyri Ebers und Brugsch. Archiv für Geschichte

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der Medizin 6: 12-20, 1912 170. PIRIE JH, RETIEF F, FERGUSON AL. Skin reactions in ankylostomiasis. Proceedings of the Transvaal Mine Medical Officers' Association 9: 19-20, 1929 171. PRUNER. Die Krankheiten des Orient's vom Standpunkte der vergleichendin Nosologie betrachtet, Palme und Enke, Erlangen, pp 472, 1847 172. RAKE B. Extracts from an inaugural address on the opportunities for research in Trinidad. British Medical Journal i: 289, 1894 173. REP BH, VETTER JC, EIJSKER M. Cross-breeding experiments in Ancylostoma braziliense de Faria, 1910 and A. ceylanicum Looss, 1911. Tropical and Geographical Medicine 20: 367-378, 1968 174. RHOADS CP, CASTLE WB. Observations on the etiology and treatment of the anemia of hookworm disease in Porto Rico. Journal of Clinical Investigation 11: 809, 1932 (Abstract) 175. ROCHE M, ENRIQUETA PEREZ-GIMENEZ M, LAYRISSE M, di PRISCO E. Study of urinary and fecal excretion of radioactive chromium Cr51 in Man. Its use in the measurement of intestinal blood loss associated with hookworm infection. Journal of Clinical Investigation 36: 1183-1192, 1957 176. ROGERS L. The debate on ankylostomiasis: a correction. British Medical Journal ii: 1348-1349, 1900 177. SANDWITH FM. Note on the entrance of Ankylostoma embryos into the human body by means of the skin. British Medical Journal ii: 690-691, 1901 178. SANDWITH FM. Hookworm. Lancet i: 255, 1905 179. SANGALLI G. Annotazioni critiche sull'anchilostoma duodenale. Rendiconti del Reale Istituto Lombardo di Scienze e Lettere, Milan, series 2, 2: 460-467, 1879 180. SCHAPIRO L, STOLL NR. Preliminary note on the anthelmintic value of tetrachlorethylene based on egg counts before and after one treatment. American Journal of Tropical Medicine 7: 193-198, 1927 181. SCHAUDINN F. Ueber die Einwanderung der Ankylostomum-larven von der Haut aus. Vorläufige Mitteilung. Deutsche medizinische Wochenschrift 30: 1338-1339, 1904 182. SCHEUTHAUER G. Beiträge zur Erklärung des Papyrus Ebers, des hermetischen Buches über die Arzneimittel der alten Aegypter. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (R Virchow) 85:343-354, 1881 183. SCHÜFFNER W. Der Wert einiger Vermifuga gegenüber dem Ankylostomum mit Bemerkungen über die Wurmkrankheit in Niederländisch-Indien. Archiv für Schiffs- und Tropen-Hygiene 16: 569-588, 1912 184. SCHULTHESS W. Noch ein Wort über Ankylostoma duodenale. Berliner klinische Wochenschrift 20: 797-800, 1886 185. SCOTT HH. Review of 89. Tropical Diseases Bulletin 23: 262-263, 1926 186. SISCO DL. Incidence of hookworm disease among persons who were cured five years ago. Journal of the American Medical Association 80: 451-454, 1923 187. SMILLIE WG, AUGUSTINE DL. Hookworm infestation. The effect of varying intensities on the physical condition of school children. American Journal of Diseases of Children 31: 151-168, 1926 188. SMILLIE WG, AUGUSTINE DL. The effect of varying intensities of hookworm infestation upon the development of school children. Southern Medical Journal 19: 19-28, 1926 189. SMITH AJ. Cited in 56 190. SONSINO P. Ankylostomiasis and beri-beri. Lancet i: 435-436, 1890 191. SOPER FL. The report of a nearly pure Ancylostoma duodenale infestation in native South American Indians and a discussion of its ethnological significance. American Journal of Hygiene 7: 174-184, 1927 192. STILES CW. A new species of hookworm (Uncinaria americana) parasitic in man. American Medicine 3: 777-778, 1902 193. STILES CW. Report upon the prevalence and geographic distribution of hookworm disease in the United States. Hygienic Laboratory Bulletin No. 10, United States Public Health and Marine Hospital Service, Washington, DC, pp 121, 1903 194. STILES CW. The American hookworm (Necator americanus) in Guam and China. Johns Hopkins Hospital Bulletin 17: 313, 1906

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195. STILES CW. Report of the scientific secretary, The Rockefeller Sanitary Commission for the Eradication of Hookworm Disease, Publication No. 2, New York, 1914 196. STILES CW. Recent studies on school children, with special reference to hookworm disease and sanitation. New York Medical Journal 102: 906-907, 1915 197. STOLL NR. On the relation between the number of eggs found in human feces and the number of hookworms in the host. American Journal of Hygiene 3: 156-179, 1923 198. STRAUB M. Tetrachloorkoulstofvergiftiging in twaalf gevallen. Geneeskundig Tijdschrift voor Nederlandsch-Indië 65: 624-645, 1925 199. TOPLEY E. Common anaemias in rural Gambia. Hookworm anaemia among men. Transactions of the Royal Society of Tropical Medicine and Hygiene 62: 579-594, 1968 200. WAITE JH, NEILSON IL. A study of the effects of hookworm infection upon the mental development of north Queensland school children. Medical Journal of Australia i: 1-7, 1919 201. WELLS HS. Observations on the blood sucking activities of the hookworm Ancylostoma caninum. Journal of Parasitology 17: 167-182, 1931 202. WIJERS DJ, SMIT AM. Early symptoms after experimental infection of man with Ancylostoma braziliense var. ceylanicum. Tropical and Geographical Medicine 18: 48-52, 1966 203. WILLIAMS CH. On the prevalence of Ankylostomum duodenale in Madras. Lancet i: 192, 1895 204. WUCHERER OE. Sobre a molestia vulgarmente denominada oppilação ou cançaço. Gazeta Medica da Bahia 1: 27-29, 39-41, 52-54, 63-64, 1866. Partly translated in 107 205. WUCHERER OE. Anchylostomos duodenaes. Gazeta Medica da Bahia ii: 150-151, 1868 206. WUCHERER OE. Ueber die Anchylostomenkrankheit, tropische Chlorose oder tropische Hypoämie. Deutsches Archiv für klinische Medicin 10: 379-400, 1872 207. YOKOGAWA S. On the oral infection by hookworm. Archiv für Schiffs- und Tropen-Hygiene30: 663-679, 1926. Also, YOKOGAWA S, OISO T. (Investigations on the life history of Ankylostoma and Strongyloides stercoralis. On oral infection with Ankylostoma.) Taiwan Igakkai Zasshi Nos. 241 and 243, 1925. In Japanese, with English summary 208. ZINN W, JACOBY MJ. Ueber das regelmäsige Vorkommen von Anchylostomum duodenale ohne secundäre Anämie bei Negern, nebst weiteren Beiträgen zur Fauna des Negerdarmes. Berliner klinische Wochenschrift 33: 797-801, 1896

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Table 20.1. Landmarks in hookworm disease __________________________________________________________________ 1838 1852-54 1866 1868 1878

1880 1880 1881 1886 1898 1901 1901 1902 1905 1907 1909 1909 1910 1911 1913 1913 1921 1925 1929 1935 1958

Dubini discovered the adult worm Bilharz/Griesinger proposed that hookworm was the cause of "Egyptian chlorosis" (gross anaemia) Wucherer indicated that latex d'higueron (fig extract in South America) was an effective treatment Camuset appreciated that hookworm in the Americas differed morphologically from A. duodenale but did not publicize the observation Grassi, Parona and Parona described the in vitro development of hookworm ova and larvae and showed that infection could be diagnosed by finding eggs in faeces Outbreak of hookworm anaemia in miners building the St. Gothard tunnel in the Italian Alps Parona showed that filix mas (male fern) was effective in treatment Bozzolo showed that thymol was effective in treatment Leichtenstern observed patent infections in humans 4-5 weeks after ingestion of infective larvae Looss first suggested that infection may be acquired by percutaneous penetration by larvae Looss demonstrated histologically the penetration of intact human skin by infective larvae Bentley described hookworm infective larvae as the cause of "ground-itch" Stiles described the morphological distinctiveness of N. americanus Looss described the migratory course throught the lungs of infective larvae in dogs Boycott differentiated microcytic hookworm anaemia from the macrocytic anaemia produced by Diphyllobothrium latum Bruning reported that oil of chenopodium was effective in treatment John D Rockefeller established a Sanitary Commission to control hookworm infection in the United States of America Looss described A. ceylanicum recovered from a civet cat by Willey in Sri Lanka (Ceylon) Looss reported the development of a patent infection in a person 71 days after percutaneous exposure Lane found humans infected with A. ceylanicum The Rockefeller International Health Commission (later Board) began hookworm control campaigns in countries outside the USA Hall introduced treatment with carbon tetrachloride Hall and Shillinger introduced treatment with tetrachlorethylene Experimental studies emphasized the role of gastrointestinal bleeding in the genesis of hookworm anaemia Anumber of investigations showed clearly the role of iron deficiency in the causation of hookworm anaemia Bephenium hydroxynaphthoate was shown to be an effective treatment by Goodwin and his colleagues

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Bui Quoc Hong and his colleagues reported that thiabendazole was an effective treatment 1970 Pyrantel was found by Desowitz and co-workers to be an effective antihookworm agent 1971 Chaia and Cunha observed that mebendazole was highly active against hookworm __________________________________________________________________

Chapter 21

RETURN TO

Strongyloides stercoralis and STRONGYLOIDIASIS

SYNOPSIS Major synonyms: Anguillula stercoralis, A. intestinalis, Rhabditis stercoralis, Rhabdonema strongyloides, Strongyloides intestinalis Distribution: widespread, especially in the tropics and subtropics Life cycle: The parthenogenetic female adult worms, 2.5 mm in length, live in the epithelial layer of the small intestine. First-stage (rhabditiform) larvae are passed in the faeces then, in the external environment, either moult twice to form third-stage (infective or filariform) larvae (the direct cycle) or moult four times to become free-living male and female adult worms which in turn produce eggs which hatch to form rhabditiform larvae which moult twice to form filariform larvae (the indirect cycle). Infective larvae penetrate the intact skin and pass via the bloodstream to the lungs where they enter the alveolar spaces, ascend the airways to the pharynx, and are swallowed and pass to the small bowel where they mature over one month or so. In addition, rhabditiform larvae released in the bowel lumen may moult to form filariform larvae and penetrate the colonic mucosa to continue the cycle (internal autoinfection) or penetrate the perianal skin to continue the cycle (external autoinfection). Finally, massive infection with widespread dissemination of larvae may supervene in immunosuppressed persons Definitive hosts: humans, dogs, cats Major clinical features: urticaria, abdominal pain, diarrhoea, weight loss, pruritus ani Diagnosis: finding larvae in faeces or duodenal fluid; serology Treatment: thiabendazole (mebendazole, cambendazole, albendazole)

DISCOVERY OF LARVAL AND ADULT WORMS AND DETERMINATION OF THEIR RELATIONSHIP In the latter part of the ninteenth century, many French troops who had bee n posted to Cochin China (Vietnam) were afflicted with severe diarrhoea which was sometimes fatal. In July 1876, a number of patients were repatriated t o France where they came under the care of Louis Normand, physician to th e Naval Hospital of St Mandrier in Toulon. Normand examined the faeces o f these patients and in some of them he found specimens of a worm which had never been described before. The parasite was just visible to the naked eye , being about one quarter of a millimetre in length. Although they were ofte n sparse, on other occasions worms were present in prodigious numbers with a million or so being excreted during the course of 24 hours. When he examined 543

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faecal samples with a microscope, Normand occasionally saw a large number of worms squirming about in an almost transparent mass as if they were trying to escape from an enclosing membrane. At other times, he observed individual worms which were sometimes caught in a clump of epithelial cells. Normand reported his discovery to Vice-Admiral Jurien de la Gravière: Today in regard to the disease called diarrhea of Cochin China, I can prove that from time to time and most often in serious cases, a parasite is found which has never been found before under similar circumstances. I searched in vain for this parasite in other patients afflicted with analogous symptoms but their afflictions apparently came from other sources.81

The Admiral in turn transmitted extracts of Normand's report together with a resumé of Normand's findings to the President of the Academy of Science s where it was presented and published on 31 July 1876 81. Meanwhile, Normand entrusted the worms to the care of his colleague, ARJB Bavay, professor of pharmacy in the Navy . Jurien de la Gravière, in the original presentation of Normand's discovery, had noted that Bavay had already called the parasite Anguillula stercoralis. This name reflected the eel-like shape of the worm as well as the discovery of the parasite in the faeces, both names being derived from the latin words "anguilla" meaning "eel", and "stercus" denoting "dung". Bavay made a number of observations on this parasite and in October 1876, P Gervais presented Bavay's more detailed description of the worm to the Academy6. In this publication, however, Bavay remarked that the wor m resembled the free-living worm, Rhabditis terricola of Dujardin or the genus Leptodera of Schneider, and indicated that he believed that the differences did not justify the creation of a new genus. Nevertheless, in his first paper, Bavay called the parasite both Anguillula stercorale and Rhabditis stercoralis 6, while in two subsequent papers he referred to it as Anguillula stercoralis "Du sous-genre [of the subgenus] Rhabditis, ou [or] Leptodera Schneider" 7,8. Bavay noted that the forms usually met by clinicians were the larvae, 0.3 3 mm in length by 0.022 mm in width, that were found in the faeces. If thes e larvae were left under favourable conditions in vitro, however, Bavay discovered that they developed into male and female adult worms after fiv e days or so. He wrote that the free-living femal e worms were 1 mm in length and cylindrical in shape, then described the morphology of the mouth, oesophagus, intestine, uterus and vulva. He noted that the eggs on deposition containe d well-formed, motile embryos and that the young forms had sometimes actually broken out of the egg-shell while still within the uterus. The male worms, on the other hand, were smaller than the female helminths. Bavay described th e anatomy of the male reproductive organs and stated that he had sometimes seen male and female worms in copula. He summarized the important differential characteristics which justified its description as a separate species: In summary, this nematode, which is very similar to the Rhabditis terricola of Dujardin....differs in its invariably smaller size, but specially in the shape of the penile apparatus.6

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In an addendum to this paper, Bavay reported that Normand had now found the larvae of A. stercoralis at autopsy in the stomach and the whole length of the intestine, as well as in the bile, pancreatic and hepatic ducts and in the gal l bladder6. Shortly thereafter, Normand also described the development of free-livin g adult worms from larvae in faeces then observed the course of events whic h occurred after eggs were liberated b y free-living female worms. Like Bavay, he observed that when eggs were expelled, each one contained a distinct, motile embryo within a membrane. After each egg had hatched, the released larva was about 0.1 mm in length. These grew gradually to about 0.3 mm long, the n developed a jagged border which gave them the appearance of a chain-saw , then moulted. Normand was unable, however, to obtain a second generation of free-living worms 82, nor did Bavay have any such success 6. Verification of Normand's discovery did not take long in coming, eve n though there was scepticism on the part of some and incredulity on the part of others. In early 1977, Alphonse Laveran (the discoverer of malarial parasites) reported that, at an autopsy he performed on 28 January 1877, he had foun d larvae which matched those d escribed by Bavay 66 in the intestines, then shortly afterwards he reported finding four more such cases 67. Laveran was followed by Libermann72, Roux95 , Chastang17 and Chauvin18 who found the worms in patients that had been infected in China or in Martinique. With the exception of Chauvin, however, these authors did not observe the maturation of larvae to adult worms in the stools. In the meantime, the situation had become somewhat more confused. In late 1876, Normand, at the autopsy of a man who had died from Cochin-Chin a diarrhoea, found another worm, which appeared to be different from A. stercoralis, in the intestines. He sent these worms to Bavay. The latter studied them and those that were obtained from a further four post-morte m examinations and concluded that they were a distinct species of worm. Again through the agency of M Gervais, B avay published a description of the parasite in February 1877, naming it A. intestinalis in order to reflect its discovery in the intestinal tract 7. These worms were about 2.2 mm in length and all of the 200 specimens or so that he examine d were female. Bavay noted that Normand had found that they were most abundant in the duodenum, less common in the jejunum, and did not reach the ileum, but that in any case, they were much less frequent than A. stercoralis. In addition to describing this parasitic female adult worm, Bavay recorde d that he and Normand had found a new type of larva which they believed was the larval form of A. intestinalis: In the stools of three diarrhoeic patients that we have kept in order to follow the development of Anguillula stercoralis, we have found that after several days, they contained certain larvae that were different from the first. They were longer, with a cylindrical oesophagus which passed almost to the middle of the body, and a tail, which instead of terminating in a fine point, was, on the contrary, apparently

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truncated. Although culture of these larvae could not be persisted with long enough to establish in an irrefutable fashion their identity with Anguillula intestinalis, we have hardly any doubt in this regard.7

Bavay went on to say that two of the patients who had had this form in thei r stools had since died, and that post mortem examination had revealed adult A. intestinalis. Moreover, he and Normand had looked in vain for these worms in the body of a man who had returned from Cochin-China three years before and in whom A. stercoralis was extremely abundant. Both the adult and larva l forms of the parasite were illustrate d by Bavay in a publication which appeared in July 18778. Although he did not realize it, Bavay had described the direc t development of larvae excreted in the faeces into infective (filariform) larvae. Similar worms were noted in the following year by Chauvin 18. Thus, at this point, it was believe d that there were two distinct species. In the case of A. stercoralis, larvae were found in the faeces and adult worm s developed in the external environment. In the instance of A. intestinalis, parasitic female adult worms were found in the gut, and they were thought to produce larvae with the truncated tail. In 1878, Grassi and Parona discovered A. intestinalis at a number of autopsies in Pavla, Italy 49. Like Normand and Bavay, they observed that th e parasitic worms were located principally in the lower duodenum and uppe r jejunum. They found that these worms deposited eggs in the intestinal lumen which hatched almost immediately after being laid. Further, they observed that these larvae in the small intestinal lumen were identical with those excreted in the faeces and these in turn appeared to be the same as the larvae described as A. stercoralis by Normand and Bavay. When m oistened faeces containing these larvae were cultured, the worms grew into forms about 0.75 mm long with an oesophagus occupying half the length of the worm. Grassi and Parona realized that these worms (now known as infective or filariform larvae) wer e undoubtedly the same forms that Bavay, and after him, Chauvin, had believed were the larvae of A. intestinalis. At no time did Grassi and Parona grow any of the free-living adult worms which other workers had obtained when A. stercoralis larvae had been cultured. Thus, the sequence of events seemed to be that parasitic female worms ( A. intestinalis) produced larvae (now known as rhabditiform larvae because of the similarity of the oesophagus with tha t seen in the genus Rhadbitis) in the intestine, which in turn developed int o filariform larvae in the free-living state. In 1879, Grassi erected a new genus which he called Strongyloides, ( [STRONGYLOS] = "round" ; [EIDOS] = "similar") because of its closeness to the genus Strongylus, in which to place the worm 43, then later in that year in a review of his ow n article, he indicated that the worm should be called Strongyloides intestinalis 44. Shortly afterwards, Eduardo Perroncito drew attention to the presence o f these parasites, as well as Ancylostoma duodenale , in the intestinal tract o f miners working in the St. Gothard tunnel (see chapter 20) 88. Initially, he

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believed that both A. intestinalis and A. stercoralis were present, with the former appearing in the faeces as eggs, and the latter as larvae. He described the development and hatching of the so-called A. intestinalis eggs, then recounted their subsequent development. He found that after 24 hours the y doubled their length and underwent internal reorganization, particularly with respect to the anatomy of the alimentary canal. As with A. duodenale, Perroncito misinterpreted the moulting process as cyst formation, and described subsequent calcification of the capsule. Similarly, he described the larvae of A. stercoralis, indicated some differences from the larvae of A. intestinalis and A. duodenale, and stated that after one day of life they too became encysted. Thus, Perroncito persisted in the erroneous differentiation of two species o f Strongyloides, believed incorrectly that A. intestinalis eggs were excreted in the faeces, described some non-exi stent morphological differences between the larvae, and became completely misled in ident ifying "encystment" of both forms of larvae89. Subsequently (1881), however, Perroncito succeeded in cultivatin g free-living adult worms (which h e renamed Pseudorhabditis stercoralis ) from rhabditiform larvae in the faece s, and described accurately their copulation, the laying of new eggs, the hatching of these and the transformation of the second generation of worms into filariform larvae 91. These filariform larvae were very similar to those that Grassi and Parona had described as developing directl y from A. intestinalis larvae. The situation was now very confused for filariform larvae had been described as developing in two ways. According to Bavay and to Grassi and Parona, filariform larvae developed from A. intestinalis whereas Perroncito had demonstrated that they were produced by free-living adul t A. stercoralis. Perroncito's assertion that A. intestinalis eggs were excreted in the faeces led to a spirited controversy with Grassi who eventually proved beyond doubt that Perroncito had been dealing with hookworm eggs 45-48,92. Grassi insisted that the rhabditiform larvae found in the faeces were direct descendants of the wor m known as A. intestinalis. Furthermore, he postulated in 1882 that as thes e larvae often developed in culture into freeliving adults called A. stercoralis, then A. intestinalis, like Ascaris nigrovenosa was dimorphobiotic 45. By this, he meant that the parasitic worm in the intestines was parthenogenetic o r hermaphroditic and produced eggs which hatched rhabditiform larvae. H e believed that when these escaped in the faeces, they developed into sexuall y differentiated free-living male and female adult worms which in turn produced descendants that were capable of develop ing again into parasitic mother worms after ingestion by the host. Rudolf Leuckart supported this view in the following year when he reported his own observations on the development of A. stercoralis. A case of strongyloidiasis, which was studied by Seifert 102,103, occurred in Gerhardt's clinic at Würzburg. The faeces contained large numbers of rhabditiform larvae typical

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of those described by Normand and Bavay and by Perroncito as A. stercoralis on the one hand, and as A. intestinalis by Grassi and Parona on the other . Seifert sent samples of the faeces to Leuckart in Leipzig who reported tha t when these were cultured, they developed into free-living male and femal e A. stercoralis, and that the new embryos developing from the eggs produced by these worms metamorphosed into filariform larvae. Leuckart was convinced that these filariform larve must pas s into another host in order to complete their development, for their structure was su ch that he did not believe that they could possibly change again into the rhabditiform form. He considered that th e mature stage of these larvae wa s undoubtedly the parasitic adult A. intestinalis, for the shape of its body and oesophagus resembled strongly that of filariform larvae. He considered that all these worms were but different phases of the life cycle of a single heterogonic parasite i.e. that there was an alternation between parasitic and free-living generations of adult worms. Leuckart renamed th e parasite Rhabdonema strongyloides 70 and concluded that: The Rhabditis stercoralis itself is to be erased from the list of essential parasites; it represents, like the Rhabditis ascaridis nigrovenosa, despite its sexual differentiation, an intermediate generation, developing externally, which forms a link in the chain of development of the Anguillula intestinalis.70

Evidence supporting this view was provided when Seifert, at the suggestion of Grassi, treated the patient who had provi ded the faeces with male fern, santonin and thymol and recovered two parasitic females in the faeces and a degenerated specimen from the vomitus, whereas no sexually diffferentiated adult A. stercoralis was ever observed in the stools 102,103. Two important questions remained unanswered, however. The firs t concerned the development of filariform larvae and the second related t o whether the parasitic worms were hermaphroditic or parthenogenetic. A s already mentioned, some observers 7,8,18,49 had noted direct development o f filariform larvae in faeces, whereas others 70,91 had described their production from larvae liberated by free- living adult worms. Leuckart, in fact, should have been in a position to resolve this prob lem, for both modes of development were observed in his laboratory in the same faecal specimens, although he wa s unaware of the event. In an illuminating insight into Leuckart's research an d teaching methods, Arthur Looss, who at the time had been a student o f Leuckart, recounted nearly 30 years later the circumstances: I....took part in these investigations in the sense that Leuckart entrusted me with the starting and controlling of the cultures, the making of the preparations etc. . and so far as I can remember personally examined only the finished preparations, not the cultures themselves. In the latter, a good many unmistakable filariform larvae were found even at a time when sexual animals were not yet mature. Since Leuckart, however, as it then appeared to me, seemed interested only in the fate of the sexual animals and I myself as yet understood but little of the purport of the investigations, I did not specially report the direct transformation of the larvae to my teacher and the fact of its existence remained unknown to him. 75

Nevertheless, Grassi (1883) once more drew attention to this capacity o f

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rhabditiform larvae to develop directly into filariform larvae 46. In 1884, Golgi and Monti in Pavia studied further cases and followed both the direc t transformation of some rhabditiform larvae obtained from parasitic femal e worms into filariform larvae, as well as indirect development of others through the free-living sexually differentiated generation: they believed the forme r course to be the commoner 40,41. This view was echoed later by Leichtenster n who studied over many years cases of strongyloidiasis occurring in brick workers along the Rhine, as well as cases imported from the tropics. He tried to vary the proportion of worms developing in each direction by altering th e environmental conditions but failed to do so 68. He then suggested that strains of temperate origin developed directly whereas those acquired in the tropic s tended to develop indirectly69. That these different courses were not due to two different strains of the worm was shown by Wilm s in Leichtenstern's laboratory, for he infected a human with filariform larvae which had developed directl y then showed that some of the rhabditiform larvae subsequently excreted in the stools developed indirectly 119. Leichtenstern's suggestion of geographica l variations in the form of free-living development was also not sustained when Darling working in Panama 22 and later Sandground in Honduras 97 found both modes of development with the indirect cycle predominating in the experience of the former observer and direct transformation being most common in th e hands of the latter investigator. Uncertainty also surrounded the status of the parasitic adult worms found in the intestinal tract. Bavay questioned whether the absence of male worms was due to their rapid disappearance following fertilization, or whether the worms were hermaphroditic with a female habitus 8. Shortly afterwards, Grass i suggested that they may be hermaphroditic or parthenogenetic 45. Leuckart concurred with these two last possibilities, and while expressing no fir m opinion, inclined to the view that they were hermaphroditic 70,71. In 1888, however, Rovelli concluded that the worms were parthenogenetic 96. On the other hand, Sandground (1926) believed that the parasitic adult worm wa s really hermaphroditic 98 but this view has not been sustained. The proble m became even more controversial when in 1932 Kreis in Faust's laboratory in New Orleans claimed to have found parasitic male adult worms in the faeces of infected humans and dogs 61. Faust endorsed the view remarking: occasionally parasitic females and males are passed in diarrheic stools....The rare parasitic males are practically indistinguishable from the free-living males of the indirect cycle.29

Faust then proceeded to compound the problem. He traced the development of twelve strains of S. stercoralis (from humans, primates and a dog) in forty dogs and declared that filariform larvae developed into "pre-adolescent" and adul t male and female worms in the respiratory tract. Fertilization was then believed to take place either there or in the lumen of the upper alimentary canal before the fertilized females became embedded in the intestinal mucosa. He furthe r proposed that fertilized eggs proceeded to direct development and unfertilized

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ova underwent indirect development 30. Although Faust continued to describe the parasitic male in his textbook as late as 1970 32, no other investigators were able to find such worms and the concept fell into disrepute. In fact, in 1936 , Graham succeeded in producing patent infections in rats exposed to a single S. ratti filariform larva each 42. The only possible conclusions from thi s observation were that the worm was either parthenogenetic or hermaphroditic, and detailed anatomical studies of the parasite since that time have confirmed the former proposition. When the identity of A. stercoralis and A. intestinalis was realized, it became necessary to use the same name for both species. Since the generic nam e Anguillula was already occupied for species of eel, however, the designation Strongyloides intestinalis suggested by Grassi in 1879 was generally accepted. As S. stercoralis had been described before A. intestinalis, however, Stiles and Hassall considered that the correct name should be Strongyloides stercoralis 110. This view was confirmed by the International Commission on Zoological Nomenclature in Opinion 66 delivered in 1915 57.

CORRELATION OF INFECTION WITH PATHOLOGY When Normand reported the presence of A. stercoralis larvae in the stools of patients with Cochin-China diarrhoea, he was in no doubt that the parasite s were the cause of this syndrome, although he w as careful to add the proviso that there were other causes of a similar condition 81. He expanded this view i n subsequent papers, but also noted that worms could be present withou t producing ill-effects82,83. When Bavay published the discovery of a secon d worm (A. intestinalis) in the gut, he asked in a rhetorical question whethe r these worms were pathogenic and concluded that it was premature to say that they were, for these worms were present in such small numbers when com pared with the frequency of A. stercoralis larvae7,8. A number of early observers including Laveran 66,67, Roux95 and Dounon 25 concurred with Normand's view that A. stercoralis was a potent cause of diarrhoea. Others, however, including Libermann 72, Chastang 17 Breton14 and Grassi43,44 were less certain. Indeed, Grassi found the parasite in the stools of so many apparently healthy individuals that he eventually asserted that thes e worms were innocent commensals of man 47. Perroncito believed that the y played a part with hookworms in the genesis of anaemia in workers in the St. Gothard tunnel 88, but this was disproven when eradication with anthelmintics of hookworms but not S. stercoralis larvae cured the anaemia. Subsequent studies, however, did confirm that the parasites could hav e profound pathological consequenc es. Golgi and Monti at autopsy (1884) found intestinal changes with worms in the crypts of Lieberkühn 40,41, then Sonsino (1891) discovered eggs and larvae, not only in the depths of the lumen of the

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crypts, but also in the mucosa 107. This was confirmed by Askanazy in 1900 who demonstrated the presence of female worms in the epithelium of the uppe r small bowel and rhabditiform larvae in the mucosa associated with a chronic inflammatory infiltrate. He also noted that eggs were often deposited in tunnels in the mucosa. He summarized his findings: The A. intestinalis bores into the intestinal wall, primarily into the mucosa and often into the epithelium of its glands, in order to absorb food....But in this connection the mother animals perform still another function, in that they deposit their eggs in the tissue of the mucous membrane. These eggs change into embryos which then emerge toward the intestinal lumen.3

Askanazy was in no doubt that the worm was pathogenic, for he conclude d from studies using special stains that the adult worms fed on the juices of the intestinal wall, and deposited their offspring in the midst of living tissue. In 1905, Thayer reviewed the question of the pathogenicity of the parasit e and summarized the position in the following way: The weight of evidence appears to be in favour of the view that, while the parasites may exist in the intestine for long periods of time without ill effects, they are by no means, as Grassi says, 'innocent commensals of man'. It would seem probably that this parasite alone may be the primary agent in many cases of chronic diarrhea. 113

The precise location of parasitic adult worms, however, continued to be a matter of argument. Whereas Ask anazy3 and others 38,63 were of the opinion that the parasites frequently entered the stroma of the mucous membrane, other s disagreed. Thus, Ophüls (1929) wrote: I have been unable to convince myself that either the mother worms or the rhabditiform embryos ever enter the stroma of the mucous membrane. They cause, however, much epithelial destruction.85

Recent observations using transmission electron microscopy in infecte d animals suggest that Ophüls was correct. With the discovery of autoinfection and overwh elming infection with S. stercoralis, as will be described shortly, it became absolutely clear that infectio n with this parasite could have devastating consequences. The means by which these effects are brought about, however, remain uncertain. Many earl y observers assumed that the effects were purely mechanical 40, while Askanazy suspected that the worm may produce a toxin 3. A few years later, Thira suggested that bacteria may enter the tissues through the portals in the mucosa left behind by the invading worms and thus exacerbate the illness 114.

ELUCIDATION OF THE MODE OF TRANSMISSION When Blanchard in 1890 reviewed the probable means by which infection occurred, he remarked that the possibilities were not too difficult to conceive . Water had been incriminated, but samples taken from the Mekong river in a heavily endemic area had been examined without finding any Strongyloides larvae. He presumed, therefor e, that the most likely method of infection was by

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consumption of vegetables which had been contaminated with worms, thu s allowing the ingested larvae to develop into parasitic adult worms in th e bowel11. That this could indeed occur was shown experimentally when Wilms (1897) infected a human volunteer experimentally by the oral route; seventeen days after swallowing infective larvae, rhabditiform larvae began to appear in the stools119. Shortly afterwards, however, Looss demonstrated that the similar hookworm larvae could produce infections by penetrating the intact skin. This stimulated Paul van Durme, a Belgian working at the Liverpool School of Tropica l Medicine in England, to investigate whether a similar route of entry might not occur with Strongyloides. Although he entitled his paper of 1901-1902 "Some observations on the larvae of Strongyloides intestinalis and their penetration through the skin", van Durme was in fact almost certainly dealing wit h S. fuelleborni, for he not only stated that the larvae were cultivated from a chimpanzee imported four months previously from Africa, but remarked that he always found eggs in the faeces (which is a characteristic of that species). Filariform larvae were applied to t he abdominal skin of guinea pigs. They were found to disappear from the cutaneous surface within half an hour, the n biopsies were taken at intervals. He wrote: After half an hour, the larvae are found already deeply engaged in the dermis. One encounters them most often in the areas surrounding the hair follicle, at the level of the sebaceous glands. The fixed skin sections, after an hour, present fragments of larvae down to the subcutaneous areolar tissue. Twenty hours after inoculation, all the larvae have not disappeared; although less numerous they can be seen at different levels in the dermis.26

Van Durme lamented that he was u nable to continue his investigations in order to determine whether worms introduced in this way passed to the intestine and produced patent infections. In 1904, Looss succeeded in infecting himself by placing several hundred S. stercoralis larvae on the skin of his forearm; 64 days later, he first found larvae in his stools and they were present in subsequen t examinations74. More than twenty years after van Durme's studies, Kosug e examined the mechanism of skin penetration in experimental animals in more detail, and concluded that larvae penetrated thin skin directly, but effecte d entrance of thick skin via the hair follicles 60. Fülleborn then investigated th e penetration of human skin by these larvae and found that only a proportion of worms succeeded in penetrating the integument, and that this was more likely when the skin was thin and the person was younger. When he tried to infec t himself (then aged 59), Fülleborn concluded that a larva only penetrated th e forearm skin when the epidermis was broken 35.

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DETERMINATION OF THE ROUTE OF MIGRATION AND TH E DISCOVERY OF AUTOINFECTION AND OVERWHELMIN G INFECTION Normand may have unwittingly app reciated the possibility of autoinfection, i.e. the multiplication of worms within the body of the host without passing to the external environment, for he noted that although worms may persist in the gut for years without causing undue inconvenience, anything which tended t o diminish the patient's resistance often resulted in an exacerbation of symptoms to produce the clinical picture of Cochin-China diarrhoea 82,83. This idea was reinforced by Grassi in 1883 when he pointed out that immature specimens of S. intestinalis were not infrequently found in the cadavers of patients who had remained in hospital for several months and in whom oral infections were most unlikely. When this observation was taken in conjunction with th e demonstration by Parona and himself that rhabditiform larvae could develo p directly into filariform larvae, and that the free-living adult forms were absent from the bowel, Grassi deduced that direct transformation of rhabditifor m larvae into parasitic adult worms must be taking place within the host without the interpolation of a sexually differentiated generation 46. Grassi undoubtedly envisaged that moulting and maturation of worms from the rhabditiform larval stage through to adult worms took place in the gut, but such concepts remained shadowy and vague until the routes of infection and migration of worms were established. A clue was provided in 1895 when Teissier claimed that he ha d found larvae in the peripheral blood of a patient with strongyloidiasis. From his description, however, the worms must have been rhabditiform larvae (which is most unusual); possibly he was dealing with a different parasite 112. In any event, the significance of the observation was not appreciated. As already indicated, Wilms had shown that infection could be acquired by ingestion of infective larvae, and van Durme had demonstrated that larvae had the capacity to penetrate the skin. Furthermore, Looss had shown that afte r hookworm larvae had penetrated the skin, they passed to the lungs where they escaped into the airways, ascended the respiratory tree and passed to th e intestine where they completed their development (see chapter 20). In the light of all these observations, Friedrich Fülleborn in Hamburg, Germany began to investigate the migratory route of S. stercoralis larvae in 1911. In his initia l experiment, Fülleborn performed a tracheotomy on a dog then infected i t percutaneously. Three days later, large numbers of larvae, some of whic h appeared to be moulting, appeared in the viscid tracheotomy mucus; the y continued to be passed until six days after infection. In this artificial situation which restricted worms to the trachea, some of the larvae moulted and became female adult worms. Furthermore, despite interruption of the pulmonary oesophageal circuit, a few rhabditiform larvae were found in the faece s beginning eight days after infection. In a second experiment, another dog had

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its oesophagus excised and was also infected percutaneously. Two days later, numerous larvae were recovered from the dog's saliva (the mouth was washed out with water), then on the following day, larvae were discharged from th e upper oesophageal fistula and continued to do so for the next three days . Between eight and twelve days after infection, rhabditiform larvae originating from female worms were found in the tracheal mucus. Fülleborn conclude d from these experiments that "the majority of Strongyloides....larvae are eliminated after interruption of the tracheo-oesophageal tract but even so, a slight infection occurs" 34. In order to determine whether the slight infection that he had noted might result from larvae which passed through the lungs the n embolized to the small bowel in the systemic circulation, Füllebor n tracheotomized a dog then injected larvae which had been obtained from th e tracheal mucus of another dog directly into the duodenal artery. Six days later, the animal was killed and female adult worms were found in the duodenum , while the lung was free from infection. In another experiment in which free living filariform larvae were injected directly into the stomach of th e tracheotomized dogs, the resul ting infection was minimal, whereas if filariform larvae obtained from tracheal mucus was injected, a severe intestinal infection developed. He concluded that in spite of only minimal morphological alter ations, the filariform larvae were altered biologically during their systemi c migration and became resistant to destruction by the gastric juices. Fülleborn summarized all these experiments thus: Chief results of the series of experiments on percutaneous infection: These proved that the normal route of infection of percutaneous penetrating....Strongyloides was from the lung to the intestine via trachea and esophagus. A small number of parasites....may pass from the lung veins and the left heart and reach the intestine by embolism via the intestinal arteries.34

In this series of infections, Fülleborn so metimes found filariform larvae in the kidneys and liver, and supposed that they reached this site via the systemi c circulation. In 1920, however, Yos hida reported that after oral infection, larvae were found in the abdominal and p leural cavities within 24 hours, and that they appeared within the abdominal cavity and viscera within a similar period when placed on the abdominal skin. These findings led him to suggest that the larvae migrated directly through the connective tissues 121. Concurrently with studies on the migration of larvae, further evidence began to accumulate gradually that was suggestive of the phenomenon of repeate d infection or autoinfection. As already mentioned, Askanazy 3 then von Kurlow 63 found larvae in the deeper layers of the intestinal wall. In 1911, John Gage in the United States reported his observations on a 48 year old alcoholic patient who presented with an acute pneumonia. On examination of the sputum, Gage was surprised to find S. stercoralis filariform larvae. The pneumonia resolved but the patient's course continued downhill and he died two months later; larvae were found throughout the wall of the intestine and in the lungs 38. Gage canvassed the ways in which autoinfection could occur. He rejected Grassi's

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hypothesis that direct transformation of rhabditiform larvae into filarifor m larvae then into adult worms may occur within the bowel as he failed to fin d evidence of intermediate stages of the parasite at autopsy. With remarkabl e accuracy, he postulated both mode s of autoinfection (external and internal) that are generally accepted today: The finding of larvae in the sputum....after the patient had been in bed for two months, indicates that he was reinfecting himself. Because of his personal filthiness and the irritation of the skin over his buttocks and back, I thought that the larvae were gaining entrance through the skin at this place, and some probably did. However, the presence of larvae in the lymph-spaces and lymph vessels of the intestinal wall suggests another plausible explanation - that the larvae pierce the intestinal walls, enter the lymph stream, pass up the thoracic duct into the subclavian vein, thence through the right heart to the lungs, appear in the sputum and, when swallowed, develop into adult parasites. . In this way a vicious circle is set up and the infection grows steadily worse....This must be a slow process and extend over many years. 38

Similarly, Yokogawa in 1913 reported that at autopsy he had found larva e (whether he was referring to r habditiform or filariform larvae is not made clear in the abstract of the Japanese paper) not only in the mucosa, muscularis and serosa of the large intestine around an ulcer, but also in the wall of the ileum, liver, lymphatic system and bloodstream of a patient 120. In 1919, Thira, also in Japan, examined the intestines of two humans and carried out experiments in cats and dogs. He found that rhabditiform larvae may transform into filariform larvae within the body, for he saw the latter forms in the muscularis and i n lymphatics and veins of the submucosa of the bowel. He concluded tha t autoinfection was possible, and in order to support this concept, infecte d successfully a dog by the rectal administration of filariform larvae obtaine d from a fresh stool 114. This view was supported by Shimura and Ogawa in 1920 who, like Gage, found filariform larvae in the sputum of a man who wa s suffering from cancer of the kidney, chronic enteritis and chronic "bronchia l catarrh", and who also had large numbers of rhabditiform larvae in his stools and vomitus 105. The factors which determine whether a rhabditif orm larva was excreted in the faeces or developed into a filariform larva within the gut were (and remain ) uncertain. Stekhoven described a case in whi ch the administration of purgatives resulted in the passage of hard faecal pellets which contained filariform larvae and suggested that this stage of the parasite could cause autoinfection 108. Similarly, in order to assess the role of constipation, Nishigori (1928) reduced intestinal motility in infected dogs by the injection of opiates or th e administration of bismuth, and found that a small proportion of rhabditifor m larvae in the constipated stools had moulted. He then described the sam e phenomenon in an infected soldier who became constipated. Further, Nishigori believed that whereas filariform larvae could penetrate the bowel mucos a easily, rhabditiform or second-stage larvae could only do so if the mucosa was already ulcerated. Nevertheless, all the larvae that he found in the variou s organs (lungs, spleen, kidney etc) and bloodstream were filariform. Nishigori

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therefore injected rhabditiform larvae intravenously or into the abdomina l cavity of dogs and found that they had transformed into filariform larvae a s early as 24 hours later. He postulated that in the process of autoinfection, larvae followed one of three routes: (1) They enter the lymphatic....vessels in the mucosa of the large intestine; they leave the intestinal wall in the flow of lymph; they then enter the lymph nodes....then, through the thoracic duct, by way of the heart, they reach the lungs. (2) Actively piercing the intestinal wall, they reach the abdominal cavity. Some of them immediately penetrate through the diaphragm into the thoracic cavity; afterwards, from the surface of the pulmonary pleura, they invade the parenchyma (lung); others penetrate through the capsule of the liver, entering the parenchyma; afterwards, they reach the lungs by way of the heart. (3) From the surface of the mucosa of the large intestine the invading larvae enter the blood capillaries; they pass through the portal system to the liver and the heart and so reach the lungs.79

Nishigori also believed filariform larvae produced by direct and indirec t means could be distinguished morphologically, with the former worms being smaller and having more cells in the genital primordium 79. This could not be confirmed by most investigators but Faust c laimed to be able to identify a dwarf filariform larva of direct type which he proposed to call "hyperinfective strain" as he considered that there was considerable evidence that this was the for m which was responsible for autoinfection 27. In confirmation of some of these speculations, Ophüls in the following year described a 36 year old man who died of gastroenteritis and in whom post mortem examination revealed large numbers of filariform larvae in the mucosa and submucosa of the colon and in the mesenteric lymph nodes 85 then similar effects were described in patients with a dual infection with strongyloidiasis and leprosy in the Philippines 80 and in two patients in Brazil 116. In addition to reinfection within the intestinal tract (internal autoinfection), Fülleborn in 1926, like Gage before him but probably unaware of that person's postulate, suggested that autoinfection might also occur in another wa y (external autoinfection). As will be detailed later, a number of persisten t carriers of infection complained of urticaria on the buttocks which Fülleborn thought was due to migrating filariform larvae: It is entirely possible that, after defecation, rhabditiform phases can develop into filariform larvae in the anal folds in residual fecal matter, particularly as I ascertained that at....the 'natural hatching oven' of the anal folds, the filariform stage of Strongyloides larvae can be found after less than 24 hours....The penetration into the surrounding skin of filariform Strongyloides larvae....not only causes urticaria but also must be a cause for permanent new infection of the Strongyloides carrier.35

By these means of internal and external autoin fection, Strongyloides infection may persist for many years. Normand understood that the natural history o f strongyloidiasis was very variable, with many people being cure d spontaneously with elimination of all the paras ites, whereas some patients at the other extreme went downhill progressively, became severely dysenteric an d

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died. In the early part of the present centu ry, it was realized gradually that there was a group of individuals who acquired a chronic illness with minimal o r moderate symptoms. Fülleborn in 1926 mentioned the instance of one of hi s patients who had been followed by him for 24 years and remarked that thi s probably represented the "welt-rekord" 35. Since that time, many patients have been reported with even longer durations of infection. Thus, infection was still present in a group of Australian former prisoners-of-war between 34 and 3 7 years after removal from an endemic area 50. Why some patients shoul d eradicate the worms while others tolerate their presence has not yet bee n discovered. Sandground showed many years ago that dogs infected exper imentally acquired some resistance to reinfection but this finding does no t necessarily extrapolate to all humans 100. There may well be genetic variations in susceptibility to infection and the capacity to mount a completely effective immune reaction but these have not yet been defined. Certainly, some patients appear to be unable to eliminate all the worms yet are able to contain the m within bounds and prevent their excessive multiplication. It has been recognized increasingly over the last 25 years, however, that this relatively happy state of affairs is not always sustained. It has become apparent that overwhelming infection, otherwise known as hyperinfection, massiv e infection, or disseminated strongyloidiasis, in which there is a greatl y heightened multiplication of worms, could supervene if patients becam e immunosuppressed for one reason or another (see next section), with con sequent breakdown of resistance to the parasites. That these effects were not simply due to massive exposure to infective larvae in the environment wa s confirmed when dogs were infected experimentally with a defined number of worms, immunosuppressed, then a vast number of worms recovered 52. Consequently, the prognosis of strongyloidiasis is uncertain, with all patients being at risk from severe disease, even though the probability of such an outcom e may be small.

RECOGNITION OF THE CLINICAL FEATURES Normand in 1876 reported that the symptoms associated with infection wit h this parasite were variable, but he was in no doubt that this infection coul d cause a severe and at times fatal disease. He described four clinical categories: Some patients who are afflicted with diarrhea of Cochin China suffer a less intense infection; the causal agent disappears quickly;....recovery comes quickly....Other patients, more heavily infected, relapse easily, even after the diarrhea has been arrested....After some time, more than a year after infection, the patient may recover. The diarrhea sometimes ceases suddenly and, little by little, he recovers a degree of vigor and weight. At other times, the disease evolves progressively into a terminal condition. This third group of patients develops enterocolitis, either after an intense infection or after a long period of alternating recovery and relapse....inflammation

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develops analogous to that which accompanies a serious dysenteric infection, and in a few hours, the patient is dead.- At other times the process is less rapid and may become entirely chronic. The patient, having fought for a long time against the effects of diarrhea, develop an extreme marasmus and succumbs, due to anemia. 81

Thus, the most important symptom was diarrhoea, which was at times mil d with three or four soft, pale motions a day, while on other occasions wa s associated with blood and mucus in the stools or was more choleraic (watery) in character. On the other hand, Darling (1911), like Grassi and others before him , concluded after a study of Strongyloides infection in humans and animals in the Canal Zone of Panama, that the parasite was not a causative factor in th e production of diarrhoea 22. Nevertheless, experimental animal studies b y Thira114 and Sandground 99, and continuing clinical observations confirmed that diarrhoea was a prominent feature of the infect ion. Thus, Gage (1911) observed that a chronic but intermittent diarrhoea was present in 13 of his 15 patient s with strongyloidiasis 38. Barlow in 1915 studied 23 infected persons i n Honduras and divided the clinical picture into four stages - "invasion " characterized by erythema and irritation of the skin at the site of entry of th e larvae, "latent" in which laxatives had an unduly excessive effect, "diarrhoea" which was intermittent, painless and unaccompanied by blood or mucus, and "neurasthenia" with anorexia, vertigo, malaise and emaciation 5. The other major symptom was a skin rash. Looss reported in 1905 that, i n older persons, some larvae: are kept back in the tissues where they wander around under the skin producing the skin disease known as creeping eruption etc. They are able to live in the of form wandering larvae....about five years.74

Although this report has been cited as indicating Strongyloides infection38, the eruption may well have been due to hookworms. In 1926, Fülleborn notice d that when S. stercoralis infective larvae were applied to the skin of previously uninfected individuals, there was a transient itch, but when a person who had been a carrier for many years was infected likewise, a severe urticarial ras h developed which extended gradually along the skin over the next few hours and appeared to be due to larvae migratin g through the integument or subcutaneous tissues. Enquiry revealed that eight out of ten of his patients who were chronic carriers experienced itching of the buttocks: an irritating pruritus accompanying the urticaria occurs, intermittently, at any time during the day but especially during the night in bed. With rubbing and scratching of the skin the urticarial patches become so large that....areas the size of a hand, at the buttocks, are indurated 'hard as a board' with urticaria; at other times the urticaria extends to the waistline in bands one or two fingers wide. 35

In 1958, Arthur and Shelley introduced the term "larva currens" to reflect the rapid rate of migration compared with cutaneous larva migrans 2. Primary involvement of organs other than the gastrointestinal tract or ski n were described from time to time. These included affection of the urogenita l tract presenting with haematuria 37 and of the lungs causing cough and wheeze 84;

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larvae were found in the urine and sputum, respectively. One of the major difficulties which has confronted attempts to define th e symptomatology of strongyloidiasis is frequent concurrent infection with other gastrointestinal pathogens. Hinman in 1939 in an uncontrolled analysis of 85 patients reported that abdominal pain was the most frequent presenting complaint, then this was followed by diarrhoea, nausea, vomiting, headache , anorexia, weight loss and weakness 56. Grove solved this problem by analysing the symptomatology of 44 men with chronic strongyloidiasis (35 years) wh o had long since left the endemic area and were no longer infected with othe r parasites, then controlled the study by a comparison with uninfected men who had been prisoners in the same camps in Southeast Asia or in non-endemi c areas of Europe. He found that two thir ds of patients complained of intermittent urticaria, with 30% having the pathognomonic larva currens, and tha t gastrointestinal symptoms including diarrhoea, indigestion, lower abdomina l pain, pruritus ani and weight loss were significantly more common in infected individuals 50. In 1951, Galliard reviewed reported cases of fatal strongyloidiasis and suggested that the patient had been debilitated in all cases of autoinfection so far recorded39, then this was echoed by Hartz55 . If it had been said that all the patients reported with overwhelming infection had been debilitated, then this would have been closer to the truth. Massive infections were recognized i n patients who were irradiated 94, given corticosteroids 20,118, or who were suffering 55,93 from leprosy80, lymphoma1,94 or protein-calorie malnutrition . In 1978, Scowden and his colleagues reviewed this syndrome, described the frequen t concomitant bacterial infections, particularly septicaemia and meningitis , emphasized that immunosuppression is usually present, and concluded tha t S. stercoralis is a powerful opportunistic pathogen 101.

DEVELOPMENT OF DIAGNOSTIC METHODS Normand described a potent means of diag nosing strongyloidiasis when he first discovered the worms, for he found them during a microscopical examination of the faeces. He also indicated that this technique was useful for assessment of the parasitological responses to treatment in patients in whom diarrhoe a persisted after therapy: "The microscope revealed immediately whether it was a matter of persistent infection or the effect of parasitism" 81. Nevertheless, many observers over the years have recognized that examination of simple faecal smears often fails to provide the diagnosis and a number of attempts have been made to improve diagnostic sensitivity by th e development of concentration techniques. Those which have been usefull y employed in strongyloidiasis include the zinc sulphate concentratio n technique31, coproculture 53, and a modification of the Baermann technique 33. In 1925, Deschiens and Taillandier showed that the diagnosis could also be made by finding parasites in duodenal fluid r emoved via a duodenal tube 24. This

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was claimed to be a much more effective tool for diagnosis by some authors 87, but not by others19. In 1970, Beal and his colleagues described a simplifie d method for obtaining duodenal fluid by means of a string coiled in a gelatin e capsule9. In many modern centres, duodenal fluid may now also be obtained at upper gastrointestinal endoscopy and may reveal parasites 50. The diagnosis has also been made from time to time by recovering larva e from other body fluids and secretions. These include urine 37, sputum38,84 , vomitus105, cerebrospinal fluid 78 and ascitic fluid 4. Radiological studies may suggest the diagnosis and provide an indication of the severity of intestinal damage. Deschiens and Taillandier describe d thickening of the duodenal wall on barium meal examination of the uppe r gastrointestinal tract 24. Gage in 1911 recounted a case of Dr AC Eustis who in 1907 had shown that the patient had strongyloidiasis and an eos inophilia of 56% 38. The first recorded case of eosinophilia in strongyloidiasis, however, was probably that of Daland who in 1908 reported a patient who had a blood eosinophil level of 38% 21. The incidental finding of an eosinophilia on routine examination of blood smear s has not infrequently stimulated a search for S. stercoralis 13. Indeed, de Langen in 1928 realized that the condition which he had previously reported a s "idiopathic hypereosinophilia" was in fact due to S. stercoralis infection64,65. Nevertheless, it is now realized t hat most patients with chronic strongyloidiasis either have no eosinophilia or, at most, a mild increase in blood eosinophi l levels50. Attempts have been made to develop immunoassays of strongyloidiasis a s experience has shown that infection is often hard to diagnose parasitologically in chronic cases. These immunodiagnost ic techniques, include skin testing with Strongyloides antigen36 and the demonstration of antibodies in the serum 12.

THE SEARCH FOR EFFECTIVE TREATMENT The first therapeutic regimen which Normand tried was to put his patients on a "rational diet" of milk. He believed this often suppressed mucus production and caused disappearance of parasites (this was undoubtedly coincidental) . Nevertheless, many patients failed to respond to such therapy and he wrote that he was currently experimenting with santonin, mercury and arsenic, and then proposed to try essential oils, sulphurs, quinine and mineral waters i n "rebellious" cases81. In the following year, he reported that large quantitites of olive oil were useful because o f its mechanical action 82. Perroncito 90 and others after him considered that ethe real extract of male fern was valuable, but Seifert did not agree and believed that thymol was better 102. Grassi, however, asserted that no known anthelmintic was of any value 46; this view turned out to be quite correct. Similarly, new agents introduced for the treatment of hookworm such as oil of chenopodium, betanaphthol, carbon tetrachloride an d tetrachlorethylene were found to be ineffective in strongyloidiasis.

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In 1925, Kudiche showed that some dye-stuffs such as crystal violet an d fuchsin killed filariform larvae in vitro 62. Three years later, de Langen reported that gentian violet given orally in conjunction with intravenous injection o f tartar emetic relieved the sympto ms, reduced the eosinophilia and expelled the worms64. In the following year, however, he advised that patients whom he had thought were cured had relapsed 65. Subsequently, Faust also showed that crystal violet and gentian violet were active in vitro, then experimented in monkey s and claimed striking results. He declared that oral administration of gentia n violet caused all infections to undergo the direct mode of larval development, and stated that examination of autopsied animals revealed that parasitic female worms were killed in situ although the viability of already hatched larvae was unaffected28. Two hundred human cases were then treated with oral gentia n violet and 45 of the 47 patients followed up we re said to be cured 29. Subsequent observations, however, have supported de Langen's view and failed to confirm the efficacy of the drug 104. Similarly, there was no support for the belief tha t "compound solution of iodine" was effec tive as had been held by some 106, or for the claims that bismuth and tin were efficacious 23. In 1957, MacCowen and his colleagues demonstrated the anthelminti c properties of a dye in the dicarbocyanine series called diathiazanine iodide 76. Unlike previous anthelmintics, this drug was shown to be active agains t S. stercoralis by Swartzwelder and co-workers who claimed cure to 89% of 18 patients111. Several fatal reactions to the drug occurred109 , however, and the drug was withdrawn from the market. In 1961, Brown and his collaborators described a new benzimidazole drug, thiabendazole, which had a broad spectrum of anthelmintic activity 16. In the following year, Vilela and colleagues re ported that this agent cured 100% of 38 patients117 but subsequent investigators did not find such uniformly high rates. Because a few resistant worms may multiply, thus permitting a relapse of the illness, attention has turned to finding a drug which will eradicate all th e worms. Martirani and Rodrigues (1976) used cambendazole, another benz imidazole compound, with ap parent success 77 and this may turn out to be more effective than thiabendazole. Finally, recent studies of mice infected with S. ratti and S. stercoralis have indicated that ivermectin, a member of the recently discovered avermectin family of anthelmintics, may be active i n strongyloidiasis 51.

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UNDERSTANDING THE EPIDEMIOLOGY AND THE EVOLUTION OF EFFECTIVE PREVENTIVE AND CONTROL MEASURES Perroncito (1880) was perhaps the first person to point out an associatio n between infection with S. stercoralis and with hookworm 88,89. Similar observations have been made by many investigators since that time. Con sequently, the factors determining the prevalence of strongyloidiasis are very similar to those already described for hookworm infection. Strongyloidiasis is but one of a number of soil-transmitted helminth infections, and no attempt s have been made to control it in isolation. The toxicity and ineffectiveness o f most anthelmintics has militated against mass treatment programmes. The most effective control measures have been the installation and usage of safe waste disposal systems, but these are unavailable in many endemic areas.

OTHER SPECIES OF STRONGYLOIDES S. FUELLEBORNI This organism is a common parasite of old world monkeys and apes. It wa s described by von Linstow in 1905 73. Infections in humans were first reported by Blackie in Southern Rhodesia (Zimbabwe ) in 1932 10. In contrast to infection with S. stercoralis, the diagnosis is made by finding the characteristic egg s instead of larvae in the faeces. Tomita reported in 1941 that he found eggs in the stools between 16 days and 11 months after experimental percutaneou s infection of a human 115, then Pampiglione and Ricciardi demonstrated ova 28 days after experimental human infection 86. In this instance, a rash appeared at the site of infection and was followed by lymphangitis. A cough was noted on the fifth day, then anorexia, malaise, abdominal pain and bouts of diarrhoe a appeared after three weeks. Infections may also be acquired by transmammary transmission. Brown and Girardeau in Zaire reported in 1977 that they ha d found that 34% of 76 children under the age of six months were infected, and they recovered three larvae from the breast milk of a nursing mother 15. In parts of Papua New Guinea, infection has been described with a S. fuelleborni-like worm which affects infants causing abdominal distension , respiratory distress and generalized oedema 59.

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REFERENCES 1. ADAM M, MORGAN O, PERSAUD C, GIBBS WN. Hyperinfection syndrome with Strongyloides stercoralis in malignant lymphoma. British Medical Journal i: 264-266, 1973 2. ARTHUR P, SHELLEY W. Larva currens. A distinctive variant of cutaneous larva migrans due to Strongyloides stercoralis. Archives of Dermatology 78: 186-190, 1958 3. ASKANAZY M. Ueber Art und Zweck der Invasion der Anguillula intestinalis in die Darmwand. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten, Abteilung originale 27: 569-578, 1900. Translated in 58 4. AVAGNINA MA, ELSNER B, IOTTI RM, RE R. Strongyloides stercoralis in Papanicolaoustained smears of ascitic fluid. Acta Cytologica 24: 36-39, 1980 5. BARLOW N. Clinical notes on infection with Strongyloides stercoralis intestinalis, based upon a series of twenty three cases. Interstate Medical Journal 22: 1202-1208, 1915 6. BAVAY A. Sur l'Anguillule stercorale. (Presentée par M. P Gervais) Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 83: 694-696, 1876. Partly translated by DI Grove 7. BAVAY A. Sur l'Anguillule intestinale (Anguillula intestinalis), nouveau ver nématoïde, trouvé par le Dr. Normand chez les malades atteints de diarrhée de Cochinchine. (Presentée par M. P Gervais) Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 84: 266-268, 1877 8. BAVAY A. Note sur l'anguillule intestinale (Anguillula intestinalis) nouveau ver nématoïde trouvé par le Dr. Normand chez les malades atteints de diarrhée de Cochinchine. Archives de Médecine Navale 28: 64-67, 1877 9. BEAL CB, VIENS P, GRANT RG. A new technique for sampling duodenal contents: demonstration of upper small bowel pathogens. American Journal of Tropical Medicine and Hygiene 19: 349-352, 1970 10. BLACKIE WK. A helminthological survey of Southern Rhodesia. London School of Hygiene and Tropical Medicine, Memoir Series, pp 91, 1932 11. BLANCHARD R. Traité de zoologie médicale, J-B Baillière et fils, Paris, two volumes, pp 1691, 1885-1890 12. BRANNON MJ, FAUST EC. Preparation and testing of a specific antigen fordiagnosis of human strongyloidiasis. American Journal of Tropical Medicine 29: 229-239, 1949 13. BRAU P. De l'Anguillula intestinalis en Cochinchine et de son diagnostic hématologique. Bulletins de la Société de Pathologie Exotique et de ses Filiales 6: 262-264, 1913 14. BRETON. Note sur les parasites de la dysenterie et de la diarrhée dite de Cochinchine. Archives de Médecine Navale 31: 441, 1879 15. BROWN RC, GIRARDEAU MH. Transmammary passage of Strongyloides sp. larvae in the human host. American Journal of Tropical Medicine and Hygiene 26: 215-219, 1977 16. BROWN HD, MATZUK AR, ILVES IR, PETERSON LH,HARRIS SA. Antiparasitic drugs. N-2-(4'thiazolyl)-benzimidazole, a new anthelmintic. Journal of the American Chemical Society 83: 1764-1765, 1961 17. CHASTANG E. Diarrhée dite de Cochinchine. Quelques notes sur son origine parasitaire et son traitement par la chlorodyne. Archives de Médecine Navale 30: 29-39, 1878 18. CHAUVIN. L'anguillule stercorale dans la dysenterie des Antilles. Archives de Médecine Navale 29: 154-155, 1878 19. COUTINHO JO, CROCE J, CAMPOS R, AMATO NETO V. Estudo comparativo entre a pesquisa de larvas de Strongyloides stercoralis no suco duodenal e nas fezes. Folia Clinica et Biologica, São Paulo 18: 125-131, 1952 20. CRUZ T, REBOUÇAS G, ROHA H. Fatal strongyloidiasis in patients receiving corticosteroids. New England Journal of Medicine 275: 1093-1096, 1966 21. DALAND J. Strongyloides intestinalis in Philadelphia. New York Medical Journal 87: 761, 1908 22. DARLING ST. Strongyloides infections in man and animals in the Isthmian Canal Zone. Journal of Experimental Medicine 14: 1-24, 1911 23. DESCHIENS R, BENEZ J. Essais expérimentaux et cliniques de traitement de l'anguillulose intestinale par le sous-nitrate et par le carbonate de bismuth. Bulletin de la Société de Pathologie Exotique 50: 70-74, 1957

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24. DESCHIENS R, TAILLANDIER O. Présence de larves rhabditoides de Strongyloides stercoralis (Bavay, 1877) dans le liquide duodénal receuilli par tubage. Considérations cliniques sur l'anguillulose. Bulletins de la Société de Pathologie Exotique et de ses Filiales 18: 525-527, 1925 25. DOUNON PL. Étude sur l'anatomie pathologique de la dysenterie chronique de Cochinchine. Archives de Physiologie Normale et Pathologique, second series, 4: 774, 1877 26. van DURME P. Quelques notes sur les embryons de "Strongyloides intestinalis" et leur pénétration par la peau. Thompson Yates Laboratories Report 4: 471-474, 1901-1902 27. FAUST EC. The Panama strains of human Strongyloides. Proceedings of the Society for Experimental Biology and Medicine 28: 253-255, 1930 28. FAUST EC. Human strongyloidiasis in Panama. American Journal of Hygiene 14: 203-211, 1931 29. FAUST EC. The symptomatology, diagnosis andtreatment of Strongyloides infection. Journal of the American Medical Association 98: 2276-2277, 1932 30. FAUST EC. Experimental studies on human and primate species of Strongyloides in the experimental host. American Journal of Hygiene 18: 114-132, 1933 31. FAUST EC, D'ANTONI JS, ODOM V, MILLER MJ, PERES C, SAWITZ W, THOMEN LF, TOBIE J, WALKER JH. A critical study of clinical laboratory technics for the diagnosis of protozoan cysts and helminth eggs in feces. American Journal of Tropical Medicine 18: 169-183, 1938 32. FAUST EC, RUSSELL PF, JUNG RC. Craig and Faust's Clinical Parasitology, eighth edition, Lea and Febiger, Philadelphia, pp 890, 1970 33. FERRIOLLI F. Diagnóstico da estrongiloidíase. Modificações do métode de Baermann-Moraes. Revista do Instituto de Medicina Tropical de São Paulo 1: 138-140, 1959 34. FÜLLEBORN F. Untersuchungen über den Infektionsweg bei Strongyloides und Ankylostomum und die Biologie dieser Parasiten. Archiv für Schiffs- und Tropen-Hygiene 18: 26-80, 1914. Partly translated in 58 35. FÜLLEBORN F. Hautquaddeln und "Autoinfektion" bei Strongyloides-strägern. Archiv für Schiffs- und Tropen-Hygiene 30: 721-732, 1926. Partly translated in 58 36. FÜLLEBORN F. Spezifische Kutanreaktionen bei Infektion mitStrongyloides und anderen Helminthen. Archiv für Schiffs- und Tropen-Hygiene 30: 732-749, 1926 37. FURÑARA P. Un caso di ematuria da strongyloide intestinale. Policlinico 30: 75-80, 1923 38. GAGE JG. A case of Strongyloides intestinalis with larvae in the sputum. Archives of Internal Medicine 7: 55-59, 1911 39. GALLIARD H. Recherches sur l'infestation expérimentale à Strongyloides stercoralis au Tonkin. Annales de Parasitologie Humaine et Comparée 25: 441-473, 1950; 26: 67-84, 1951 40. GOLGI C, MONTI A. Intorno ad una questione elmintologica. Rendiconti del Reale Istituto Lombardo di Scienze e Lettere, Milano, second series, 17: 285-288, 1884 41. GOLGI C, MONTI A. Sulla storia naturale e sul significato clinico-patologico delle cosi-dette anguillule stercorali e intestinali. Atti della Reale Accademia delle Scienze di Torino 21: 55-59, 1885. Also, Archivio per le Scienze Mediche, Torino 10: 93-107, 1886 42. GRAHAM GL. Studies on Strongyloides. I. S. ratti in parasitic series, each generation in the rat established with a single homogonic larva. American Journal of Hygiene 24: 71-87, 1936 43. GRASSI GB. Sovra l'Anguillula intestinale. Rendiconti del Reale Istituto Lombardo di Scienze e Lettere, Milano, second series, 12: 228-233, 1879 44. GRASSI GB. Parassitologia umana Rivista. Sovra l'Anguillula intestinale. La Medicina Contemporanea, Milano 3: 495-497, 1879 45. GRASSI GB. Anchylostomi e anguillule. Gazzetta degli Ospedali e delle Cliniche, Milano 3: 325, 1882 46. GRASSI GB. Un ultra nota sulle anguillule e sugli anchilostomi. Giornale della Reale Accademia di Medicina di Torino, third series, 31: 119-121, 1883 47. GRASSI GB. Intorno ad una questione parassitologica. Un ultima parola al Prof. Perroncito. Gazzetta Medica Italiana Lombardia, Milano, eighth series, 5: 260-262, 1883 48. GRASSI GB. Intorno ad una questione parassitologica. Un ultissima parola al Prof. Perroncito. Gazzetta Medica Italiana Lombardia, Milano, eighth series, 5: 391-392, 1883 49. GRASSI GB, PARONA. Sovra l'anguillula intestinale (dell'uomo) e sovra embrion i probabilmente d'anguillula intestinale. Archiv per le Scienze Mediche, Torino 3: 1-15 ,

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1879 50. GROVE DI. Strongyloidiasis in Allied ex-prisoners of war in southeast Asia. Britis h Medical Journal i: 598-601, 1980 51. GROVE DI. Effects of 22,23 dihydroavermectin B 1 on Strongyloides ratti and S. stercoralis infections in mice. Annals of Tropical Medicine and Parasitology 77: 405-410, 1983 52. GROVE DI, HEENAN PJ, NORTHERN C. Persistent and disseminated infections with Strongyloides stercoralis in immunosuppressed dogs. International Journal fo r Parasitology 13: 483-490, 1983 53. HARADA Y, MORI O. A new method for culturing hookworm. Yonago Acta Medica 1: 177-179, 1955 54. HARTZ PH. Human strongyloidasis with internal autoinfection. Archives of Pathology 41: 601-611, 1946 55. HARTZ PH. Strongyloidasis wit h internal autoinfection in children. Documenta Medicina Geographica et Tropica 6: 61-68, 1954 56. HINMAN EH. A study of eighty five cases of Strongyloides stercoralis infection, with special reference to abdominal pain. Transactions of the Royal Society of Tropica l Medicine and Hygiene 30: 531-538, 1937 57. INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE . Nematode and Gordiacea names placed in the official list of generic names (Opinion 66), Smithsonian Institution Publication 2359, Washington DC, pp 171-176, 1915 58. KEAN BH, MOTT KE, RUSSELL AJ. Tropical Medicine and Parasitology. Classi c Investigations, Cornell University Press, Ithaca, pp 677, 1978 59. KELLY A, LITTLE MD, VOGE M. Strongyloides fülleborni -like infections in man in Papua New Guinea. American Journal of Tropical Medicine and Hygiene 25: 694-699, 1976 60. KOSUGE I. Histologische Untersuchungen ueber das Eindringen von Strongyloides stercoralis in die Haut von Versuchstieren. Archiv für Schiffs- und Tropen-Hygiene 28: 15-20, 1924 61. KREIS HA. Studies on the genus Strongyloides (Nematoda). American Journal o f Hygiene 16: 450-491, 1932 62. KUDICHE R. Neue Verfahren zur Untersuchu ng und Prüfung von Wurmmiteln. Versuche an Finnen und Strongyloidesl arven. Archiv für Schiffs- und Tropen-Hygiene 29: 189-197, 1925 63. von KURLOW MG. Anguillula intestinalis als Ursache akuter blutiger Durchfalle beim Menschen. Centralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten , Abteilung originale 31: 614, 1902 64. de LANGEN CD. Anguillosis en het ziektebe eld van de "idiopathische hypereosinophilie". Geneeskundig Tijdschrift voor Nederlandsch-Indië 68: 973-990, 1928 65. de LANGEN CD. Postscript about anguillosis and eosinophilia. Mededeelingen van den Dienst der Volksgezondheid in Nederlandsch-Indië 18: 310-314, 1929 66. LAVERAN A. Note relative du nématoïde de la dysenterie de Cochin-Chine. Gazett e Hebdomadaire de Médecine et de Chirurgie 14: 42-43, 1877 67. LAVERAN A. Deuxième note relative aux auguillules de la diarrhée chronique d e Cochinchine. Gazette Hebdomadaire de Médecine et de Chirurgie 14: 116-117, 1877 68. LEICHTENSTERN O. Ueber Anguillula intestinalis . Deutsche medicinisch e Wochenschrift 24: 118-121, 1898 69. LEICHTENSTERN O. Zur Lebensgeschichte der Anguillula intestinalis . Centralblatt für Bakteriologie, Parasitenkunde und Infek tionskrankheiten, Abteilung originale 25: 226-231, 1899 70. LEUCKART R. Ueber die Lebensgeschichte der sogenannten Anguillula stercoralis und deren Beziehungen zu der sogenannten Anguillula intestinalis . Bericht über die Verhandlungen der königlich sachsischen Gesellschaft der Wissenschaften zu Leipzig . Mathematische-Physische Classe (1882) 34: 85-107, 1883. Partly translated in 113 71. LEUCKART R. Die Parasiten des Menschen und die von ihnen herrührenden Krankheiten.

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92.

93. 94.

95. 96.

97. 98. 99.

100.

101. 102. 103. 104.

105.

106. 107. 108. 109.

110. 111.

112.

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Pseudorhabditis sterc oralis (Mihi) hors de l'organisme humain. Journal de l'Anatomie et de la Physiologie 17: 499-519, 1881 PERRONCITO E. Osservazioni alla nota del Dott. Grassi fatte nella seduta in cui essa venne letta. Giornale della Reale Accademia di Medicina di Torino, third series, 31 : 121-133, 1883 PURTILO DT, MEYERS WM, CONNOR DH. Fatal strongyloidiasis i n immunosuppressed patients. American Journal of Medicine 46: 488-493, 1974 ROGERS WA, NELSON B. Strongyloidiasis and malignant lymphoma. "Opportunistic infection" by a nematode. Journal of the American Medical Association 195: 685-687, 1966 ROUX PA. De l'anguillule stercorale et de son rôle dans l'étiologie de la diarrhée d e Cochinchine, Thèse, Paris, pp 42, 1877 ROVELLI G. Ricerche sugli organi genitali degli Strongyloides (Anguillula, Rhabdonema), Como, 1888. Abstracted in Centralblatt für Bakteriologie un d Parasitenkunde, Abteilung originale 4: 660-661, 1888 SANDGROUND JH. Some biological studies on the life cycle in the genu s Strongyloides. Archiv für Schiffs- und Tropen-Hygiene 13: 528-533, 1926 SANDGROUND JH. Biological studies on the life cycle in the genus Strongyloides Grassi, 1879. American Journal of Hygiene 6: 337-388, 1926 SANDGROUND JH. The role of Strongyloides stercoralis in the causation of diarrhea. Some observations on the condition of dogs and cats experimentally infected with th e parasite. American Journal of Tropical Medicine 6: 421-433, 1926 SANDGROUND JH. Some studies on susceptibility, resistance and acquired immunity to infection with Strongyloides stercoralis (Nematoda) in dogs and cats. America n Journal of Hygiene 8: 507-538, 1928 SCOWDEN EB, SCHAFFNER W, STONE WJ. Overwhelming strongyloidiasis: a n unappreciated opportunistic infection. Medicine (Baltimore) 57: 527-544, 1978 SEIFERT O. Ueber Anguillula stercoralis und Cochinchinadiarrhoe. Sitzungsberichte der physikalische-medicinischen Gesellschaft zu Würzburg pp 22-32, 1883 SEIFERT O. Ueber ein Entozoon. Verhandlungen der Congress für innere Medicin ii: 337, 1883 SHIKOBALOVA NP, SEMENOVA NE. (On the problem of the clinical study an d treatment of strongyloidiasis.) Meditsinskaya Parazitologiya i Parazitarn e Bolezni 11: 76-83, 1942 SHIMURA S, OGAWA T. (O n the filariform larvae found in vomit of a patient infested with Strongyloides.) Tokyo Iji Shinshi No. 2197, pp 1829-1836, 1920. In Japanese . Abstracted in Tropical Diseases Bulletin 19: 223, 1922 SIMPSON VE. Strongyloidiasis. Journal of the American Medical Association 112 : 828-832, 1939 SONSINO P. Tre casi malattia da Rhabdonema intestinale e rhabdonemiasis. Rivist a Generale Italiana di Clinica Medica, Pisa 3: 47-56, 1891 STEKHOVEN JH. Researches on nemas and their larvae. III. Strongyloides stercoralis Bavay. Zeitschrift für Parasitenkunde 1: 231-261, 1928 STEMMERMAN GN, NAKASONE N. Strongyloides stercoralis infestation. Malabsorption defect with reaction to dithiazanine iodide. Journal of the America n Medical Association 174: 1250-1253, 1960 STILES CW, HASSALL A. Strongyloides stercoralis , the correct name of the parasite of Cochin China diarrhea. American Medicine 4: 343, 1902 SWARTZWELDER JC, FRYE WW, MÜHLEISEN JP, MILLER JH, LAMPERT R, PEÑACHAVARRIA AA, ABADIE SH, ANTHONY SO, SAPPANFIELD RW . Dithiazanine, an effective broad spectrum anthelmintic. Journal of the American Medical Association 165: 2063-2067, 1957 TEISSIER P. De la pénétration dans le sang de l'homme des embryons de l'anguillule stercorale: rapports de la présence de ces embryons dans le sang avec certain fièvres des pays chauds. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences

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120: 171-172, 1895. (Presentée par M Potain) 113. THAYER WS. On the occurrence of Strongyloides intestinalis in the United States. Journal of Experimental Medicine 6: 75-105, 1901-1905 114. THIRA T. (Studien über Strongyloides stercoralis .) Mittheilung der medicinische n Gesellschaft zu Tokio 33: (11) 2-3, 1919. In Japanese, with German summary 115. TOMITA S. (On local reaction of infected skin, clinical symptoms and changes in blood picture in experimental infection with Strongyloides papillosus amd S. fülleborni.) Taiwan Igakkai Zassi 40: 427-442, 1941. In Japanese. Abstracted in Tropical Diseases Bulletin 39: 100, 1942 116. TORRES CM, de AZAVEDO AP. Lesoes produzidas no honem por Strongyloides. Sobre a 'hyperinfection'. Livro Jub ilar do Prof. L. Travassos, Rio de Janeiro, pp 475-488, 1938. Abstracted in Tropical Diseases Bulletin 36: 844, 1939 117. VILELA M de P, RODRIGUES LD, CAPELL JI, BRANDÃO JA, MARTIRANI I , ZACATO M. O emprego do tiabendazol no tratamento da estrongiloidiase de outra s parasitosis humanas. Hospital, Rio de Janeiro 62: 691-710, 1962 118. WILLIS AJ, NWOKOLO C. St eroid therapy and strongyloidiasis. Lancet i: 1396-1398, 1966 119. WILMS. Anchylostoma duodenale und Anguillula intestinalis . Schmidt's Jahrbucher der In- und ausländischen gesammten Medicin 256: 272, 1897 120. YOKOGAWA S. On the pathogenesis of Strongyloides stercoralis . Far Eastern Association of Tropical Medicine: Comptes Rendus Troisième Congrès Biennal, Saigon (1913), pp 329, 1914. Abstracted in Tropical Diseases Bulletin 6: 304, 1915 121. YOSHIDA S. A new course for migrating Ancylostoma and Strongyloides larvae after oral infection. Journal of Parasitology 7: 46-48, 1920

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Table 21.1. Landmarks in strongyloidiasis ___________________________________________________________________ 1876

Normand discovered larvae (in retrospect, rhabditiform), which were then named Anguillula stercoralis by Bavay, in faeces of French troops returned from Indochina, and proposed the parasite as a cause of Cochin-China diarrhoea 1876 Bavay described the development of free-living adult worms from faecal larvae and the subsequent appearance of larvae (rhabditiform) [He observed the indirect cycle of development] 1876 Normand, at autopsy, discovered parasitic adult worms in the intestine; this was at first considered to be a distinct species and was named A. intestinalis 1877 Normand and Bavay found larvae (in retrospect, filariform) in faeces which had been kept for several days. They believed that the larvae were the offspring of the worm found by Normand in the intestines of a patient [Although they did not realize it, they had observed the direct development of rhabditiform into filariform larvae] 1878 Grassi and Parona showed that the larvae produced by A. intestinalis in the gut were identical with A. stercoralis larvae, and observed their further development in vitro into filariform larvae but not into free-living adults (the direct cycle) 1880 The parasite was found to infect miners working in the St. Gothard tunnel 1881 Perroncito cultivated free-living adults from rhabditiform larvae, then observed the laying of eggs and the hatching of rhabditiform larvae which developed into filariform larvae (the indirect cycle) 1882 Grassi postulated that the parasitic adult worms were parthenogenetic 1883 Looss observed both direct and indirect development in vitro simultaneously in the same preparations but did not report the fact 1883 Leuckart concluded that A. intestinalis and A. stercoralis were the same parasite and that there was an alternation between the parasitic and free-living generations 1883 Grassi suggested that autoinfection with direct transformation of rhabditiform to filariform larvae may take place in the gut 1884 Golgi and Monti reported that rhabditiform larvae could undergo either direct or indirect development 1891 Sonsino described the presence of parasites in the mucosa of the small intestine 1897 Wilms produced a patent infection in a human volunteer 17 days after ingestion of filariform larvae 1901-2 van Durme described the penetration of Strongyloides (probably S. fuelleborni) filariform larvae through the skin of guinea pigs 1904 Looss produced a patent infection in himself after placing larvae on the skin of his forearm 1905 S. fuelleborni was described as a parasite of monkeys and apes 1911 Fülleborn showed using dogs with a tracheotomy or oesophagostomy that the majority of migrating filariform larvae followed the tracheo-oesophageal route described for hookworm by Looss 1911 Gage found filariform larvae in the sputum of a human 1919 Thira produced patent infections by rectal administration of filariform larvae,

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thus supporting the possibility of internal autoinfection Larvae were found in duodenal fluid obtained with a duodenal tube Fülleborn suggested that external autoinfection may occur when rhabditiform larvae develop into filariform larvae in the perianal folds, described the frequent occurrence of urticaria in infected patients, and described a skin test for the diagnosis of strongyloidiasis 1932 Kreis and Faust claimed (erroneously) to have found male adult parasitic worms 1932 S. fuelleborni was described by Blackie as a parasite of humans 1945+ Disseminated infections in immunosuppressed persons became increasingly recognized 1957 Dithiazinine iodide was reported to be an effective treatment by MacCowen and colleagues but was subsequently withdrawn following fatal reactions 1962 Thiabendazole was reported to cure patients with strongyloidiasis by Vitela and coworkers 1976 Martirani and Rodrigues reported that cambendazole cured patients with strongyloidiasis but the drug was subsequently withdrawn ___________________________________________________________________ 1925 1926

Chapter 22

Trichinella spiralis and TRICHINOSIS

SYNOPSIS Common name: fleshworm Major synonym: Trichina spiralis Distribution: worldwide except Oceania Life Cycle: When infective larvae in cysts in meat are ingested by a carnivore, they excyst in the upper small intestine, invade the gut epithelium and moult four times. The adult worms, 1-2 mm long, produce newborn larvae which enter the bloodstream and seed the muscles.They penetrate intracellularly, become surrounded by a cyst wall, and become infective within three weeks Hosts: most mammals Major clinical features: fever, diarrhoea, myositis in persons with heavy infections Diagnosis: demonstration of larvae in muscle biopsy; serology Treatment: supportive

DISCOVERY OF THE LARVA IN HUMANS In December 1834, Paolo Bianchi, a middle-aged Italian barometer-maker, was admitted to St. Bartholomew's Hospital in London, England under the care of Dr George Roupell, lecturer in materia medica. Bianchi complained of loss of appetite, cough and back pain and was found on examination to be emaciated and weak and to have an enlarged liver and lower limbs swollen with fluid. His urine tasted sweet suggesting the presence of sugar and contained large quantities of protein. Despite supportive treatment with various tonics and sedatives, a nutritious diet, and the application of leeches, his condition deteriorated. His abdomen became distended and painful and he died on 29 January 1835 following the passage of bloody, diarrhoeic stools. At post-mortem examination, tuberculous cavities were found in the upper lobe of each lung, the liver was enlarged and fatty, the kidneys showed features of chronic nephritis, and the small intestine was ulcerated92. When the body was dissected three days after death, an immense number of minute, whitish specks were observed scattered throughout the muscles. Such a condition had come to the attention of the demonstrator of anatomy, Thomas Wormald, on a number of occasions previously, sometimes as a result of the 571

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gritty nature of the specks leading to rapid blunting of the scalpels. These specks had been regarded as bone spicules in the muscles, or else were thought to be caused by deposition of earthy matter. In the dissecting room at the time was James Paget, a 21 year old first year medical student. It is uncertain whether Paget himself was the first to observe the specks in this patient. Certainly, Owen thought so, for he wrote in his paper printed later that year: "it was observed by Mr. Paget, an intelligent student, that the muscles presented an uncommon appearance" 76 and also: "Mr. Paget....first observed the worms in the Italian"74. On the other hand, Paget himself recalling the events 31 years later wrote: "The report soon ran through the dissecting room that there was another body with spiculae of bone in the muscles"80, thus suggesting that another dissector may have first noticed the abnormality. What is clear, however, is that Paget did not rest content with the explanation of bony spiculae, or else wished to see them in more detail for himself, for he examined the specks with a lens and found that they were cysts. Moreover, almost immediately afterwards, he found that a small worm was coiled up within nearly every cyst. Being desirous of investigating these creatures further, he sought a microscope with which to them examine them more closely. Unfortunately, no such instrument was to be found in the hospital at that time, so he repaired to the only scientist he knew in London, one Mr. Children, principal keeper of the natural history collection at the British Museum. Children had no microscope either, so he took Paget to the celebrated botanist, Robert Brown. Paget himself has recounted what then happened: I remember that when Mr. Children entered his room, he said 'Brown, do you know anything about intestinal worms?' and answer was, 'No, thank heaven - nothing whatever.' Mr. Brown at once lent me his simple dissecting microscope, with which I soon observed structures within the worm which were before invisible. He dexterously pulled a worm from a cyst, and I believe I still possess my sketch of it.80

Thus began a saga which has remained a subject of interest, controversy, and at times, acrimonious debate, even to the present day. A number of factors must have contributed to the successful outcome of Paget's tenacious search. He was clearly of an energetic nature and enquiring mind. There is no doubt as to his intellectual ability for he won the prizes in medicine, surgery, chemistry and botany in 1835. Finally, he was wellacquainted with the biological world, for despite his youth, he had already published together with his brother Charles a book on the natural history of Yarmouth. Paget himself attributed his success to the fact that he "looked-at" and "observed" the specks rather than merely "saw" them as others, both teachers and fellow-students, had done83. As the discoverer of the entozoon, Paget was invited to communicate his findings to the Abernethian Society which was the medical students' society at St. Bartholomew's Hospital. This he did on 6 February 1835 with Dr. Arthur Farre in the chair, the salient features being recorded in the Minute Book of the Society101. Paget's presentation met with sufficient approbation that he was

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encouraged by Edward Stanley, lecturer in anatomy and physiology at St. Bartholomew's Hospital, to submit a manuscript describing the discovery to the London Medical Gazette. Such a report headed "Description of a peculiar animalcule observed in human muscle"81,82 was duly written, together with an introductory note, dated 10 February 1835, to the Gazette's editor. Paget described the appearances of elliptical cysts with pointed ends 1/40 of an inch in length and the entrapped, spirally-coiled worms 1/25 of an inch long. He noted that the parasites were rounded bluntly at both ends but tapered towards the end that appeared to be the head, and believed that they possessed an intestinal canal. Paget considered that the genus to which the entozoon most closely approached was that of the roundworm, Capsularia, described by Zeder110 . But the paper was never sent and it was to remain unpublished for nearly 150 years until it was printed in 197882 and again in 197981. It was at that point in 1835 that the story began to go awry. Instead, it was left to Richard Owen, 30 years of age and lecturer in comparative anatomy at St. Bartholomew's Hospital, to publicize the discovery, name the worm, and become immortalized in print. On the evening of 24 February 1835, Owen presented a paper entitled "Description of a microscopic entozoon infesting the muscles of the human body"75 to the Zoological Society of London and demonstrated the parasite with the aid of a microscope belonging to Mr Prichard. This presentation was published with minor variations not fewer than four times in the ensuing year; it was written twice in the first person76,77 and twice ostensibly as third person reports but undoubtedly written by Owen74,75 Owen had some trouble classifying the parasite, but finally admitted it to the Class Entozoa of Rudolphi, created a new genus, Trichina, from the Greek (THRIX) [combining form - (TRICH-)] meaning "hair", and gave it the specific designation "spiralis" to indicate its spiral form. The terms "trichinosis" or, occasionally, "trichiniasis" were therefore used to denote the disease caused by the organism. In 1896, Railliet86 altered the generic name to Trichinella since the name Trichina had been employed for a genus of the Diptera (flies) in 1830. Although the disease might therefore more correctly be called "trichinellosis", "trichinosis" is entrenched in the literature and is hallowed by tradition. Since Paget had not only discovered the worm but had prepared an account for publication, it is almost incredible to find that it was Owen who provided the definitive report. Given that this happened, however, one then turns to Owen's text for due and explicit acknowledgement of Paget's role. The best that can be said for Owen is that he obscured the truth by a masterpiece of dissembling. In one version published in April 183574,75, Paget's name was sandwiched between those of Wormald and Farr, with the comment being made that Wormald had previously seen them a number of times (thus implying that Paget's finding was not out of the ordinary) and Farr being praised as one "who has paid much attention to the subject"75. Concerning Paget, it was merely said

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that: (the specks) having been again remarked....by Mr. Paget, a student of the hospital, who suspected it to be produced by minute Entozoa. The suspicion was found to be correct, and Mr. Owen was furnished with portions of the muscle and made the following observations.75

In the account printed in the following December, Paget is patronized as an "intelligent student"76 and this time a footnote, the antithesis of clarity, is added: The existence of the entozoon was at the same time satisfactorily determined by Mr. Paget with the assistance of Mr. Brown and Mr. John Bennett at the British Museum.76

The clear implication of this, of course, is that Owen claimed for himself the priority of independent discovery of the parasite. Why should Paget have given way to Owen like this? Many years later (1866), Paget wrote: "The admirable memoir of Professor Owen (was) much more complete and exact in zoological detail than anything I could have written"80. This suggestion that Paget was incapable of writing an expert zoological description does not stand up to critical analysis. When Paget's and Owen's texts are both examined, the former compares quite favourably with the latter. Indeed, Paget did not make the two blunders that Owen did when he called the tail of the worm its head and denied the existence of an alimentary tract in the parasite. This question has recently been discussed intensively by Campbell26 who has also published two letters written by Paget soon after the discovery. In writing on 11 February 1835 to his brother Charles, Paget said: You will be interested in learning that I have lately discovered a perfectly new animalcule, infesting in myriads the human muscle, during life....and the account is to be published either in the Transactions of the Zoological or the Medico-Chirurgical Society. I do not yet know whether I shall write the description myself, or whether Mr. Owen, our lecturer on comparative anatomy will do it - I should rather think the latter, as he having used far more powerful microscopes than I had, has been able to make out their organization more clearly. Whichever be the case, I have taken care that I should receive at least some credit for the discovery, though this was not to be had without some trouble.81,82

In a subsequent letter two weeks later, he added: I think I have done rightly in not publishing this account for the folln. among many reasons. It is a subject with which I was PREVIOUSLY entirely unacquainted, and I might very easily have fallen into error as to the affinity of species - as well as to their peculiar structures....I should probably have been obliged to send it to some (minor?) periodical, or the Society at which the description might have been read, would not have printed it in their earliest transactions, giving preference to papers by members. Besides the subject....comes so near the marvellous that it required some good name to authenticate it to prevent its being....utterly disbelieved. You may add perhaps, self interest, (wh.?) said that it would in the end be best not to stand too far forward, but I fear not modesty....I am very well contented that in the papers which will probably be published....I shall be mentioned as the first observer of their existence.81,82

From all of this, Campbell26 has distilled four likely reasons for Paget's actions. First, despite his explicit denial, modesty seems a strong factor for he was but

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a first year medical student embarking on a career in an intensely hierarchical profession. To this may be added political expediency, for he was a student of Wormald who, as Paget later indicated "disliked me . . and became the chief opponent of my progress" 83. Thirdly, it is possible that Paget may have been embarrassed and frustrated by having no suitable illustrations of the parasite whereas he could have expected Owen and his illustators to produce masterful and detailed drawings. Finally, his lack of access to a powerful microscope made him diffident about describing the structure of the worm in detail. Thus, Paget was in a position of ethical superiority but political and technical weakness. Not only did he have his own reasons for yielding to Owen, but the two of them struck a deal. Owen agreed to give Paget credit in his presentation, but this accord was gained only with "some trouble" on Paget's part, and as has been seen, was carried out in the most niggardly and obscurantist fashion by Owen. It is little wonder then, that for the next three decades, most writers on this subject generally referred to Owen as the discover or Trichina spiralis. During this period, however, the waters were muddied even further. The definitive discovery of the parasite caused various commentators to attempt to diagnose in retrospect some of the reports in the earlier literature. Owen and Paget had done this themselves, for they both referred to the patient recorded in 1833 by John Hilton, demonstrator in anatomy at Guy's Hospital, London55. Hilton had described cysts in the muscles of a cadaver but had thought that they were probably cysticerci. It now seemed probable that they were in fact T. spiralis. Furthermore, it became apparent that a specimen of sternomastoid muscles deposited in Guy's Hospital museum in 1828 by its then curator, Mr H Peacock, also contained cysts of this worm; this finding had never been published 107. In a similar vein, a number of German writers led by Henle52 in turn insisted that these bodies were first seen by F Tiedemann and published in Froriep's Notizen in 1822. This passage has been translated by Cobbold: At the post-mortem examination of a man who had been a great brandy drinker and who died from thoracic dropsy after several severe attacks of gout, Tiedemann found white stony concretions in most muscles, especially at the extremities. They lay in the cellular tissues between the fibre-bundles; frequently also attached to (or near) the walls of the arteries, being from two to four lines long, and roundish. the chemical examination conducted by Gmelin yielded 73 parts phosphate of lime, 7 parts carbonate of lime, and 20 parts of animal matter, resembling albumen or fibrin.98

Claims that Tiedemann's concretions were trichinellae were dismissed by Leuckart on the grounds that they were too big and the work was mostly concerned with chemical analysis of their nature67. In any event, it is now clear that whether or not they were trichinellae is irrelevant since they were certainly not recognized as such by Tiedemann. It was not until the epidemics of trichinosis in Germany in the 1860's brought the worm and the affliction that it caused to general attention that interest in the

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question of its discovery was rekindled. When a writer in the Pall Mall Gazette in England indicated that the history of Trichinella "was not yet clearly made out". Spencer Cobbold thought it his duty to write to The Times to put forth the facts. This led to a spirited exchange in the columns of both that paper and The Lancet. This included a letter from Paget himself making plain his view of the facts80 and a communication from "Two former presidents of the Abernethian Society"101 who quoted an extract from the Society's minute book of 6 February 1835 which described Paget's talk. Cobbold summed it up by writing in The Lancet: In the interests of truth, I rejoice that our knowledge of the circumstances connected with the discovery of the fleshworm is now complete. The letters....unequivocally establish Mr Paget's priority in this relation.32

Perhaps not surprisingly, Owen remained uncharacteristically silent publicly during this period, although he was to comment sixteen years later. It may be that senility impaired his judgement or his memory when he took up the cudgels again in the correspondence columns of The Lancet in November 1882, and once more claimed to be the discoverer of the T. spiralis 78. Indeed, his own communication did little to advance his cause, for he quoted the note from Wormald which accompanied the specimen of muscle: Dear Owen, - I send you some sort of organised being, as I believe, which occupies the muscle of a subject under dissection at St. B. H., and, as I know you are a keen hand for parasitical things, from 'crabs' downwards, I send the enclosed for your inspection.109

Not only does this note imply that it was already known that the specks were of an animal nature, but the apparent spontaneity of the missive does not square with Owen's own account in 1835 when Owen declared that he had sought the material from Wormald. This last letter of Owen's stimulated another exchange between Cobbold34,35 and Owen79, with the latter's incomprehensible circumlocution doing nothing to change Cobbold's conviction that Paget had discovered the parasite. Paget's discovery and Owen's promulgation of awareness of the parasite raised many important questions. These included the nature of the organism and its cyst and its significance for the host. But first it was critical that the initial observations be validated by finding the same parasite in other people. This was not long in coming from a number of quarters. In St. Bartholomew's Hospital itself, a second patient was found to be infected just two weeks after the initial discovery74 and yet a third patient from that hospital was described later that year by Farre41. Cases were then reported by Harrison in Ireland, Knox in Edinburgh and by various observers in continental Europe and in North America. Uncertainty surrounded the nature of the cyst enclosing the spiral worm. Owen thought it was a single layer of host origin, saying: the cyst is adventitious, foreign to the entozoon and composed of the cellular substances of the body infested, morbidly altered by the irritation of the worm"76. On the

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other hand, a number of investigators including Vogel, Bristowe and Rainey considered that the cyst was a product of the worm itself, while Hubert Luschka, professor of anatomy at Tübingen, (in present-day West) Germany, was of the view that it had two components, an outer coat of fine fibres laid down by the host, and an inner homogeneous layer derived from the parasite70. It is only in recent times that it has been shown with the aid of the electron microscope that the cyst is formed by multiple infoldings of the sarcolemmal sheath of the muscle fibre38. Although Owen had described the parasite correctly as a worm, its precise nature was obscure to the early observers for they had little concept of helminth life cycles. In particular, it was not at first realized that the parasite living in muscles was a larva and not an adult worm. Even though Owen was inaccurate in many aspects of his description of the worm, he was correct in denying the presence of mature reproductive organs; he thought it possible that the worms reproduced by a process of gemmation or budding74. Farre in the same year described a complete digestive tract which convinced him that the worm was not one of the "simple parenchymatous forms" but approximated the "more highly organised species of entozoa"41, in particular, the roundworms. However, Farre identified certain structures as gonads and mistakenly thought that the encysted worms were sexually mature animals, an error which was perpetuated by Theodor Bischoff, a prominent anatomist in Heidelberg, (West) Germany22. Some of these erroneous observations were corrected by Luschka who demonstrated that what Owen had called the head was in reality the tail, but the most telling points had been made several years earlier by the German, 40 Carl von Siebold95, and the Frenchman, Felix Dujardin , who both stated unequivocally that the encysted trichinella was a juvenile form. Moreover, those workers were of the view that trichinellae were probably the offspring of a roundworm that was already known in its adult state by another name. The stage was about to be set for elucidation of the life cycle of the parasite, but first it was necessary to have a system in which these events could be investigated experimentally. IN ANIMALS In 1846, Joseph Leidy, a 23 year old American doctor was at home eating a slice of pork when he noticed some minute specks in the meat which reminded him of the trichinous spots that he had seen in the muscles of a human cadaver only a few days previously. When he examined a portion of the flesh under the microscope, he found that it was teeming with chalky cysts, each containing a coiled worm; fortunately for him, they had all been killed by cooking62. Leidy could detect no difference between this parasite and the T. spiralis observed in human muscle and duly communicated his findings to a meeting of the Academy of Natural Sciences in Philadelphia. A brief abstract was prepared by

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the secretary of the society and was published in its minutes61. Despite its annotation in a British journal and in a German publication, the implications of this observation for an understanding of the epidemiology of trichinosis were not realized. In fact, Diesing in his Systema Helminthum in 1851 classified the worm found by Leidy as T. affinis 39 on the assumption that T. spiralis was peculiar to humans. Trichinellae had in fact been observed in a non-human host a year earlier than Leidy had seen it. In August 1845, Ernst Herbst had found large numbers of trichinellae, which corresponded exactly with those described by Owen, in the voluntary muscles of an old cat. Herbst then extended these observations in 1848 by finding similar worms in the muscles of a dog. Neither of these discoveries were reported until 185153 by which time, Guret (1849) had recorded his discovery of trichinellae in a cat48. Subsequently, a wide range of mammals was found to be infected in nature, and others were shown in the laboratory to be susceptible to infection with this organism33,37,45.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE ADULT WORMS EXPERIMENTAL TRANSMISSION OF INFECTION When von Siebold declared in 1844 that trichinellae in human muscle were larvae, he suggested that they were an intermediate stage awaiting transfer to another host95. This idea followed naturally from the recent publication by Steenstrup of his theory of the alternation of generations (see chapter 2). Nevertheless, von Siebold could see difficulties with this postulate; in the current state of civilisation, the eating of human flesh was not a common occurrence, and transmission of the parasite this way must have been rare indeed. The discovery of trichinellae in pigs, cats and dogs opened the way for exploration of these ideas and it was Herbst who had the initiative and perseverance to follow it through. When Herbst found trichinellae in a cat in 1845, he first attempted to transmit the infection directly by inserting 30 cysts containing live larvae between the skin and muscles of another cat. On examination four weeks later, the cysts had attached to the connective tissues and the muscles, but the encapsulated worms were dead. The second experiment followed his discovery of trichinellae in a badger. Herbst had kept this badger in captivity for one and a half years and had fed it partly on vegetables and partly on the remains of animals that he used in his work. When the badger died in November 1850, Herbst found a considerable number of trichinellae in its muscles. This time, he fed the flesh to three dogs that were six weeks old. One animal was sent to the country and left free to roam while the other two were retained. Three and a half months

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later, abundant worms were found in the muscles of both dogs. The third dog was examined one year after eating infected badger meat and multiple trichinellae were found in a biopsy of one of its muscles. Herbst was convinced of the source of infection in these dogs and speculated that, in some as yet undetermined fashion, eggs were liberated in the gut and passed via the bloodstream to the muscles: "there can be no doubt that their growth in the aforementioned three dogs had resulted from the intake of badger meat"53. These findings were greeted with considerable scepticism, principally because the trichinellae of animals were regarded as being distinct from those found in humans, but also because Herbst's descriptions of the worm were inaccurate and it was believed that he may have confounded some other species of roundworm with trichinellae. A number of years were to pass before similar experiments were repeated and Herbst's observations were confirmed and extended. DISCOVERY OF THE ADULT WORM Three figures - Leuckart, Virchow and Zenker - were to play leading roles in the next phase of discovery. They each undertook investigations independently and almost contemporaneously in the mid 1860's. Heller has remarked that it is not easy to determine the merits of each one from his publications, particularly as Virchow106 and Zenker112 felt compelled to defend their positions against Leuckart who was constantly appearing in print with incomplete notices. The account which follows generally approximates the conclusions that Heller made after a careful examination of the literature51. To Virchow must go the credit for first finding the adult worms in the intestines, while Zenker hammered into place the final link in the chain of events by explaining how human infections were acquired. But these achievements only came after a false start induced by a theory of Friedrich Küchenmeister. Küchenmeister, who had recently shown that cystic worms, previously thought to be distinct species, were in reality immature stages of tapeworms, carefully examined the anatomy of T. spiralis and other nematodes found commonly in humans. He came to the conclusion that T. spiralis was an immature form of the intestinal whipworm, Trichocephalus dispar (now known as Trichuris trichiura). By the same token, Küchenmeister believed it likely that the trichinellae found in the pig were identical with T. spiralis and, with a modicum of misguided foresight, thought that humans might possibly become infected with T. dispar by consumption of pork beset with trichinellae. Alternatively, he suggested that ingestion of Trichuris eggs by humans might result in liberation of larvae which then bored through the intestinal wall and migrated to the muscles where they encysted as T. spiralis 58. Rudolf Leuckart took up the question and fed T. spiralis cysts to rabbits, cats

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and dogs; he searched without success for Trichuris adults that might have developed from ingested trichinellae. In 1857, however, he reported that when he had examined the intestinal mucus of mice shortly after ingestion of such cysts, he had found that the larvae had escaped from their capsules and doubled in size63 . In 1859, Leuckart fed trichinous flesh to pigs, but on this occasion waited five weeks before examination of the intestines. He found a dozen mature Trichuris in the bowel and, in accordance with Küchenmeister's hypothesis, Leuckart took these to be the sexual form of T. spiralis. He despatched word of this observation to PJ van Beneden in Louvain, asking him to communicate these results to the Academy of Sciences in Paris. This van Beneden undertook to do, but, in translating Leuckart's letter from the German, inadvertently mistook "duizend" (dozen) for dutzend (thousands), and thus it was printed on 26 September 185964. In the meantime, Rudolf Virchow had not been idle. In July 1859, he fed trichinous meat to a dog; three and a half days later it died. When the intestines were examined macroscopically at autopsy, the only parasites apparent were tapeworms. On microscopical examination of the mucus, however, Virchow found swarms of lively nematodes 1-2 mm long within which he could see eggs or sperms. These parasites did not resemble Trichuris at all, but in view of Kuchenmeister's assertions, Virchow merely concluded cautiously that muscle trichinellae are able to continue their development in the intestinal tract of a carnivorous animal. Since he was about to leave for Norway, Virchow made known his results at a meeting of the Berlin Medical Society on 1 August 1859 102 then sent a written account to the Academy of Sciences in Paris. According to Reinhard88, however, there was difficulty in deciphering his handwriting and a French version was not published until 7 November 1859103. His detailed paper followed the next year104 On receipt of this information, and in a true spirit of scientific enquiry, Leuckart repeated his studies and infected a number of dogs and cats. He found the fullgrown worms described by Virchow in the intestines of these animals and, in an exemplary and forthright fashion, Leuckart declared that Virchow was absolutely right65. At the same time as Leuckart confirmed Virchow's observations in experimental animals, Zenker independently found adult worms in the small intestine of a human111, as will be described later. Zenker sent portions of trichinous muscles from this person to Leuckart, Luschka and Virchow, and all four of them began experimental studies using this material. STUDIES ON THE MIGRATION AND DEVELOPMENT OF LARVAE When Herbst transmitted experimentally infection from a badger to dogs, he remarked that: the greatest difficulty lies in explaining the process by which the very small and very

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elastic, but solidly formed particles representing worm eggs have been able to enter the blood vessels from the intestinal cavity, since the ample, simultaneous, and equal distribution of the trichinae through all voluntary muscles justifies the assumption that their eggs have been carried to the respective places of settlement by means of the blood circulation.53

The discoveries of Virchow, Leuckart and Zenker provided the clue to the solving of this question. In his series of experiments, Leuckart made two further important observations. Firstly, he found that in contrast to muscle larvae, adult worms were mere transients in the bowel. For example, by the twelfth day after infection, adult worms had moved from the small intestine to the colon prior to expulsion. Secondly, Leuckart discovered that female adult worms were viviparous and released minute filariform embryos that immediately penetrated the intestinal mucosa then passed to the muscles. There, he found that the worms penetrated the fasciculi and within the space of 14 days acquired the size and structure of the well-known T. spiralis 66. Unfortunately, Leuckart blotted his copybook by declaring that it could scarcely be doubted that Man acquired his trichinellae, like echinococci, from the dog. Meanwhile, Virchow was independently pursuing his own studies. Initially, he fed trichinous flesh to rabbits and found that they died five to six weeks later as a consequence of muscular degeneration. He passaged the worms through five successive generations and found that the severity of illness and the likelihood of death was dependent upon the size of the inoculum of infective larvae. Like Leuckart, Virchow observed that trichinellae were larviparous and found larvae within seven days of ingestion in the mesenteric glands and the serous cavities, but he could not find them in the bloodstream. He then studied the development of larvae and showed for the first time that they were located not between the muscle fibres, as had been previously thought, but within them. In addition, he noted that the cyst was first seen four to five weeks after infection and that the muscle fibres then atrophied105. Although the development of adult worms in the gut and of infective larvae in the muscles was fairly well understood, there was considerable doubt as to the manner in which larvae passed from the gut to the muscles. Leuckart66 held that the larvae reached the muscles via the connective tissues and, because of his great authority, this view held sway for many years. Nevertheless, there were voices of dissent. Virchow105 had found larvae in the mesenteric lymph nodes, thus suggesting that the worms might find their way into the bloodstream, although he was not able to prove this point. This view was supported by Zenker111 and sustained by Fiedler43 who found larvae in the right heart of experimentally infected rabbits. Final proof that larvae may travel via the bloodstream was provided by Herrick and Janeway who in 1909 found newborn larvae in the blood of a woman suffering from trichinosis 54. Uncertainty has surrounded the relationship between intestinal adult worm numbers and muscle worm burdens. It has never been defined clearly in humans how many muscle larvae are produced for each adult worm in the gut

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during the course of an infection, but it was eventually shown in experimentally-infected guinea pigs that approximately 1,300 muscle larvae are produced per female adult worm91. Whether or not immunity to reinfection develops in humans has never been clearly shown, but extrapolation from animal experiments suggests that some resistance probably develops. It has been shown in such animals that considerable resistance is induced by natural infection71 and after immunization with Trichinella antigens72. Furthermore, this resistance can be partially transferred with immune serum36 and with immune lymphoid cells60 and is directed against both the larval stages in the muscles as well as against the worms in the intestines29.

RECOGNITION OF THE CLINICAL FEATURES In his discussion of the two patients who were found to be infected in the St. Bartholomew's Hospital dissecting room in 1835, Owen remarked that although there were vast numbers of parasites in the voluntary muscles, neither person had any symptoms referable to the muscular system. He concluded that "it is not improbable that in all cases the patient himself will be unconscious of the microscopic parasites which are enjoying their vitality at his expense"76. Paget, on the other hand, was more cautious, noting in his private letter to his brother Charles on 11 February 1835 that "their immense numbers may prove important when more cases have been found and compared, so as to see whether they accompany any particular illness"81. Publication of Owen's paper induced Henry Wood, a practitioner in Bristol, England to challenge Owen's view and describe a patient who in retrospect may well have had symptomatic trichinosis. A 22 year old man had been admitted to the local infirmary in October of the previous year with "acute rheumatism" of the trunk and extremities. He died a few days later and post-mortem examination disclosed pneumonia, pericarditis and multiple punctate lesions in the muscles. Despite observing the latter with a microscope, Wood was unable to make out their nature. When he read Owen's paper, however, Wood wondered whether the patient had had trichinosis. He therefore suggested that it may "be well to ascertain....(if) there was any symptom or inflammation of any kind in the muscular system"108 in retrospect in patients in whom trichinellae were found at autopsy. Nevertheless, Wood's was a voice crying in the wilderness and Farre in 1850 expressed the consensus of opinion when he wrote that trichinellae: have been found equally in the diseased and in the healthy; in those who have died from chronic diseases attended by atrophy; and in those who have been cut off in robust health by some violent accident. No symptoms have been in any case manifested during life which could lead to the supposition of their existence; and in all cases, the individuals themselves appear to have been unaware of their presence.42

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All this changed dramatically at the beginning of 1860. On 12 January of that year, a 20 year old servant girl was admitted to hospital in Dresden, (East) Germany under the care of Dr Walther. She had become ill two weeks previously when she complained of great fatigue, thirst and painful abdominal distension. Despite the absence of splenomegaly, a provisional diagnosis of typhoid fever was made whereupon she suddenly developed severe pains in, and marked swelling of, the muscles which prevented her from flexing her knees or elbows. This was followed by the appearance of pulmonary symptoms, thought to be consistent with a diagnosis of typhoid fever, and she died on 27 January. Prior to formal autopsy, samples of her muscles were examined by Friedrich Zenker who was particularly interested at that time in the pathological changes occurring in muscles during typhoid fever. He was astounded to find in his first glance at the first microscopical preparation, dozens of unencysted trichinellae lying free in the muscle parenchyma. Further examination showed that all the muscles were permeated in this way by massive numbers of worms. Moreover, the muscle fibres were extensively degenerated. On complete post-mortem examination, nothing could be found to substantiate a diagnosis of typhoid fever, the only other discernible abnormalities being bronchopneumonia and intestinal inflammation. Zenker was in no doubt that the patient had died from a trichinous invasion of the musculature 111. Not only did Zenker demonstrate the potential clinical importance of trichinosis, but this patient also enabled him to make some important contributions to the understanding of the zoology, pathogenesis and epidemiology of this infection. Firstly, on careful examination of the musculature, he found some larvae that were smaller in size but similar in form to the usual trichinellae; this observation led him to conclude rightly that they were embryos infiltrating the muscles, probably reaching that site via the bloodstream. Secondly, he had put aside a portion of intestinal mucus obtained at autopsy; when he examined a sample of this material two weeks later, he found, again in the first drop, abundant sexually mature worms that were identical with those described shortly before by Virchow. This was the first time that adult worms were found in a human. Thirdly, as will be described later, Zenker ascertained the source of infection in this patient. Zenker's discovery was followed by reports of a number of epidemics of trichinosis, as will be recounted later. It was rapidly accepted that the severity of the clinical manifestions was dependent upon the intensity of the dose of infective larvae30. One study later calculated that patients with 1,000 larvae per gram49. Only the most heavily infected persons died and these often developed features of pneumonia, myocarditis, encephalitis and renal damage in addition to the usual gastrointestinal and muscle disturbances23. Recovery in the survivors was rarely followed by any permanent sequelae, most patients feeling well within several

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months21. This was despite the continuing presence of infective larvae in the muscles which may remain viable for many years. For example, calcified, encysted trichinellae were found at autopsy in the muscles of a man who had died in the Vienna Krankenhaus (Hospital). Enquiry revealed that 26 years previously he had suffered from a severe attack of "rheumatism" that had kept him confined to bed for several months. When these cysts were fed to rabbits, trichinellae developed in the gut and muscles100.

DEVELOPMENT OF DIAGNOSTIC METHODS It was soon realized that a diagnosis of trichinosis could be suspected on clinical grounds in a patient who had features resembling those of typhoid fever except that a rash and splenomegaly were replaced by severe muscle pain and swelling. Nevertheless, confirmation of the diagnosis depended upon demonstration of the parasite. There were a number of ways in which this could be done. Firstly, trichinellae could be sought in the faeces. This had been successfully achieved by Zenker and Waldeck by 1862113, but subsequent experience showed that it was an unsatisfactory method because such worms were few in number and were present only early in the illness. An alternative approach was to demonstrate larvae in muscle biopsies. This was suggested by Küchenmeister in 186159, then the value of the technique was proven in the following year by Friedreich of Heidelberg, (West) Germany, who found parasites in a fragment of muscle taken from a butcher44. This has remained the method of choice for the diagnosis of trichinosis to the present day, although it suffers from the twin disadvantages of necessitating the subjection of a patient to a biopsy and the probability of finding a worm being dependent upon the size of the specimen removed and the intensity of infection. Using this technique, it has been claimed that a T. spiralis cyst was found in an intercostal muscle of a 3,200 year old Egyptian mummy buried in the Valley of the Kings across the river Nile from Luxor24. The third method depends upon observing larvae in the peripheral blood. This was first achieved in 1909 by Herrick and Janeway54 who investigated a small family outbreak of trichinosis. A mother and seven of her children ate contaminated pork chops on 24 February of that year; larvae were found in the blood of the mother 23 and 25 days later but not in the children's blood. This diagnostic method became popular and successful in the early part of this century. For example, Salzer94 claimed that he had found T. spiralis larvae in the blood of 9 out of 14 patients. Nevertheless, this method of diagnosis has fallen out of favour and is rarely mentioned in modern textbooks. Finally, larvae have been found in the cerebrospinal fluid16,68, but this is not a standard diagnostic technique. Another laboratory investigation which may point towards the diagnosis of

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trichinosis is the appearance of an increased number of eosinophils in the blood. This was first observed in 1896 by Thomas R Brown, a medical student at Johns Hopkins University, Baltimore, USA, who found a marked eosinophilia in a 23 year old man six or seven weeks after the onset of the symptoms of trichinosis25. Although much has been made of this observation by a number of American writers, it is of limited diagnostic value since eosinophilia is common in other tissue helminth infections as well as a in variety of unrelated conditions. Greater diagnostic specificity was sought by employment of immunodiagnostic techniques. Ströbel in 1911 was the first to investigate these possibilities. He prepared an extract of Trichinella antigen from trichinous meat after digestion of the muscle fibres with pepsin and hydrochloric acid. Although alcoholic extracts of this material were not promising, caustic soda and antiformin extracts yielded antigens which gave positive complement fixation reactions with sera from infected humans and experimental animals97. Bachman introduced an improved antigen with which he was able to demonstrate the presence of precipitating antibodies in the serum of experimentally-infected rabbits and guinea pigs, as well as the induction of delayed hypersensitivity reactions after intradermal injection of antigen into these animals19,20. This was followed by the demonstration that such antibodies could be found in the serum and that similar skin reactions occurred in humans with trichinosis18. Despite refining of techniques, immunological tests have remained of limited value as they are not able to differentiate between recent and long-standing infections17, nor are they able to quantify the intensity of infection.

THE SEARCH FOR EFFECTIVE TREATMENT The initial attempts to treat trichinosis were directed towards accelerating expulsion of the adult worms from the intestines. Logically enough, the effects of various purgatives such as calomel, turpentine and Glauber's salts were tried 30,37. Professor Mosler of Giessen, (West) Germany in 1864 convinced himself that: benzine is of all the remedies the best anthelmintic and that it may be taken by man in large doses....it destroys the trichinae in the intestines and thereby prevents the spread of their embryos; that it is therefore the only rational remedy which can be employed in trichina disease in man.73

The concept was rational enough, but the approach was scarcely feasible in the vast majority of instances since the diagnosis was rarely made before the adult worms in the gut had done their damage seeding the muscles and then been largely expelled. Indeed, this is a problem which has bedevilled the anthelmintic therapy of trichinosis to the present day. A multitude of anthelmintic drugs were tried in trichinosis but were found to be uniformly

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unsuccessful until Campbell and Cuckler in the early 1960's showed that the new benzimidazole, thiabendazole, eliminated intestinal worms and killed many muscle larvae in infected pigs27,28. This drug was then used on an infected woman who, whether coincidentally or not, improved96. Nevertheless, a controlled trial of thiabendazole in human trichinosis does not appear to have been done. In any case, it is doubtful whether any agent effective against muscle larvae will be of much benefit as much of the damage will already have been done before the diagnosis is made and treatment instituted85. An alternative approach was tried by Salzer in 1916 who gave serum from previously infected persons to two patients; he claimed that this procedure produced a fall in temperature and in the level of eosinophilia 94. This was followed by experimental studies in trichinous animals50, but immunological treatment has not found a place in the management of trichinosis. The realization that the inflammatory reaction around muscle larvae was responsible for producing many of the ill effects of trichinosis led to trial of ACTH69 and corticosteroids 90 in the alleviation of symptoms. Although some success was claimed at first, the value of such therapy is probably small, particularly as it may inhibit immunological expulsion of worms from the gut and thus lead to even greater numbers of muscle larvae. This could probably be overcome by the simultaneous administration of thiabendazole, but the value of such a regimen remains to be proven.

UNDERSTANDING THE EPIDEMIOLOGY When Zenker found mature worms in the intestines of his patient, he realized that trichinellae go through their whole cycle of development in one and the same host. He reasoned, therefore, that infection was likely to have been acquired by consumption of trichinous meat. Consequently, he went to the nearby village of Plauen, (East) Germany where the dead woman had come from and interviewed the owner of the estate. The farmer indicated that he had ordered a pig to be slaughtered on 21 December but could not say whether the servant girl had eaten any raw meat, although he was aware that she was fond of picking at food. Further enquiry revealed that the owner of the estate and the housekeeper had both been ill with an abdominal complaint in early January and the the butcher had been extremely ill, being confined to his bed for three weeks with fever and a paralysing weakness. Fortunately, some of the original ham was still available and on microscopical examination of it, Zenker found numerous encysted T. spiralis larvae111. Thus, it became clear that humans were infected by eating trichinous pork and that infection presumably passed from pig to pig by consumption of trichinous scraps. Sporadic cases of illness or death attributed to trichinosis were reported following Zenker's detailed description and a mild epidemic was recognized in

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Plauen in 1862, but it was not until 1863 that the full import of trichinosis impressed itself upon the minds of both the medical profession and the public at large. In October of that year, an outbreak of trichinosis occurred in Hettstadt, a small town of about 6,000 inhabitants near the Hartz mountains in (East) Germany. Just over 100 people attended a dinner in a hotel in the town in order to celebrate the fiftieth anniversary of the battle of Leipzig. Included on the menu were Röstwurst und Gemüse (roast sausages and vegetables). The Röstwurst had been ordered from the butcher a number of days previously in order that it could be properly smoked. The butcher went to a neighbour and bought a pig from his steward. Unfortunately, the steward sold a sickly pig contrary to his employer's instructions. The pig was duly killed and the pork worked into sausages which were then smoked and delivered to the hotel where they were in turn fried and served to the guests at the dinner table. On the following day, several persons who had been at the dinner were attacked with diarrhoea, abdominal discomfort, prostration and fever. The number of persons so afflicted rapidly increased and there was great alarm and apprehension that an epidemic of typhoid fever was impending. When some of the patients developed pneumonia and evidence of muscle inflammation, Zenker's report was remembered. The remnants of the sausages were examined microscopically and found to be swarming with encapsulated trichinellae. Muscle biopsies were taken from several of the victims and larvae of T. spiralis were found in all stages of development. Most of the diners became ill and over 20% of them died. A number of others in the town were also infected with this pork; eventually nearly 150 became ill and 28 persons died, the diagnosis of trichinosis being confirmed at autopsy1,3. Awful though this was, even worse was to befall the town of Hedersleben in Germany two years later in 1865. In this small village of 2,100 people, 398 persons, most of them young, fell ill and 102 of them died4,8,57. A visitor to the town soon afterwards has described the scene, saying that: the place was almost deserted, the manufactory closed, and that 90 orphans were weeping over the graves of their parents. Upwards of 200 convalescents were wandering about without work, and bearing in their features traces of the fearful malady.8

The background to this outbreak has been recorded most graphically: All this havoc has been caused by one trichinous pig! The butcher, having recognised the abnormal appearance of the meat of this pig, had carefully disguised it by mixing it with the meat of two healthy pigs, or added it in small pieces to larger joints of pork to make up weight. He made this confession shortly before his death, which was caused by trichinosis contracted from his own meat. His wife also died of the disease.8

Following the outbreak of trichinosis in Hedersleben, a review was made of the epidemic which had occurred in 1849 in Wegeleben, a community located about half a mile away, in which 160 persons had been affected and 30 had died. Biopsies of muscles from some of these people who were still alive showed that that epidemic had also been caused by T. spiralis 93. A number of

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other epidemics in various parts of Europe were also diagnosed in retrospect, although with much less certainty. In the wake of the outbreak of trichinosis at Hedersleben, Professors Delpech and Reynal of France were charged with studying trichinosis in Germany. In the following year, they presented their pioneering report in which it was concluded that every clinical case had been caused by eating imperfectly cooked pork7. The prevalence of infection in humans was investigated in Leipzig, (East) Germany where 6 in every 100 persons coming to autopsy were found to be infected. In places where infection was common, such as Dresden, (East) Germany and Vienna, Austria, rats inhabiting the slaughterhouses were often infected with T. spiralis. Similar studies in France by the same observers found little evidence of trichinosis, and the Englishman, Cobbold, self-righteously observed that trichinosis was most prevalent in Germany because "the otherwise abstemious inhabitants of the Fatherland display a remarkable fondness for chopped pork"30. Indeed, the use of raw meat had become very common in Prussia and Saxony because workmen, having no means of cooking or else not taking the trouble to do so, found it more convenient to eat raw, minced pork6. Despite the institution of control measures, there were 13 major epidemics of trichinosis in Saxony alone between 1860 and 1876 with 1,266 people being afflicted12. Similar epidemics have since been noted in many other parts of the world, but with improving public health control measures and agricultural methods, they have declined in both frequency and severity.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES The recognition that humans became infected with T. spiralis by consumption of contaminated meat, especially pork, caused some to look backwards and seen the Mosaic interdiction (Leviticus 11: 7, Authorised Version), "and the swine, though he divide the hoof and be clovenfooted, yet he cheweth not the cud, he is unclean to you", as evidence that the Israelites recognized the relationship between trichinosis and swine. It seems more likely, however, that if they were able to connect pigs and human illness at all, then the tapeworm, Taenia solium, was responsible as this parasite is at least visible macroscopically. The Mosaic prohibition was perpetuated in Islamic law and has undoubtedly serendipitously prevented many Muslims from being infected with T. spiralis. Understanding of the mode of transmission opened up means for the prevention of infection. The prevalence of infection in both animals and humans needed to be ascertained, methods had to be found for the destruction of muscle larvae, then appropriate measures had to be encouraged and, if necessary, policed. In many places, public health policy and political considerations

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became inextricably linked. However, not everyone believed that trichinosis was a serious problem. A Prussian ministerial journal asserted that "trichina-disease" was nothing but a revolutionary proceeding propagated by the enemies of the government 6. In another incident, Virchow addressed a meeting of town councillors, butchers, doctors and a sprinkling of the general public shortly before Christmas 1865 on the prevention of trichinosis. At the conclusion of his speech, he handed to the president of the meeting a piece of smoked sausage and a piece of meat from a pig which had been recognized as trichinous. What happened next has been recorded in The Lancet: Thereupon a veterinary practitioner, of the name of Urban, rose and combated all that science had acquired during the last five years as an unfounded illusion. 'Trichinae', he said, 'are the most harmless animals in the world. It is only the doctors without practice who make a noise about them in order to create some occupation for themselves.' &c. (Great interruption; the president is obliged to stop the veterinarian). Drs. Virchow and Mason demand an apology from M. Urban. Dr. Mason challenges Urban to eat some of the sausage on the President's table (Great applause). Urban wishes to explain. The meeting calls upon him to eat. 'He had not spoken of Berlin doctors (Eat! Eat!); but of those at Hedersleben (Eat!). He would first see if the sausage contained trichinae.' (Great laughter and continued shouts of Eat! eat! eat!). Whereupon M. Urban suddenly seizes the sausage on the president's table, bites off a piece and eats it, and leaves the hall forthwith, amidst the applause and laughter of the assembly. About five days later (on 23 December), the Oelkszeitung reported that the veterinarian, Urban, was ill. He was confined to his bed and his arms and legs were paralysed. A hope was expressed that the illness was not caused by trichinae in the sausage of which he had been badgered to swallow a piece. Vain hope!"8

It appeared at that time that the prevention of trichinosis was founded upon two practical propositions - recognition of infected meat and the cooking of pork sufficiently well to kill the worms. Prof. Kuhne of Halle in (East) Germany had shown in his report to the Prussian government that it was frequently not possible to recognize a trichinous pig9. The (undoubtedly apochryphal) story has been told about how a Holstein peasant solved this problem. When he killed a pig, he was careful to send a portion of it - ham or sausage - to his pastor then await the consequences for 14 days. If the pastor remained healthy, then he felt perfectly easy in his mind and, assured that the pork was fit to eat, thereupon disposed of it amongst his own family13. This technique not being generally applicable, the butchers of Berlin, finding that the trade was almost extinguished, voted 200 to 9 in December 1865 to make arrangements for microscopical examination of all pork and petitioned the municipality to make such examinations obligatory upon them all8. This was done in many parts of Germany and between 1864 and 1874, 623 infected pigs were found and withdrawn before human infection could occur11. Eventually, thorough microscopical examination by government inspectors of pork products for sale was commonplace throughout Germany, with any such products found to be infected being confiscated. This was done by compressing

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fragments of meat between two plates of glass and searching for parasites with the aid of a magnifying glass or the low power lens of a microscope. In one instance, the Supreme Court of Prussia found a butcher guilty of manslaughter because he sold trichinous meat which caused the death of a person, the meat not having been examined microscopically 11. There were some, however, who remained sceptical. Reinhard88, for example, believed that not only was microscopical examination inaccurate, but that the frequency of trichinosis in swine was so small as to not justify the effort made at its detection. A vivid demonstration that microscopical examination could not be relied upon occurred at Emersleben in Germany in 1883. In September of that year, a butcher bought a pig, killed it on the 12th and sold its flesh from the 13-19th of that month. Out of a population of 700 persons, 250 were attacked and 42 died. Although incompetent, there is little doubt that the inspector, a barber, acted in good faith for both he and the butcher partook of the infected meat and suffered in consequence 15. In the 1870's, it became apparent, following several epidemics of trichinosis in humans and the demonstration that 3-16% of the pigs in Indiana were infected, that trichinosis was not uncommon in the United States of America10. Much of this pork was exported to Europe in the form of hams and sides of bacon. Despite being strongly salted and dried, some worms remained viable as was indicated by the outbreak of trichinosis which occurred in Bremen, (West) Germany, after consumption of sides of imported American pork. In 1879, ordinances were passed in Austria, Hungary and Italy prohibiting the importation of porcine products from the United States, then a similar decree was proclaimed in the following year in Germany, Norway, Portugal and Spain. By the end of the decade, the majority of European countries forbade the importation of American pork. The economic consequences of these actions were such that the United States Congress in 1890 passed an act requiring microscopical examination of all pork destined for export. Between 1896 and 1906, more than 8 million carcasses were examined and 1.4% were eliminated as being trichinous 46. On subsequent examination of the remaining certified pork, German inspectors found that another 1% were still infected. Consequently, Germany reinstated the prohibition which had been repealed in 1890 on the initiation of testing. Extensive post-mortem surveys were undertaken in the USA to define the prevalence of infection in humans and in swine. Sixteen per cent of 11,000 human cadavers examined between 1931 and 1942 were infected. Studies of swine showed that the frequency of pigs infected with this parasite depended upon the method of feeding them; those fed on cooked garbage or allowed to forage in the open fields and woods, 0.5%; those fed principally on grain, 1-1.5%; those given uncooked garbage, 4-6%; and those permitted to feed on slaughter-house offal, 10-20% 46. In 1952, a severe epidemic of vesicular exanthema, a viral infection of swine, broke out which led to legislation requiring that pigs grown for commercial use be fed cooked garbage or grain.

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This resulted parenthetically in the prevalence of trichinosis in the pigs falling from 0.95% in the 1930's to 0.12% in 1961-5 114, and in humans from 16% to 4% in 1966-8 115. The other feasible prophylactic measure was proper preparation of meat to ensure destruction of larvae. Salting was found to often render meat innocuous, but this was unreliable since the time necessary to achieve killing of larvae was uncertain and variable14. Similarly, smoking could not be trusted to decontaminate meat. Cooking by boiling was the most effective method if continued for long enough but quick roasting leaving the central parts of the meat red was of little avail. Eventually, it was shown that refrigeration at -15o C for 20 days was also an effective means of killing larvae87. Finally, irradiation has been shown to be effective47, but this technique has not found widespread commercial application. Despite the marked association between human trichinosis and the consumption of infected pork, other sources of infection have sometimes occurred. T. spiralis has been found in nearly 60 different species of mammals. Occasional localized outbreaks of human trichinosis have followed the consumption of a variety of contaminated meats ranging from polar bear to white whale, emphasizing that the only sure prophylactic measure is thorough cooking of all meat before ingestion46.

REFERENCES 1. ANONYMOUS. Recent outbreaks of fleshworm disease, or trichiniasis, in Germany. British Medical Journal i: 75-77, 1864 2. ANONYMOUS. Benzine and trichinosis. British Medical Journal ii: 395, 1864 3. ANONYMOUS. The new disease. Lancet i: 100-101, 1864 4. ANONYMOUS. British Medical Journal i: 76, 1866 5. ANONYMOUS. British Medical Journal i: 287, 1866 6. ANONYMOUS. British Medical Journal i: 342, 1866 7. ANONYMOUS. Trichinosis. British Medical Journal i: 375-376, 1866 8. ANONYMOUS. The last new disease. Lancet i: 16, 1866 9. ANONYMOUS. Scientific report on the trichina. Lancet i: 163, 1866 10. ANONYMOUS. Trichinosis. Lancet ii: 843, 1875 11. ANONYMOUS. Trichiniasis. Lancet i: 76, 1876 12. ANONYMOUS. Trichina epidemics. British Medical Journal ii: 492-493, 1877 13. ANONYMOUS. New test for trichinae. British Medical Journal ii: 714, 1880 14. ANONYMOUS. Trichinae. Lancet i: 385, 1881 15. ANONYMOUS. Trichinosis. British Medical Journal i: 118-119, 1884 16. ANONYMOUS. Trichinae in the cerebrospinal fluid. Lancet ii: 240, 1916 17. ANONYMOUS. Laboratory tests for trichiniasis. Lancet ii: 295, 1943 18. AUGUSTINE DL, THEILER H. Precipitin and skin tests as aids in diagnosing trichinosis. Parasitology 24: 60-86, 1932 19. BACHMAN GW. A precipitin test in experimental trichiniasis. Journal of Preventive Medicine 2: 35-48, 1928 20. BACHMAN GW. An intradermal reaction in experimental trichiniasis. Final report. Journal of Preventive Medicine 2: 513-523, 1928 21. BERCOWITZ Z. Residual symptoms in patients following recovery from acute infestation

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with trichinosis. American Journal of Tropical Medicine 20: 849-857, 1940 22. BISCHOFF TL. Ein Fall von Trichina spiralis. Medicinishe Ann., Heidelberg 6: 232-250, 1840 23. BLUMER G. Trichinosis with special reference to changed conceptions of pathology and their bearing on symptomatology. New England Journal of Medicine 214: 1229-1235, 1936 24. de BONI U, LENCZNER MM, SCOTT JW. Autopsy of an Egyptian mummy - ROM I: trichinosis. Canadian Medical Association Journal 117: 461-473, 1977 25. BROWN TR. Studies on trichinosis. Johns Hopkins Hospital Bulletin 8: 79-81, 1897 26. CAMPBELL WC. History of trichinosis: Paget, Owen and the discovery of Trichinella spiralis. Bulletin of the History of Medicine 53: 520-552, 1979 27. CAMPBELL WC, CUCKLER AC. Effect of thiabendazole upon experimental trichinosis in swine. Proceedings of the Society of Experimental Biology and Medicine 110: 124-128, 1962 28. CAMPBELL WC, CUCKLER AC. Thiabendazole treatment of the invasive phase of experimental trichinosis in swine. Annals of Tropical Medicine and Parasitology 56: 500-505, 1962 29. CHUTE RM. The dual antibody response to experimental trichinosis. Proceedings of the Helminthological Society of Washington 23: 49-58, 1956 30. COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference more particularly to internal parasites of man, Groombridge and Sons, London, pp 480, 1864 31. COBBOLD TS. On the discovery of Trichina. Lancet i: 224-225, 1866 32. COBBOLD TS. On the discovery of Trichina. Lancet i: 291, 1866 33. COBBOLD TS. Experiments with Trichina spiralis. Journal of the Linnean Society 9: 205-212, 1867 34. COBBOLD TS. The discovery of Trichina spiralis. Lancet ii: 911, 1882 35. COBBOLD TS. The discovery of Trichina spiralis. Lancet ii: 1056, 1882 36. CULBERTSON JT, KAPLAN SS. A study upon passive immunity in experimental trichiniasis. Parasitology 30: 156-166, 1938 37. DAVAINE C. Faits et considérations sur la trichine (Pseudalius trichina). Gazette Médicale de Paris, third series, 18: 58-59, 75-78, 130-131, 174-177, 1863. Abstracted in Lancet i: 424-426, 1863 38. DESPOMMIER DD. Adaptive changes in muscle fibres infected with Trichinella spiralis. American Journal of Pathology 78: 477-496, 1975 39. DIESING CM. Systema Helminthum, Wilhelmum Braumüller, Vindobonae, two volumes, pp 1267, 1849-1851 40. DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairie Encyclopédique de Roret, Paris, pp 654, 1845 41. FARRE A. Observations on the Trichina spiralis. London Medical Gazette 17: 382-387, 1835 42. FARRE A. Cited in 99 43. FIEDLER CL. Beiträge zur Entwicklungsgeschichte der Trichinen nebst einigen Mittheilungen über die Einwirkung einzelner Medicamente und anderer Agentien auf dieselben. Archiv der Heilkunde 5: 1-29, 1864 44. FRIEDREICH N. Ein Beitrag zur Pathologie der Trichinenkrankheit beim Menschen. Archiv für Anatomie und Physiologie und für klinische Medicin (Virchow) 25: 399-413, 1862 45. FUCHS CJ, PAGENSTECHERHA. Die Trichinen. Nach Versuchen im Auftrage des Grossherzoglich Badischen Handelsministeriums ausgeführt am zoologischen Institute in Heidelberg, W Engelmann, Leipzig, pp 116, 1865 46. GOULD SE. The story of trichinosis. American Journal of Clinical Pathology 55: 2-11, 1971 47. GOULD S E, GOMBERG HJ, BETHELL FH. Control of trichinosis by gamma irradiation of pork. Journal of the American Medical Association 154: 653-658, 1954 48. GURET. Lehrbuch der pathologische Anatomie der Hausthieren, Berlin, pp 144, 1849 49. HALL MC, COLLINS BJ. Studies in trichinosis. III. The complex clinical picture of trichinosis and the diagnosis of disease. Public Health Reports 52: 539-551, 1937 50. HALL MC, WIGDOR M. An experimental study of serum therapy in trichinosis. Archives of Internal Medicine 22: 601-609, 1918 51. HELLER A. In, Cyclopaedia of the Practice of Medicine, H von Ziemssen (editor), volume

Trichinosis

52. 53.

54. 55. 56. 57. 58.

59. 60.

61.

62. 63. 64.

65.

66.

67. 68. 69. 70. 71. 72. 73. 74.

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3, Chronic infectious diseases, translated by AH Buck, The Sydenham Society, London, pp 615-660, 1875 HENLE. Annotation to a German translation of reference 74. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin, p 228, 1835 HERBST M. Beobachtungen über Trichina spiralis. Nachrichten von der Georg-August Universität, Göttingen. Königliche Gesellschaft der Wissenschaften, pp 260-264, 1851. Abstracted in Quarterly Journal of Microscopical Science 1: 209-211, 1853. Translated in 56 HERRICK WW, JANEWAY TC. Demonstration of the Trichinella spiralis in the circulating blood in man. Archives of Internal Medicine 3: 263-266, 1909 HILTON J. Notes of a peculiar appearance observed in human muscle, probably depending upon the formation of very small cysticerci. London Medical Gazette 11: 605, 1833 KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classic investigations, Cornell University Press, Ithaca, two volumes, pp 677, 1978 KRATZ F. Die Trichinenepidiemie zu Hedersleben, Wilhelm Engelmann, Leipzig, pp 125, 1866 KüCHENMEISTER F. Die in und an dem Korper des lebenden Menschen vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung der thierischen und pflanzischen Parasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to the group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 KüCHENMEISTER F. Ueber Trichinen. Deutsche Klinik 13: 367-368, 1861. Abstracted in British Medical Journal ii: 402-403, 1862 LARSH JE, GOULSON HT, WEATHERLY NF. Studies on delayed (cellular) hypersensitivity in mice infected with Trichinella spiralis. I. Transfer of lymph node cells. Journal of the Elisha Mitchell Society 80: 133-135, 1964 LEIDY J. Entozoon in the superficial part of the extensor muscles of the thigh of the hog. Secretary's abstract. Proceedings of the Academy of Natural Sciences, Philadelphia 3: 107-108, 1846 LEIDY J. Remarks on Trichina. Secretary's abstract. Proceedings of the Academy of Natural Sciences, Philadelphia 10: 9, 1866 LEUCKART R. Bericht über die Leistungen in der Naturgeschichte der niedern Thiere wahrend des Jahres 1856. Archiv für Naturgeschichte 23: 165-272, 1857 LEUCKART R. Expériences sur la trichina spiralis (ce ver devient un trichocéphale dans l'intestin du porc). Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 49: 453-457, 1859 LEUCKART R. Der geschlechtrsreife Zustand der Trichina spiralis. Eine vorlaüfige Mittheilung. Zeitschrift für rationeile Medicin 8: 259-262, 334-335, 1860. Translated in Quarterly Journal of Microscopical Science 8: 168-171, 1860 LEUCKART R. Untersuchungen über Trichina spiralis. Nachrichten von der Georg-August Universität, Göttingen. Königliche Gesellschaft der Wissenschaften, pp 135-138, 1860. Translated in Quarterly Journal of Microscopical Science 8: 168-171, 1860 LEUCKART R. Cited in 31 LINTZ W. Trichinosis and the cerebrospinal fluid. Journal of the American Medical Association 66: 1856, 1916 LUONGO MA, REID DH, WEISS WW. The effect of ACTH in trichinosis: a clinical and experimental study. New England Journal of Medicine 245: 757-760, 1951 LUSCHKA H. Zur Naturgeschichte der Trichina spiralis. Zeitschrift für wissenschaftliche Zoologie 3: 69-79, 1851 McCOY OR. Immunity of rats to reinfection with Trichinella spiralis. American Journal of Hygiene 14: 484-494, 1931 McCOY OR. Artificial immunization of rats against Trichinella spiralis. American Journal of Hygiene 21: 200-213, 1935 MOSLER. Cited and partly translated in 2 OWEN R. Description of a microscopic entozoon infesting the muscles of the human body. London Medical Gazette 16: 125-127, 1835

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75. OWEN R. Description of a microscopic entozoon infesting the muscles of the human body. Proceedings of the Zoological Society of London, part 3, pp 23-37, 1835. Identical with 74; very similar to 76, 77 76. OWEN R. Description of a microscopic entozoon infesting the muscles of the human body. London Medical Gazette 17: 472-478, 1835. Identical with 77; very similar to 74, 75 77. OWEN R. Description of a microscopic entozoon infesting the muscles of the human body. Transactions of the Zoological Society 1: 315-324, 1835. Identical with 76; very similar to 74, 75 78. OWEN R. The discovery of Trichina spiralis. Lancet ii: 869, 1882 79. OWEN R. The discovery of Trichina spiralis. Lancet ii: 989, 1882 80. PAGET J. On the discovery of Trichina. Lancet i: 269, 1866 81. PAGET J. Cited in 26 82. PAGET J. Cited in 56 83. PAGET J. Cited in 84 84. PAGET S. Memoirs and letters of Sir James Paget, Longmans, Green and Co., London, pp 438, 1901 85. PHILLIPSON RF, KERSHAW WE. The production, deposition and growth of the larvae of Trichinella spiralis and their significance in the chemotherapy of the infection. Annals of Tropical Medicine and Parasitology 54: 250-251, 1960 86. RAILLET A. Quelques rectification à la nomenclature des parasites. Receuil de Médicine Véterinaire 3: 157-161, 1896 87. RANSOM B H. Effect of refrigeration upon larvae of Trichinella spiralis. Journal of Agricultural Research 5: 819-854, 1916 88. REINHARD. Statistiche Rückblicke auf die Trichinen-Epidemien im Königreich Sachsen. Archiv für Heilkunde 18: 241-250, 1877. Abstracted in British Medical Journal ii: 492-493, 1877 89. REINHARD EG. Landmarks of Parasitology. II. Demonstration of the life cycle and pathogenicity of the spiral threadworm. Experimental Parasitology 7: 108-123, 1958 90. ROSEN E. Cortisone treatment of trichinosis. American Journal of Medical Science 223: 16-19, 1952 91. ROTH H. Experimental studies on the course of trichina infection in guinea pigs. I. The minimum dose of trichina larvae required to produce infestation of the muscles; with an account of the productiveness of the female trichina. American Journal of Hygiene 28: 85-103, 1938 92. ROUPELL G. Cited in 76 93. RUPRECHT B. Eine Besuch in Hedersleben. Berliner klinische Wochenschrift 2: 503-507, 1865 94. SALZER BF. A study of an epidemic of 14 cases of trichinosis with cures by serum therapy. Journal of the American Medical Association 67: 579-580, 1916 95. von SIEBOLD CT. Parasiten. In, Handwörterbuch der Physiologie mit Rücksicht auf physiologische Pathologie, R Wagner (Editor), Braun Schweig, 2: 641-692, 1844 96. STONE OJ, STONE CT, MULLINS JF. Thiabendazole - probable cure for trichinosis. Report of a case. Journal of the American Medical Association 187: 536-538, 1964 97. STRöBEL H. Die Serodiagnostik der Trichinosis. Münchener medizinische Wochenschrift 58: 672-674, 1911 98. TIEDEMANN F. In, Froriep's Notizen aus dem Gebiete der Natur und Heilkunde, p 64, 1822. Partly translated in 31 99. TOPHAM J. Notes of interesting cases occurring in medical practice. Lancet i: 45-46, 1850 100. TURNER DF. Trichinosis. Lancet i: 934, 1889 101. TWO FORMER PRESIDENTS OF THE ABERNETHIAN SOCIETY. On the discovery of Trichina. Lancet i: 270, 1866 102. VIRCHOW R. Futterungverswuch mit Trichina spiralis. Deutsch Klinik 11: 430, 1859 103. VIRCHOW R. Recherches sur le développement de la trichina spiralis (Ce ver devient adulte dans l'intestin du chien). Comptes Rendus Hebdomadaire des Séances de l'Académie des Sciences 49: 660-662, 1859 104. VIRCHOW R. Helminthologische Notizen. 3. Ueber Trichina spiralis. Archiv für

Trichinosis

105.

106. 107. 108. 109. 110.

111.

112. 113. 114. 115.

595

pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 18: 330-345, 1860. Abstracted in British and Foreign Medico-Chirurgical Review 26: 515-516, 1860 VIRCHOW R. Note sur le Trichina spiralis. Résultat de ses nouvelles expériences. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 51: 13-16, 1860. Abstracted in British Medical Journal ii: 563-564, 1860 VIRCHOW R. Trichinosis. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 32: 332-371, 1865 WILKES S. The discovery of trichinae. British Medical Journal i: 190; Lancet i: 269-270, 1866 WOOD H. Observations on the Trichina spiralis. London Medical Gazette 16: 190-191, 1835 WORMALD T. Cited in 78 ZEDER JG. Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer von JAE Goeze mit Zusätzen und Anmerkungen herausgegeben von J G H Zeder, Siegfried Lebrecht Crusius, Leipzig, pp 320, 1830 ZENKER FA. Ueber die Trichinen-krankheit des Menschen. Archiv für pathologische Anatomie und Physiologie und für klinische Medicin (Virchow) 18: 561-572, 1860. Translated in 56 ZENKER FA. Beiträge zur Lehre von der Trichinenkrankheit. Deutsche Archiv für klinische Medizin 1: 90-124, 1866 ZENKER, WALDECK. Cited in 59. Abstracted in British Medical Journal ii: 402-403, 1862 ZIMMERMANN WJ, BRANDLEY PJ. The current status of trichiniasis in U.S. swine. Public Health Reports 80: 1061-1066, 1965 ZIMMERMANN WJ, STEELE JH, KAGAN IG. The changing status of trichinosis in the United States. Public Health Reports 83: 957-966, 1968

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Table 22.1. Landmarks in trichinosis ___________________________________________________________________ 1835 1845 1846 1851 1857 1859

Paget discovered larvae in the muscles of a human and Owen reported the fact Herbst found larvae in the muscles of a cat but did not report the observation Leidy observed larvae in pork Herbst infected dogs by feeding them infected badger flesh Leuckart observed that cysts hatched larvae in the small intestine of mice Virchow found adult worms in the small intestine of a dog fed with trichinous meat 1860 Leuckart confirmed Virchow's discovery and found newborn larvae 1860 Zenker proved that T. spiralis may cause a severe illness in humans, found adult worms in the small intestine of a human, demonstrated that muscle larvae were located intracellularly, and connected acquisition of infection with consumption of uncooked trichinous pork 1863 First major epidemic, with high mortality, of trichinosis recognized in Hettstadt, Germany 1865 Another major outbreak of trichinosis in Hedersleben, Germany in which 102 persons died 1909 Herrick and Janeway found larvae in the blood 1911 Ströbel described a complement fixation test 1963 Treatment with thiabendazole suggested ___________________________________________________________________

Chapter 23

Wuchereria bancrofti, FILARIASIS

Brugia

species

and

SYNOPSIS Common name: filaria causing elephantiasis Major synonyms: i. Wuchereria bancrofti: Filaria Bancrofti, Filaria sanguinis hominis, Filaria nocturna, Wuchereria pacifica ii. Brugia malayi: Filaria malayi, Wuchereria malayi, microfilaria malayi iii. B. timori: Timor microfilaria Distribution: i. Wuchereria: tropics and subtropics ii. Brugia: southeast Asia Life cycle: The thread-like, adult worms, 4-10 cm long, dwell in lymph nodes and adjacent lymphatic vessels. Microfilariae are produced and released into the bloodstream; they usually appear in the bloodstream only at a defined time in each 24 hours, a phenomenon which is known as periodicity. When microfilariae are ingested by appropriate mosquitoes of the genera Aedes, Anopheles, Culex and Mansonia, they develop over two weeks into infective larvae which pass to the proboscis and infect the host at the next blood meal. Infective larvae migrate to the lymphatic system and mature over the next 12 months or so Definitive host: i. Wuchereria, periodic B. malayi, and B. timori: humans ii. subperiodic B. malayi: humans, monkeys Major clinical features: i. acute inflammatory filariasis: lymphangitis, epididymitis ii. chronic obstructive filariasis: lymphoedema, hydrocele, elephantiasis Diagnosis: demonstration of microfilariae in the peripheral blood Treatment: diethylcarbamazine

DISCOVERY OF THE MICROFILARIA In July 1862, an 18 year old man, originally from Havana, Cuba, presented to a hospital in Paris with a left-sid ed scrotal tumour. A trocar was inserted by the surgeon, Jean-Nicolas Demarquay and whitish-yellow fluid similar to milk was aspirated. In August of the following year, the patient returned with a similar problem on the other side of the scrotum. Demarquay again inserted a trocar, aspirated some 100 ml of thick, bluish-white fluid, ascertained that the testi s was normal and demonstrated that the fluid had been located in the tunic a 597

598

A History of Human Helminthology

vaginalis. The hydrocele fluid was examined microscopically by one of th e house surgeons, Dr Lemoine. In addition to the fat globules, pus cells an d filaments of fibrin, he found many specimens of a parasite: Attention was drawn above all to a little elongated and cylindrical creature. The anterior four fifths of the body had almost a uniform diameter: the posterior fifth became thinner and thinner and terminated in a fine point. This worm had extremely rapid movement of coiling and uncoiling in its different parts, especially its terminal extremity. The worm was completely transparent and did not show anything which resembled the digestive system or the genital system. 73

Samples of the fluid were sent to CJ Davaine for an expert opinion. H e devoted half an hour to searching vainly for the parasites. Nevertheless, h e remarked that from a consideration of the drawings that had been made of the worms and from the description of a ctive movements, it seemed likely that they were nematodes, or more probably in view of the absence of visible organ s within the parasite, larvae of a nematode. He added that the only larva l nematodes which had been observed th us far in humans were those of Trichina (= Trichinella) spiralis and Filaria (= Dracunculus) medinensis. Demarquay was disappointed by Davaine's failure to confirm their observations, but remarked sagely: If we were mistaken, this fact would thus remain useless; but if, as we think, it relates a new fact, subsequent observations will not fail to provide all its scientific value.73

He was also perplexed about the means by which the worms had entered the body, but with a flash of insight suggested that the whole phenomenon may be related to the patient having lived in Cuba. The discovery of these worms by Demarquay and his team heralded little interest and three years were to pass before they were seen again. In 1866 in Bahia, Brazil, they were found, this time in the urine, by Otto Wucherer who was completely unaware of the French discovery. Two years earlier, Wucherer had been stimulated by a letter from Griesinger in Germany to examine th e urine of patients with haematuria in order to see if he could find any evidence of Schistosoma haematobium infection in South America. He looked at specimens from a number of such patients but without success. On 4 August 1866, Wucherer inspected a clot from some milky urine obtained from a femal e patient who was under the care of Dr Silva Lima in the Misericordia Hospital. Using the microscope he saw: some threadlike worms which were very thin at one end and blunt at the other. In the blunt end a small point was visible which could not be identified as an opening. The body was transparent and seemed to contain a granular mass; however, it was not possible to distinguish its internal structure. 239

Suspecting that these may have been a contaminant, he asked the woman t o void again into a clean container and onc e more found the helminths. Nevertheless, since he had examined the urine of haematuric patients many times an d never found anything similar on previous occasions, Wucherer attached n o great importance to this discovery. On 9 October 1866, however, he agai n

Filariasis

599

found similar worms in the urine of another lady with haematuria. Wuchere r wondered whether they came from the vagina, but this idea was negated when some time later he found the same parasites in the chylous urine of a man: They were alive and were making very brisk, wavy motions. They had the diameter of a white blood corpuscle and their length exceeded that of the latter, 60 or 70 times.239

Wucherer could find no reference to similar parasites in the works of Küchenmeister, Cobbold or Davaine, but he did not report them as a new species . According to Manson-Bahr 173, Wucherer sent specimens of the worm preserved in glycerine to the renowned parasitologist, Leuckart in Leipzig, Germany, but the latter dismissed them as being of no importance, considering the parasites to be members of the family Strongylidae. Wucherer's observations were confirmed several years later by Timoth y Lewis in India and by Jules Crevaux of the French Navy 65, the worms found by the latter also being described by Corre 63. In March 1870, Lewis, apparentl y unaware of Wucherer's discovery, fo und the worms in the chylous urine of a 25 year old East Indian. When he examined the urine, Lewis found delicat e filaments which he at first thought were fungi. On continued observatio n though, he saw that they coiled and uncoiled and realized that they wer e worms131. Subsequently, Lewis found the same worms in somewhere between 15 and 20 patients 132. As with many other important discoveries in medical helminthology, there was the odd pretender to the throne. Spencer Co bbold claimed that in July 1870 he had found similar worms in the urine of a South African girl wit h schistosomiasis. Cobbold did not publish news of this observation until 1872, when he also asserted that the worms found in the urine of a patient in 1868 by Salisbury in the United States 207, and which that observer had called Trichina cystica, were in reality filariae 54. Lewis's co-investigator, Cunningham , disposed of this latter instance by showing that the patient was a 55 year ol d rheumatic woman suffering from cystinuria, not chyluria, and that the parasites were almost certainly those of Enterobius vermicularis , then expressed the same view about the worms found in Cobbold's patient 67. Despite these cogent arguments, they were not accepted by Cobbold 60. Even more remarkable was the letter by WO Priestly written to the British Medical Journal : As long ago as 1857, I described a case of chylous urine, in which the milk-like fluid passed from the bladder was found on microscopical examination to contain innumerable linear vibrios, or filariae which moved in every direction across the microscopic field.195

This was demolished summarily and in caustic fashion by a correspondent: The 'active linear vibrios' common in decomposing fluids....have, of course, nothing to do with these nematoid filariae; unless, indeed, we adopt very advanced views on transmutation not of species, but of classes.197

Meanwhile, the original discovery by Demarquay and his colleague s remained unappreciated. Two authorities, Cobbold and da Silva Lima, in their historical reviews in 1878 of the discovery of this parasite were ignorant o f

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A History of Human Helminthology

Demarquay's contribution, with the former writing "the larval forms firs t described by Wucherer" 60 and the latter remarking "Dr Wucherer....the firs t investigator who proclaimed the existence of a new human entozoan, demonstrating its embryos in chylous urine" 220. It was not until 1888 that Demarquay's contribution became widely known when his countryman, Lanceraux i n Guadeloupe, pointed out with som e acerbity that not Wucherer but Demarquay had first found the parasite 125. Two years after Lewis found organisms in chylous urine, he made a much more important further observation. In July 1872, while examining the blood of a patient with diarrhoea who was under the care of Dr Chuckerbutty in the Medical College Hospital in Calcutta, Lewis "observed nine minute Nematoid worms in a state of great activity, on a single slide" 132. He showed them to his colleague, Douglas Cunningham, who co ncurred with Lewis's opinion that they were the same as those that had been seen earlier in chylous urine. On th e following morning, Lewis went back to the Hospital to review the patient' s clinical history, but found to his intense disappointment that the patient ha d discharged himself one hour earlier. All attempts to find him, even invoking the aid of the police, proved fruitless. Several days later, however, Lewis agai n found worms in the urine of a woman with haematochyluria. Perhaps burned by his previous experience, L ewis visited her that same evening. In view of the subsequent discovery of the nocturnal periodicity, i.e. the transient surge o f microfilariae into the bloodstream at night after a complete or almost complete absence during the day, this was undoubtedly a fortuitous event, for "O n pricking her finger with a needle, and distributing a drop of blood over several slides, I found that Filariae were present in it also" 132. Lewis kept her under observation for about two months, and found that although there was littl e change in her clinical condition and there was only a slight reduction in worms in the urine, the numbers of worms in the blood diminished markedly (blood samples were presumably taken during the day): the numbers obtainable by pricking the fingers or toes certainly decreased and eventually, out of half a dozen or more slides, not more than one or two Haematozoa could be detected; on a few occasions several slides were examined without any being found.132

Shortly afterwards, Lewis encountered a third patient, a 22 year old Eas t Indian who spent most of his time employed as a cook on a lighter lying in the mouth of the River Hooghly. Lewis was amazed to find: that no matter at what portion of his body the circulation is tapped with the point of a needle, numerous active, well-developed Haematozoa are invariably obtained; on one occasion I observed as many as 12 of these creatures on a single slide....the number infesting his whole body may be imagined. 132

Indeed, Lewis calculated that one patient was host to some 140,000 of th e parasites. Nevertheless, he noted that this was not a common occurrence and that it was often necessary to examine several of the slides before the parasite could be found, each slide taking about 15 minutes to complete. When Lewis went to the Government Printing Es tablishment to examine the

Filariasis

601

galley proof of his report on the discovery of microfilaria in the blood, he was astounded to find that the man setting up the type was none other than the first patient in whom he had found microfilaria in the urine. Enquiry revealed that he was healthy and examination of his blood disclosed the presence of sparse numbers of worms 132. Lewis described the morphology of the parasite and discerned the sheath, indicating that it was an extremely delicate tube closed at both ends, withi n which the worm was capable of elongating and shortening itself. This feature led him to surmise that the pa rasite had no means of perforating the tissues and that its normal habitat was the blood. In addition, he noted a bright spot at the blunt end of the worm which was suggestive of a mouth. Lewis's long paper was published as an appendix to the Annual Report for 1871 of the Sanitary Commissioner 132 and was abstracted later in The Lancet 7, but news of his discovery was first revealed in an annotation in The Lancet of 31 August 1972 5. The same commentator noted that the nature of the worm had been determined by George Busk , who stated that the helminth belonged to the genus Filaria of Müller179 and that Busk had also suggested a name for th e parasite: A specimen of the embryo of the chylous-urine worm has been submitted to Mr. Busk, who considers it to be some kind of Filaria; and it may not be inappropriate to christen the new entozoon 'Filaria sanguinis hominis'.5

The name, of course, meant that the filar ia had been found in human blood. The name "filaria" was a modern Latin derivative, "filarium" indicating "ball o f thread", of the Latin word "filum", meaning "thread". Nematodes and flukes had been found in the blood of molluscs, fish, frogs, birds, rats and dogs, but this was the first occasion on which multitudes o f worms had been found in the general circulation of humans, although schistosomes had been found in the portal vein and its tributaries by Bilharz in 1851 and it was suspected that Trichinella spiralis larvae might migrate to th e muscles through the bloodstream. The discovery by Lewis of worms in th e blood, which he termed haematozoa, caught the imagination of the Englis h medical world in particular, and became the subject of a multitude of paper s and letters. An editorial writer in the British Medical Journal remarked: That organisms so high in the scale as nematoids should be found to swarm as parasites in this situation is not a little surprising, though it is perhaps still more astonishing that they should produce such a comparatively trivial amount of inconvenience.6

Lewis's discovery was confirmed by Sonsino in Egypt on 1 February 1874 while searching for schistosomes in peripheral blood: I put a drop of blood (from the finger of the boy) under the microscope, placing it directly under the objective glass, when with astonishment I discovered a living organism in the midst of haematic globules. The nematoid had the shape of an Anguillula. It glided amongst the blood globules, which were tossed to and fro by lively movements.221

Also in 1874, Rowland 206 and then Bancroft22 , both in Australia, foun d

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microfilariae in blood, the latter's observation being announced by Cobbold 56 who observed microfilariae in blood sent to him in capillary tubes vi a Bancroft's old teacher, Dr W Roberts of Manchester, a specialist in urinar y diseases.

DISCOVERY OF THE ADULT WORM WUCHERERIA BANCROFTI After Cobbold received a specimen of blood from Joseph Bancroft in Australia, he wrote to Bancroft suggesting that he look for the adult worms whic h Cobbold felt must be present in the human body. Cobbold was strengthened in this belief when he saw an empty egg shell which he interpreted as being the remnant of the egg from which the filarial larva had come (it is impossible in retrospect to say what in fact this was). Bancroft took up Cobbold's suggestion and on 21 December 1876 found an adult worm. Subsequently, he found four more specimens and wrote to Cobbold on 20 April 1877 of his discovery: I have laboured very hard to find the parental form of the parasite, and am glad to tell you that I have now obtained five specimens of the worm. The worm is about the thickness of a human hair, and is from three to four inches long. By two loops from the centre of its body it emits the filariae described by Carter in immense numbers. My first specimen I got on December 21st 1876 in a lymphatic abscess of the arm. Four others I obtained alive from a hydrocele. 23

Cobbold sent Bancroft's letter together with some explanatory notes to The Lancet wherein it was published on 14 July 1877. In his letter, Cobbold named the worm Filaria Bancrofti in honour of Bancroft: "Such Sir, is Dr Bancroft's account of his 'finds', and from the brief description furnished I propose to call the adult nematode Filaria Bancrofti.57 Bancroft later described the circumstances surrounding his discovery i n somewhat more detail: I opened an abscess in the arm of a youth employed as a butcher. I collected the matter as usual in a small vessel. As a preliminary enquiry, the blood had to be inspected for embryonic filariae. This was the second case in which the blood contained the parasite in question. On examining the matter....a threadlike body came into view, under the microscope it was without doubt a worm, and embryos were seen coming out of its body. On March 21, the following year, I tapped a hydrocele, in an elderly patient with a trochar and cannula. On withdrawing, a lash of hairlike bodies was caught in the eyes of the instrument. At once suspecting their real nature, I put them in the hydrocele fluid when they began to move around with great activity. Embryos in abundance were found in the hydrocele fluid and in the patient's blood.21

Meanwhile, Bancroft sent the adult filariae to Cobbold who received them on 28 August 1877. Cobbold found four female worms and multitudes of ova and larvae which he described in some detail in a paper published on 6 October

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187758. In this paper, he persisted in an error which he had made previously in believing that the microfilarial sheath was a commencing ecdysis. In the previous issue (29 September 1877) of the same journal, Timoth y Lewis also described his find ing of two adult worms after spending eight hours searching through scrotal tissue removed at operation from a young man i n Calcutta by Dr Gayer: At last, however, whilst teasing a blood clot under a dissecting microscope, my eye was arrested by white thread-like objects in a state of great activity. These on being transferred for examination under a higher power, were found to be specimens of two mature filariae. One of these contained ova, with embryoes identical in appearance with the free embryoes in the blood. 134

One parasite was clearly a female worm. The other helminth was damaged and Lewis thought it may have been a fragment of a male worm, but th e important caudal part was unfortuna tely missing. In contrast to Cobbold, Lewis recognized that the egg "shell" became the sheath of the microfilaria: It is....difficult to state whether they are to be considered as freed embryoes or not, as the egg-'shell' has become so extremely attenuated and translucent as can only with difficulty be distinguished....It would, however, appear probable that, even when the embryo acquires worm-like appearances, the envelope is usually not lost in this species as long as it continues in the blood. 134

Moreover, Lewis emphasized the diagnostic impo rtance of this feature in differentiating these microfilariae from those found in the blood of dogs. Despite being aware of Cobbold's designation of a similar worm as Filaria Bancrofti, Lewis retained the name originally applied to the embryo - Filaria sanguinis hominis - on the grounds that a new name would only lead t o confusion. Cobbold therefore attached an appendix to his second paper on the subject of the adult worm: Since the above was written, Dr Lewis has himself furnished additional means of identification. His mature Filaria sanguinis hominis and my F. Bancrofti are clearly the same species....If Lewis's trinomial name for the adult worm be adopted in place of Filaria Bancrofti, I have personally no objection.58

Subsequently, female adult worms we re found in patients in South America by da Silva Araujo on 16 October 1877 218 and by dos Santos on 12 November 1877210, then by Manson in Amoy, China in 1881 161. It was not until 1888 that a complete specimen of a male worm was found. Brigade-Surgeon Sibthorpe at the Madras General Hospital, India, foun d worms in an amputated lymph scrotum and sent them off to Alfred Bourne , professor of biology in the Presidency College. Bourne found that one of th e parasites was a male filaria. He published a brief record of the discovery in the British Medical Journal in 1888 37, then a more detailed descriptio n incorporating Bourne's written comments was published by Sibthorpe in th e same journal in the following year 217. Meanwhile, Bourne himself als o published an extended, illustrated version in an Indian journal 38. Although Bourne and Sibthorpe claimed that this was the first time the complete mal e worm was described, Saboia in Bahia, Brazil in 1886 had found two filaria l

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parasites in the right side of the heart of a boy who had died from a n undisclosed illness. It is possible they were immature Dirofilaria immitis, although de Magalhães 150 sent a copy of this account, including figures, t o Joseph Bancroft in Brisbane who accepted them as a female and male Filaria bancrofti, noting that this was the first time in which the male parasite had been described 21. On the other hand, Daniels considered the parasites distinct , giving them quite different dimensions 71. Several other names apart from Filaria sanguinis hominis and Filaria bancrofti have been used to describe these parasites. Manson called it Filaria nocturna in order to distinguish it from the microfilaria which had a diurna l periodicity (which turned out to be Loa loa)165, and Manson-Bahr proposed the name Wucheria pacifica for the aperiodic form of the parasite 172. In 1877, da Silva Araujo called the worm which he found in a lymph scrotum "Wuchereria Filaria"218, but whether he meant to use "Wuchereria" as a true generic name is doubtful; more likely he was refer ring to "Wucherer's filaria". In any event, two years later, da Silva Araujo called the same worm Filaria wuchereri 219. In 1921, Seurat formally separated this pa rasite from the other filarial parasites on zoological grounds and adopted da Silva Araujo's Wuchereria as the generic name, the worm henceforth being known as Wuchereria bancrofti 216. DIFFERENTIATION OF BRUGIA SPECIES In 1927, Lichtenstein in Bireu ën in the Dutch East Indies (Indonesia) indicated that filariasis was common in the area but that the microfilariae, although of a periodic type, were not infective to a variety of culicine mosquitoes 137. In the following paper in the same journal, SL Brug reported that the microfilaria e which were present in the blood sa mples, that had been sent to him by Lichtenstein, were different morphologically from those of W. bancrofti. In contrast to the latter worm, there were t wo or three nuclei in the tail and the anal pore was further forward. It was not possible to obtain adult worms because o f opposition to autopsy examination by the local Muslim population, but Brug proposed the name Filaria malayi for the parasite 41. Although it is generally accepted that Brug first proposed the name Filaria malayi, Sasa211 believes that the credit should be given to Lichtenstein who not only found the microfilariae, described the essential morphological differences and reported the unexpected insusceptibility of Culex fatigans (= quinquefasciatus), but also wrote that the filaria discovered in Bireuën is hencefort h named Filaria malayi 137. Parenthetically, it must also be said that in 190 5 Ashburn and Craig described a ca se of filariasis in the Philippines in which the microfilariae were not only different morphologically from those of W. bancrofti, but were also non-periodic; they named this parasite Filaria philippinensis 16. It is quite possible that these worms were B. malayi, a belief which is supported by Manson-Bahr's statement that he had examined the photo -

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micrographs in Ashburn and Craig's paper and concluded that it was possible that they had described microfilaria malayi 172. If this is true, then the correct name for B. malayi would be Brugia philippinensis. Be that as it may, microfilariae morphologically indistinguishable fro m Brug's worm were recognized increasingly in parts of Southeast Asia an d southern India, beginning with Korke in India 123. The resemblance betwee n these microfilariae and those of Loa loa led to some speculation that the parent worm of these microfilariae may resemble the latter worm. In 1939, Poynton and Hodgkin indicated that they had found similar microfilariae in a Kr a monkey (Macacus irus)194. In the following year, Rao and Maplestone reported the recovery of the parent worms of microfilaria malayi from a patient with a lymphatic cyst on the forearm. The female specimens were quit e indistinguishable from those of W. bancrofti, but those authors detected some slightly more substantial differences in the male worms, so they included them in the genus Wuchereria. Nevertheless, they believed that the morphological appearance of the microfilariae and their development in different species o f mosquitoes justified specific status, so they designated the worms Wuchereria malayi 198. Their views were confirmed soon afterwards by Bonne and hi s colleagues35, then a more complete description of what was presumed to be W. malayi was provided by Buckley and Edeson with material recovered from a monkey47. On the basis of a study of these specimens, Buckley erected a new genus, Brugia, in honour of Brug, to house B. malayi and two closely related worms, B. pahangi of cats, dogs and monkeys in Malaysia, and B. patei of dogs and cats in East Africa 45,46. In 1955, Buckley and Edeson described Wuchereria pahangi, a parasite of cats47. As already mentioned, this worm was subsequently renamed Brugia pahangi by Buckley46. That the parasite was capable of infecting humans was proven by Edeson and his colleagues in 1960: two volunteers were infected ; both experienced episodes of lymphangitis and lymphadenitis, then on e developed microfilaraemia 84 days after inoculation 80. In the early 1960's, HL David observed that two kinds of microfilariae were present in the blood of military recruits in what was then Portuguese Timor . One was microfilaria bancrofti and the other resembled microfilaria malayi. In 1965, David and Edeson published their finding that this latter worm was a distinct microfilaria which they named Timor microfilaria 72. Eventually, Partono and his colleagues fed Aedes togoi on people with this microfilaraemia in a village on Flores, Indonesia, infected Mongolian gerbils with the infective larvae, then recovered and described the adult worms which they designate d Brugia timori 190. In 1971, Ash and Little described Brugia beaveri, a parasite of the raccoon15. Six human cases of infection in the United States with this or a closely related parasite have been published, the first being reported b y Rosenblatt and colleagues 203.

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ELUCIDATION OF THE LIFE CYCLE: DISCOVERY OF TH E MOSQUITO INTERMEDIATE HOST In 1873, some microfilariae that had been discovered in the blood by Lewi s were exhibited at a meeting of the Pat hological Society of London. This excited considerable interest and in the ensuing discussion consideration was given to the possible life cycle of this parasite. Cobbold, basing his argument upon the recent demonstration of the role of crustaceans in the transmission o f Dracunculus medinensis, extrapolated this to conclude that an intermediat e host was always required for nematodes. While this would prove to be false as a general rule, it turned out to be true in this particular case. Cobbol d postulated that either adult worms which produced these forms were normally present but unnoticed in humans or that they we re the progeny of an adult worm which had strayed into humans from some carnivorous animal 55. Bastian and Harley objected to any idea that man could be an intermediate host; they could not believe that tens of thousands of these worms could get in from the external environment, so inferred that adult worms must live within the human body 31. All of these ideas remained mere speculation, however, until Patric k Manson entered the fray. Manson had practised for eight or nine years in the Orient and had seen many cases of elephantiasis and lymph scrotum. When he returned to Britain on furlough in 1875, he acquired both a microscope an d knowledge of Lewis's discovery. 1876 saw him back in Amoy, China, and he soon found microfilariae in the blood of a number of patients. He was puzzled about the fate of these larvae and determined to try to ascertain their destiny. Since a person might harbour hundreds of thousands of larvae, Manson thought it most unlikely that they matured withi n the human body, otherwise they would kill the host and thus prevent transmission to another host. This was clearl y untenable as it would lead to extermination of the parasite. He postulated that the larvae must escape from the host, then develop further, either in a free-living state, or in some intermediate host where they matured befor e ingestion by another person. Manson dedu ced that the most likely means of exit was via a blood-sucking insect, so he considered the possible roles of fleas , bedbugs, lice, mosquitoes and sandflies. In blissful ignorance of the almos t world-wide dissemination of mosquitoes, he selected these insects as th e probable candidates because he thought their geographical distributio n coincided most closely with t hat of the parasite. In order to test this hypothesis, he procured some mosquitoes and fed them on 10 August 1877 on the blood of his gardener, Hin-Lo, who had a marked microfilaraemia, then examine d their abdominal contents at daily intervals. In an almost banal fashion, Manson wrote: I found that my idea was correct, and that the haematozoon which entered the mosquito a simple, structureless animal, left it, after passing through a series of hightly interesting metamorphoses, much increased in size, possessing an alimentary canal, and being otherwise suited for an independent existence. 156

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Manson's true feelings on that day in 1877 may be guessed better from a speech which he later gave and which was reported in the Daily Telegraph: I shall not easily forget the first mosquito I dissected. I tore off its abdomen and succeeded in expressing the blood the stomach contained. Placing this under the microscope, I was gratified to find that, so far from killing the filaria, the digestive juices of the mosquito seemed to have stimulated fresh activity. And now I saw a curious thing. The little sac or bag enclosing filaria, which hitherto had muzzled it....was broken through and discarded.169

The bare bones of his find have been recorded in his diary: Hin-lo brought me four mosquitoes which he had caught this morning in his mosquito net and which were distended with his blood. I examined them this morning. No. 1. Blood corpuscles not distinct....Several cylindrical bodies of a pale grey colour and distinct outline. These were about the size and might have been embryo filariae dead. No. 2. Blood corpuscles also digested and two bodies one of which had a distinct to and fro movement of the head half of the body and the appearance of ciliary current at the mouth. No. 3. and 4. Blood corpuscles distinct - in both live active filariae and in one of them ten specimens. Different from those in man's blood in being perhaps more active. Tail not well seen; anterior head loop often very distinct, oral movements very apparent. Perhaps an oesophagus developing. Double outline and transverse striation on the integument most distinct.168

In his original paper, Manson noted that the mosquitoes took only a minute or two to become engorged with blood and seemed to have the capacity t o concentrate microfilariae fro m the bloodstream. He then described the changes in the appearance of the microfilariae. Thirty six hours after ingestion by th e mosquito, the larvae ceased their movements and entered a "sort of chrysalis condition" and became shorter and fatter s o that by the third day they resembled a sausage. A mouth and intestinal tract then appeared and the worms grew in length. Manson had great difficulty in observing these later stages, whic h occurred around the fourth to the sixth day because most of his mosquitoe s died. Out of hundreds of mosquitoes that he watched, only four lived beyond this stage, and in one of these he saw a gradation of forms from the passiv e chrysalis to an active larvae between 0.5 and 1 mm in length. Because of the paucity of specimens, he was uncertain of the details of this stage o f metamorphosis but found that the alimentary tract became distinguished more clearly and thought that the worm may have a boring apparatus on its head. Manson remarked that these processes always took place within femal e mosquitoes, for he had never seen a male mosquito engorged with blood . Further, he stated that his studies were always performed with the mor e common of the two mosquitoes prevalent in his region, a dingy brown insect about 8 mm in size (C. quinquefasciatus, while the other species was probably Aedes aegypti). He observed the replete mosquitoes fly off to near stagnan t water, remain there for several days, then deposit eggs, following which, h e assumed, they died. Manson surmised that the life cycle of the worm wa s

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completed in the following manner: There can be little doubt as to the subsequent history of the Filaria, or that, escaping onto the water in which the mosquito died, it is through the medium of this fluid brought into contact with the tissues of man, and then either piercing the integuments, or, what is more probable, being swallowed, it works through the alimentary canal to its final resting place. Arrived there, its development is perfected, fecundation is effected, and finally the embryo filariae we meet within the blood are discharged.156

Manson knew little about the natural history of mosquitoes. He was wrong about their geographical distribution and their life span and was not aware that they could bite more than once. But he was not alone - there had been littl e incentive to interest anyone in mosquitoes prior to his epochal discovery . Desperately searching for inf ormation, he wrote to the British Museum and the relevant authority replied regretfully that no such work existed, and forwarded him a treatise on cockroaches in the hope that that would do instead. Indeed, Manson was positively misled about these aspects by the one book that h e eventually found on the subject. Manson's paper was first published in the Medical Reports of the Chin a Imperial Maritime Customs 156. He sent copies to Lewis in India, Cobbold in England and Leuckart in Germany. Manson eloquently expressed his reasons for this in his letter to Cobbold of 27 November 1877: I live in an out-of-the-world place, away from libraries, and out of the run of what is going on, so I do not know very well the value of my work, or if it has been done before, or better.167

Lewis replied to him from Calcutta on 14 January 1878: Allow me to congratulate you on your extremely interesting observation regarding the embryonic nematode in the mosquito. I had frequently examined these insects, but in a cursory way, but had not observed any parasites in them at all resembling the embryo, Filaria sanguinis hominis, until I received your note. On receipt of this, I repeated such examinations and found that several of the mosquitoes which were examined contained little nematodes resembling most perfectly those found in human blood. Whether they are actually identical or not it would, perhaps, hardly be safe to assert positively without further experience. 136

Cobbold received Manson's communication on 4 January 1878. He wrot e immediately to The Lancet (12 January 1878) conveying news of the observation and also remarking that Joseph Bancroft in a letter to Cobbold in April the previous year had written: I have wondered if mosquitoes could suck the haemotozoa and convey them to water. They appear to die in water. I will examine some mosquitoes that have bitten a patient to see if they suck up filariae.24

Nevertheless, Cobbold was fulsome in his praise of Manson: Whether or not this conception of the possible host-relationship, as between man and mosquito, primarily originated with Bancroft or some other observer, I cannot stop to inquire, but certain it is that what Bancroft surmised Dr Manson has demonstrated to be a fact....I consider Manson's discovery almost of a par with the separate announcements of Lewis and Bancroft. 59

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Adequate recognition has not been given t o Bancroft in this regard. Manson was lucky while Bancroft was unlucky. Manson chanced upon an efficien t vector of the parasite (C. quinquefasciatus) for use in his studies. According to Cilento53, Bancroft in April 1877, before Manson had begun his studies, fed some Aedes vigilax, a poor vector as it turned out, on an infected person bu t was discouraged by the negative results. In March 1878, Cobbold communicated formally Manson's account i n which the latter characterized the mosquito as a "nurse" of the worm, to th e Linnean Society in London. In the discussion that followed, Manson's opinions were accepted by a number of eminent authorities. The publication 157 which followed Cobbold's verbal report was the same as the parasitological com ponent of Manson's Custom's Report 156 except that the illustrations of th e various forms of developing larvae were omitted. It was not until June of that year, however, that the British Medical Journal was constrained to publish an editorial entitled "Is the mosquito the intermediary host of the Filaria sanguinis hominis?"8. This article was stimulated by the publication by Lewis in Calcutta of the results of his attempts to repeat Manson's experiments. At first Lewi s was in considerable doubt, for in contrast to Manson who had squashed th e whole of the posterior portion of the mosquito and assumed that the variou s events took place within the gut, Lewis removed the alimentary canal an d examined it separately, and saw fe w parasites after the third day. Subsequently, however, he found that the same worms "actually perforate the walls of th e insect's stomach, pass out, and then undergo developmental stages in it s thoracic and abdominal tissues" 135. Lewis's conclusion was very cautious , although it left open the possibility of mosquitoes being the intermediate host of filariae: With regard, however, to the inference that the mosquito is the particular intermediary host of nematoid haematozoa, it cannot be said that even these later observations are sufficiently conclusive to warrant a positive statement being made at present; for though, assuming that of the various parasitic forms which have been seen several are actually transitional stages in the development of one and the same entozoon, it is to be noted that even the most advanced stage hitherto observed is still a very immature one . . and every attempt hitherto made by myself to obtain a more advance condition has been unsuccessful. Further observation, however, may overcome or explain this want of success.135

In the middle of 1878, da Silva Araujo in Brazil also confirmed Manson' s observations when he found W. bancrofti larvae in mosquitoes fed on the blood of a French priest who had a microfilaraemia 219. While Cobbold accepted Manson's views unreservedly, and Lewis did not altogether dismiss them, Leuckart appeared to pay no attention at all to them. Manson's biographers, Manson-Bahr and Alcock, have remarked that Leuckart was initially an unbeliever and seems never to have given Manson's discovery anything but a grudging and disparaging a cknowledgement 175. This seems a fair comment, for in the 1886 edition of his Parasites of Man, Leuckart discourses

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at some length on the discovery of microfilariae in the urine (mostly quotin g Lewis) as a means of escape for microfilariae and although he alluded t o Manson's discovery of the periodicity of microfilariae, made no mentio n whatever of his studies with mosquitoes: The haematozoa, then, after a longer or shorter sojourn in the blood-vessels, would appear to leave the body of their host in some way or other, and continue their life-history under other conditions.130

Stung by such indifference to his discovery, or the reservation with which it was accepted, Manson repeated and amplified his observations in 1883 and communicated the results through Cobbold to the Linnean Society in London in 1884. He dissected over 1,000 mosquitoes. The most advanced larvae were recovered from two mosquitoes 6.5 days after they had fed on Hin-lo, th e gardener; these were infective larvae 1.5 mm long. Manson illustrated th e metamorphoses in great detail and anticipated the fact that the larval filaria e underwent at least two ecdyses in the mosquito. Finally, he pointed out that of the four species which he now recognized in Amoy, only the form now known as C. quinquefasciatus permitted complete development and one of the other three allowed development only up to a certain point 164. In the same year, Sonsino in Egypt also confirmed Manson's observations when he found a n infective larva in a C. pipiens captured in the house of a filarious woman 222. Although Manson suggested the possibility of skin penetration by infective larvae through the use of the "boring apparatus", he preferred the alternativ e option of ingestion of larvae liberated f rom dead mosquitoes in water. In March 1888, an anonymous reviewer (?Cobbold) in the Veterinarian suggested the true mechanism when he wrote that the infective larva (which he called th e "parent") is "deposited by the mosquito in the act of biting" 10. This suggestion was not taken up with any enthusiasm. Indeed, another anonymous reviewe r five years later stated that the larvae probably penetrated the skin of bathers 11. It was not until 1899 that Thomas Bancroft, Joseph's son, put the piece s into place so that the puzzle cou ld be solved. Thomas Bancroft, in Queensland, discovered that mosquitoes could be bred and kept alive in confinement for up to two months when fed upon ripe bananas 26. Carlos Finlay in Cuba had in fact shown in 1881 that mosquitoes could be kept alive for weeks on blood o r sugar86 but this information was lost sight of and never acted upon. Ronal d Ross also re-discovered this phenomenon in his experiments on the malaria l parasites of birds, when he kept them alive by re-feeding them on blood 205, but Bancroft was apparently unaware of these contributions. In the event, Bancroft used these laboratory-reared and maintained mosquitoes ( C. ciliaris = C. quinquefasciatus) and fed them upon a 15 year old girl. As so frequentl y happens in science, the course of events did not run smoothly, for whe n Bancroft was ready to embark upon the scheduled experiments, he found that his patient had left town, having secured a position elsewhere as a domesti c servant. Fortunately, he was able to induce her with the aid of a seven pound grant from the Queensland B ranch of the British Medical Association to return

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and live with her parents for three months. In contrast to Manson who ha d found filariae in various stages of development within the one mosquito , Bancroft observed that all of his larvae were at the same stage of development. Moreover, 16 days were required in warm temperatures for development to be completed, then no further changes occurred for the next six weeks. In view of these findings, Bancroft suggested that the rare, fully-developed larvae which Manson had seen seven days or so after feeding must have been derived from an earlier blood meal, for Manson had caught wild mosquitoes. Bancroft first published notification of his findings in the Australasian Medical Gazette in 189925. In that letter he noted that infective larvae were not killed by bein g placed in water, and suggested that infection for the human host via thi s medium should be confirmed experimentally on life-sentenced prisoners and offering them a free pardon as a reward. In his more detailed report published later that year, however, Bancroft modified his earlier statement and reported that the larvae died three to four hours after immersion in water. This led him to cast doubts of the water-transmission theory, and he wrote in an addendum dated 1 June 1899: It has occurred to me that young filariae may gain entrance to the human host whilst mosquitoes bearing them are in the act of biting. The entrance of warm blood into the mosquito may excite the young filariae in consequence of which they pierce the oesophagus and pass down the proboscis into the human skin. In this way, injury from human digestive agents would be avoided.26

Bancroft then sent some filariated mosquitoes that he had prepared t o Manson in London who in turn passed them on to George Low who was working under his direction at the London School of Tropical Medicine. Thes e mosquitoes were fixed in celloidin and histological sections were cut. In June 1900, Low published some magnificent figures of larval filariae in the abdomen and thorax then illustrated their passage past the salivary glands into th e proboscis, pushing forward between the labium and hypopharynx: "Here I have frequently found them stretching along almost the entire length of th e proboscis, the head being invariably in advance" 140. With masterly understatement Low then wrote: It is difficult to avoid the deduction that the parasites so situated are there normally, awaiting an opportunity to enter the human tissues when the mosquito next feeds on man.140

Many commentators have given Low the credit for discovering the tru e manner of transmission of filariasis from mosquito to man. Nevertheless, h e was but the technician who made the final but inevitable observation. Thomas Bancroft determined the underlying conditions necessary for carrying out the experiment, prophesied the outcome, and actually prepared the mosquitoe s from which the sections were made. If he had had the appropriate technica l resources at hand, he would undoubtedly have followed the whole proces s through to its logical conclusion. Much credit must also be given to Captain SP James of the Indian Medical

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Service in Travancore, India. Stimulated by Thomas Bancroft's report tha t mosquitoes could be kept alive by feeding them on bananas, he adopted th e same technique and independently of Low, showed that infective larva e migrated into the proboscis of certain anopheline mosquitoes 116. Shortly afterwards, the members of the second malaria expedition to West Africa of the Liverpool School of Tropical Medic ine, stimulated by Low's report, announced that they had confirmed the observations by finding filariae in the proboscis of Anopheles 12. Soon after publication of Low's paper, Kennard in British Guiana, afte r noting that Low had stated that the larvae were located between the labium and hypopharynx, objected that the la bium is not inserted when the mosquito feeds, but is applied against the skin and encircles those parts of the proboscis which do penetrate the integument - the hypopharynx, mandibles and maxillae . Kennard did not believe it possible for the hypopharynx to admit so large a n organism as the infective larva, so cast do ubt upon this mode of transmission 118. Similar comments were made by Grassi and Noè who wrote that when dogs were bitten by Anopheles mosquitoes infected with Dirofilaria immitis, the larvae escaped through a rupture in the bent labium 99. These authors, then Noè alone183,184 claimed that the mosquito propagation of filariasis was an "Italian discovery", a claim that was roundly cond emned by Sambon 208 and Ross204. The latter (who had suffered previously at the hands of Grassi with respect t o malaria research) wrote trenchantly: the work is not a serious effort of science, but only an attempt to peg out a fresh claim for priority by, or on behalf of, Professor Grassi. One notes at once that he adopts in his new enterprise precisely the same devices as he used previously in connexion with the mosquito theory of malaria. The moment Dr. Low's work was published, he hastily issued with Dr. Noè a 'preliminary note' in which he began by implying (but without giving details) that he himself had independently made the same discovery - a thing for which I have reasons for disbelieving; and then proceeded to deprecate Dr. Low's work by inventing imaginary faults in it - an artifice which he consistently adopts in regard to my own work. Having thus shifted the merit of the inoculation hypothesis of filariasis to his own credit, he permits his pupil, Dr. Noè to draft the entire subject into his account by saying that the 'Italian discovery now at last enables us to place the prophylaxis of filariasis upon a solid basis'. Needless to say, neither he nor his pupil has ever made a single new observation on filariasis.204

Ross then recounted a number of other i nstances of similar chicanery by certain (but by no means all) Italian writers, and concluded: It is a question how to deal with such efforts. In my humble opinion, science is too great a thing to be made a field for tricks like those of a pettifogging village attorney and we have every right to resent their introduction. Moreover, absolute honesty is the first qualification in all scientific work and the man who attempts to deceive his readers on the question of priority can hardly complain if we refuse to believe in his researches....Others may do as they please, but for my own part....I fear I cannot do myself the honour of including the labours of Professor Grassi in any future writings

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of my own and think that science will not lose much if the papers by him and Dr. Noè on filariasis are similarly excluded from monographs on that subject. 204

Meanwhile, Thomas Bancroft in 1901 used D. immitis as a model to show clearly that larvae escaped through the labe lla at the tip of the labium 27. Further, in a well-controlled experiment on 30 December 1902, he exposed a thre e week old uninfected pup to 183 filariat ed mosquitoes, two of which bit the dog. Nine months later, microfilar iae appeared in the peripheral blood, then the dog was killed and 16 male and 16 female adult D. immitis were recovered from the right ventricle and the pulmonary artery 28. Thus, there seemed little doubt that a similar mechanism was involved in human filariasis. Basic knowledge of mosquito biology was poor in those early years. No t only were the behaviour and natural history of mosquitoes dimly understood, but many species were undiscovered or unnamed. Neverthless, mosquitoe s were observed, categorized, and their ability to permit development o f microfilariae determined experimentally. In 1900, 110 species of mosquitoes were known. By 1922, more than ten times that number had been described 81. The original mosquitoes which Manson had used in his experiments wer e proven more than 50 years later to be Culex quinquefasciatus (= fatigans) when some mosquitoes that he had filariated and sent to Cobbold wer e discovered in bottles at the Royal College of Surgeons in England 174. In 1900, James in India reported that Anopheles rossi was a vector of W. bancrofti 116, then he was followed by Annett, Dutton and Elliott in Nigeria in 1901 wh o showed that Anopheles costalis was a vector 3 and then by Bahr in Fiji wh o worked with Aedes variegatus (= pseudoscutellaris = polynesiensis)19. By 1922, Edwards was able to list seven species in which complete development of W. bancrofti microfilariae had been shown. In addition, 23 species were said to allow partial development 81. In 1930, Brug and de Rook reported that th e newlydiscovered B. malayi completed its development in Taeniarhynchus annulipes (= Mansonia annulipes = M. dives) and T. annulatus (= Mansonia annulata)43, then several years later, Feng showed that the major vector of this parasite in Huchow, China was Anopheles hyrcanus var. sinensis 85. When Sasa came to write his review of filariasis in 1976, hundreds of species o f mosquitoes were known to be transmitters of this infection, although wit h varying degrees of efficiency 211.

DISCOVERY OF THE MICROFILARAEMIA

NOCTURNAL

PERIODICITY

OF

During 1876 and 1877, Manson noticed that microfilariae could not always be found in patients whom he knew from previous observations to be infected . Eventually, he trained two Chinese a ssistants to make blood examinations. One of these persons worked during the day and the other laboured at night. Manson was struck by the fact that the night worker found more parasites than did the

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daytime attendant but he did not arrive at the correct explanation. In 1879 , however, he gave directions for a particular patient's blood to be examine d daily and found that on some days there were abundant microfilariae whereas on others there were none or ve ry few. Closer analysis of these results revealed that more microfilariae were found on busy days when the blood examination had to be left to the evening. This reminded him of the earlier discrepancie s with his two assistants, so he made a series of systematic examinations every few hours on this patient and in a number of others. He wrote to Cobbold in a letter dated 27 February 1880: The young escape into the circulation at regular intervals of twenty four hours, the discharge commencing soon after sunset and continuing till near midnight, from which time till the following noon their numbers gradually decrease. By 2 or 4 o'clock till 6 they are nearly completely absent....It is marvellous how nature has adapted the habits of the filariae to those of the mosquito. The embryos are in the blood just at the time the mosquito selects for feeding. 168

Manson confirmed his observations on further patients and published th e results in the Customs Report 159. In addition, Cobbold presented Manson' s communication to the Quekett Microscopical Club on 27 February 1880 160. Manson was very thankful for the efforts, for he later wrote to Cobbold: I am very grateful to you for the trouble you have taken in bringing these forward and cannot but feel that unless for your kind assistance, my work would lie entombed in the 'Customs Gazette' of little use to anyone. 160

Cobbold's presentation of Manson's finding was greeted with astonishment by some and with downright disbelief by others, with one wag enquirin g "whether the filariae carried watches" 9. In 1881, however, WW Myers o n Formosa (Taiwan) confirmed Manson's observations 180, then the scoffers were silenced when Stephen MacKenzie in London in the same year not onl y demonstrated microfilarial periodicity in a 26 year old patient who had acquired the infection in India but, at the suggestion of Vandyke Carter, succeeded i n reversing the periodicity by persuading the patient to sleep by day and stay up at night146. On hearing about MacKenzie's experiment , Manson repeated the procedure in three patients and found partial or compl ete reversal four days later 162. Meanwhile, Manson had wondered whether th e microfilariae died each day and were replaced by a new brood, or whether they hid themselves during the day. H e tried to investigate this with a dog inf ected with D. immitis, which he found had partial periodicity. The animal was killed with prussic acid and Manson found that most of the microfilariae were in the lungs 163. Many years later, he had an opportunity to prove that the same phenomenon occurred in humans. On 1 9 February 1897, a man who had been known to have a microfilaraemi a committed suicide with prussic acid and died almost instantly at 8.30 in th e morning. Following a post-mortem examination, Manson concluded: Filaria nocturna during its temporary absence from the cutaneous circulation is present in the larger blood vessels, particularly the arteries, that a few are found in

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the capillaries of the muscles and brain, a few in the vessels of the kidneys, a considerable number in the muscle of the heart; but the majority are lodged in the blood vessels of the lungs.166

The mechanism by which this phenomenon occurs has attracted a great deal of attention since those early days but still remains a mystery. The central thesis proposed by Lane 126 was that there was a cyclical release of embryos from adult worms, but most other authors fro m Manson on 14,108,171 have thought it far more likely that periodicity depends upon an interaction between the microfilaria e and the host, with microfilariae retiring to the viscera during the daytime. In 1896, Thorpe reported that the microfilariae seen in Tonga in the south Pacific exhibited no nocturnal perio dicity, being found in the blood both by day and by night228, then this observation was confirmed by Lynch in Fiji145 . In 1912, Fülleborn showed that this aperiodic form of W. bancrofti was present only eastwards of approximately 140oE longitude. Whereas he found aperiodic W. bancrofti in Samoan troops stationed in Hamburg, Germany, when h e visited northeastern New Guinea and parts of eastern Indonesia, onl y nocturnally periodic W. bancrofti was seen93. Lichtenstein in 1927 showed that the new microfilaria in his area, late r named B. malayi, was nocturnally periodic, like that of W. bancrofti 137. In 1957, Turner and Edeson 230, then Wilson and his colleagues 236 , reported that there were two distinct patterns of microfilarial periodicity in B. malayi infections in Malaya. In addition to the previously recognized periodic for m which was transmitted by Anopheles mosquitoes and was endemic in open rice fields and swamp areas, a subperiodic form (i.e. microfilaraemia occurre d throughout the 24 hours with a mild peak at night) was seen among inhabitants of forested areas. This strain was shown to be transmitted by Mansonia mosquitoes, and was found to be a zoonosis, occurring in wild and domesti c animals, especially cats and monkeys 79,124.

RECOGNITION OF THE CLINICAL FEATURES Swollen legs have been recognized since an tiquity. While the commonest cause of subacute cases of this condition is conges tive cardiac failure and even though relatively frequent problems such as deep vein thrombosis and rare conditions such as Milroy's disease (congenital absence of the lymphatics) and Dercum's disease (lipomatosis) may have accounted for a proportion of patients wit h chronic enlargement of the limbs, the most common cause in endemic areas has undoubtedly been filarial parasites. In gross cases with thickening of the skin, the resemblance of the limb to that of an elephant's leg led to the description of the condition as "elephantiasis". Similarly, there are many causes of hydrocele, but again, the majority of such cases in endemic areas, especially whe n associated with lymphatic thickening of the scrotal tissues have probably been

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due to filariasis. A statue of Mentuhotep I II, a pharaoh of the XI Dynasty (about 2,000 BC) shows pronounced enlargement of both legs which may be due to filariasis112,127,215. T Lucretius Carus, a Roman living in the century befor e Christ, regarded elephantiasis as a characteristic disease of Egyptians, stating that elephantiasis arose along the Nile and was facilitated by the climate o f Egypt: "est elephas morbus qui propter flumina Nili signitur Aegypto in media nequen praetera usquam" 144. Elephantiasis was also known in West Africa and has been reproduced in ancient works of art. For exampl e, in the museum of Jos in Nigeria, there is the torso of a terracotta statuette of the Nok period (c.500 BC-200 AD) whic h reveals elephantiasis of the scrotum 112. Similarly, a figurine recovered from a Mayan temple in Yucatan, Central America, dating from around 500 AD displays gross scrotal swelling 2. Descriptions of hideous deformity have been provided in more recent times. The Portuguese, Tomé Pires, who had been apoth ecary to Prince Alphonso, son of King John II of Portugal, and was later to become ambassador to China, was sent to the Malabar coast of India (Kerala) as factor of drugs from 1512-1515. In the record of his experiences, he wrote: Many people in Malabar, Nayars as well as Brahmans and their wives - in fact about a quarter or a fifth of the total population, including the people of the lowest castes - have very large legs, swollen to a great size; and they die of this, and it is an ugly thing to see....the swelling is the same from the knees downward, and they have no pain, nor do they take notice of this infirmity.193.

Later that century, Ralph Fitch, an Englishman living in India described th e same condition at Cochin: This bad water causeth many of the people to be like lepers, and many of them have legs swollen as big as a man in the waste, and many of them are scant able to go. 88

Indeed, the tradition arose that Thomas, the disciple of Christ, had lived an d preached in that part of the world and was there slain with a lance whil e praying in the church. This in turn led to the legend that this illness was th e result of the curse of St. Thomas 128. The Dutchman, John Hughen van Lin schoten, who had lived in Goa between 1588 and 1592, gave the followin g account: they say that the progeny of those that slew him, are accursed by God, which is that they are all borne with one of their legges and one foote from the knee downwards as thick as an Elephantes legge....whereof I have seen many, both men and women for that thereabouts there are whole villages and kyndreds of them that are borne in the said land of St. Thomas . . They have no let nor trouble in their going, but only the unsightliness and evil favoured fashion.138

While legs appeared to be affected most in this region (and was possibl y due to B. malayi), involvement of the genitals appears to have been mor e common in West Africa, as described by John Barbot in 1732: Here is another unknown and foul distemper, the Blacks are subject to, throughout all the country about Sierra Leone, and in Quoya; i.e. a wonderful swelling of, or in the Scrotum....which causes violent pains, and hinders their co-habiting with women.29

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A particularly gross case was recorded in t he India Journal of Medical Science and abstracted in The Lancet in 1844: Moodoosudun Dos, aged 23, an emaciated, sickly-looking native Christian, admitted into the surgical ward of the College Hospital, Calcutta on the 20th November 1843, with an enlarged scrotum, indurated in appearance, and extending down nearly to his knees. the prepuce presented a knotty appearance in the centre of the tumour; the integument over the pubes was not much implicated in the disease, and the spermatic cords could be felt easily on either side. 4

After having reviewed the operative treatment, the armchair reviewer back in the comfort of England facilely remarked that with such opportunities, ou r knowledge of the nature and cause of this formidable disease should have been advanced even more that it had been by the communication unde r consideration. An even worse case in a 30 year old Indian living in Madras was described by Godfrey in 1851: The tumour is of immense size, hanging down nearly to the level of the ankles, and causing him by its bulk and weight great difficulty in moving about. The following are the dimensions taken in the erect position; length from superior to inferior part 26 inches [65 cm]; circumference, one yard and a half [135 cm]; general shape ovoid; feels dense, brawny, oedematous.95

The tip of the penis was buried at the end of a tunnel 10 inches [25 cm] deep. Not surprisingly, the patient had not the least sexual desire. The diseased mass removed at operation weighed 70 lb [32 kg] and would have weighed eve n more had not the fluid that it contained esc aped. The record size for an enlarged scrotum was probably that reported by Pelletier who operated on one whic h weighed 100 kg 192. There was considerable confusion in the minds of many concerning thi s complex of diseases. Two forms of elephantiasis were described. Clinician s gradually separated Elephantiasis Graecorum fro m Elephantiasis Arabum. With the discovery of the organisms causing each condition, it became apparent that Elephantiasis Graecorum was leprosy and that Elephantiasis Arabum wa s filariasis. A third clinical syndrome, chyluria, was also recognized, although it s relationship with the other presentations of filariasis was not appreciate d immediately. One such patient was recorded by G eorge Bonyun in Georgetown, British Guiana (Guyana) in 1846: H.K.-, aged thirty-one, creole of Demerara, good constitution, bilious temperament, has enjoyed good health for several years; on the 8th May observed that his urine was turbid of a brownish colour; this turbidity increased from day to day, until the urine acquired a milky appearance....June 8th.- Urine decreased in quantity, quite white, and coagulating immediately after being passed, so as to resemble blancmange ....Tenth month....urine, three pints daily....white, firmly coagulating, and separating after remaining some hours into a substance resembling curds and whey.36

The relationship between these chronic conditions, as well as acute inflammation of the lymphatics, with filarial parasites unfolded only slowly, and was for a number of years the subject of much controversy, as will be described in

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the next section. To this constellat ion of disorders, some authors gave the name "filariasis", a term which Cobbold damned, bellowing that "this vague and too comprehensive sort of nomenclature cannot be allowed to stand" 62. His opposition, however, was doomed. During the second world war, an opportunity arose to study the clinica l manifestations of early filariasis in detail. Several hundred American servicemen stationed in the south Pac ific, particularly in Samoa, became infected with W. bancrofti. Acute inflammatory lesions were seen in persons who had been in the endemic area for three months or more. Lesions in a limb usually began as a lymphadenitis which then spread in a retrograde or centrifugal fashion , while genital involvement was indicated by a highly characteristic scrotal lesion with funiculitis and epididymitis. There w as a tendency to multiple involvement and recurrence, the attacks generally lastin g for a few days and being associated with fever in about 20% of cases 76,119. The minds of not a few United State s servicemen were distressed by the possibility that these symptoms were a harbinger of hideous deformity yet to come. Babione in 1945 wrote a reassuring article entitled: "A few facts about filariasis for folks who fear that filaria-infected fellows will fetch f ilariae from the front" 18 in which he predicted that few individuals would suffer serious consequences and divined tha t development of microfilaraemia and secondary transmission was unlikely. He was eventually proven correct, for when Trent reviewed these patients 15-16 years later, he found that only less than 1% had a swollen leg or genita l complaint, and none of them had either elephantiasis or microfilaraemia 229. When infection with Brugia malayi was differentiated, the symptomatology in malayan filariasis was found to be broadly similar to that seen in bancroftian filariasis, although there were differences in emphasis. Lichtenstein in 192 7 observed that acute filarial disease was infrequent and that even thoug h elephantiasis was common, this was generally restricted to the lower lim b without involvement of the genitals 137. His views were echoed by Brug 41 and many subsequent workers, although acute inflammation was recognized from time to time and genital disease was seen occasionally.

CORRELATION OF INFECTION WITH PATHOLOGY AN D CLINICAL FEATURES Although the pathogenesis of elephantiasis was a matter of much dispute, an English surgeon, E Bascome, who h ad spent many years of residence in British Guiana was remarkably accurate in his perception of the problem. After separating the condition from leprosy, he wrote in 1845: I am induced to think the hypertrophy is caused in two ways - viz., from erysipelas, and from a want of tone in the lymphatics....When the sequelae of erysipelas, it is not until after repeated attacks of the disease, and the persistence longer of each attack, that enlargement of the part ensues, the inflammatory action at each accession seemingly penetrating deeper, involving the whole of the subcutaneous

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619

cellular substances producing infiltration of that tissue and ultimately, extensive partial disorganization, which degenerating into a variety of shapes, becomes studded with stone-like excrescences....intersected....with weeping fissures. When it commences in the lymphatics, a weariness is felt along their course in the limb, and a benumbed sensation....It is unattended by fever or discoloration....Should the scrotum become fastened on, a puffiness and intolerable itchiness are present, and if the surface be abraded....lymph exudes profusely forming crusts....The parts by-and-by become thickened into lumps, and run into one confused mass, attaining in some cases to an enormous size, with so little sensation as to admit of its being kicked like a football; in one case, when amputated, the scrotum weighed ninety two pounds avoirdupois, filling a pork-barrel! The testes are usually sound....hydrocele is, however, a pretty frequent concomitant.30

Nevertheless, Bascome had no idea what was the underlying cause of thes e changes and put them down to climatic conditions. The involvement of th e lymphatics was confirmed a few years later by surgeons working in India 83. When Demarquay discovered worms in hydrocele fluid in 1863, he wa s admirably cautious about drawing any connection between the two events, but invited others to report any similar observations 73. In like manner, when Wucherer published a report of his finding parasites in chylous urine in 1868, he also refrained from conjecturin g about any aetiological relationship between the worms and haematuria and chyluria until he had the chance of examining a cadaver of an afflicted patient at autopsy. Unfortunately, he had no suc h opportunity before his death five years later 239. Lewis, on the other hand, had no such compunction when he indicated his discovery of microfilariae in the bloodstream of patients, some of whom ha d chyluria: The blood of persons who have lived in tropical countries is occasionally invaded by living microscopic Filariae....which may continue in the system for months or years without any marked evil consequences being observed; but which may, on the contrary, give rise to serious disease, and ultimately be the cause of death. The phenomena which may be induced by the blood being thus afflicted are probably due to the mechanical interruption offered (by the accidental aggregation, perhaps, of the Haematozoa), to the flow of the nutritive fluids of the body in various channels, giving rise to obstruction.132

At first, Lewis connected microfilaraemia only with chyluria. As he continued his observations, however, he fou nd microfilariae in the blood of 11 patients or in one or other of the tissues or secretions in 30 individuals. Since all of these persons suffered from either chyluria or elephantiasis, this convinced him that his previous proposal of a causal relationship was correct. Further, Lewi s suggested that these problems were due to lymphatic obstruction which was in turn possibly a consequence of either encysted mature worms or migratin g immature worms in the lymphatics, or the result of the activity of liberate d microfilariae 133. The views of Lewis were soon supported by Manson. During his first tour of duty in Amoy, Manson had encountered a number of examples of elephantiasis and had concluded from his surgical observations that the scrotal disease

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was "a sort of dropsy" 154. On his return to China after furlough in Britain , Manson examined 190 local people who were selected randomly, the onl y requirement being that they were willing to have a finger pricked; he foun d microfilariae in the blood of 15 of them. Manson noted that some of thes e infected persons were in perfect health but that others had evidence o f lymphatic obstruction with lymph scrotum, elephantiasis, or recurrent attacks of fever accompanied by oedema which was not due to heart disease or renal failure155. During 1877, he confirmed his investigations and found parasites in 62 of 670 persons. Among these individu als were patients with lymph scrotum, elephantiasis of the leg or genitalia, chyluria and inguinal lymphadenopathy ; some 60% of these patients had microfilaraemia compared with less than 10% of the normal population. Although the tests of experimental infection an d post-mortem examination were wanting, Manson was convinced that he ha d proven that these diseases were due to the worm, and like Lewis, conclude d that the essential feature was obstruction of the lymphatics by these parasites. Nevertheless, he appreciated that ther e were two unresolved problems - the not infrequent presence of microfilaraemia without disease, and the somewhat less common reverse situation. Manson thought that the former merely indicate d that the disease was merely an accidental side-effect, and explained the latter on the basis that the worms h ad either died, the infection was unisexual, or that the adult parasites had become encysted so that the larvae could not escape . These clinical findings were published, together with his observations on the development of larvae within mosquitoes, in the Customs Reports 156, then reprinted in the Medical Times and Gazette 158. In the meantime, confirmation of the existence of lymphatic pathology was provided by Bancroft's discovery of an adult worm in a lymphatic abscess, and was consistent with his subsequent recovery of them from hydrocele fluid 20. Nevertheless, there were still opponents of these ideas. Dr Tilbury Fox, a London dermatologist, published a pa per in 1878 denigrating the work of these "recent writers"90. Following a presentation of two cases of elephantiasis b y Joseph Fayrer at a meeting of the Pathological Society of London 84, Fox again asserted that evidence linking filarial infections with elephantiasis was ver y weak, claimed to have seen cases of elephan tiasis in patients who had never left England, and emphasized the abs ence of microfilaraemia in some patients with elephantiasis or chyluria, and cont rasted that with the extremely high frequency of microfilaraemia that Manson had observed in China. Furthermore, Fo x claimed that it was not proven that elephantiasis and lymph scrotum were the same disease, and argued that the escape of chyle in the urine and effusion of lymph into the tissues were two quite different matters. To this, Fayrer replied that while he did not stand up as the champion for the filarial theory of th e disease, the association was of great interest and he considered, moreover, that the observations of men working in the tropics should not be disparage d because it was a very different thing researching in China and India compared with similar undertakings in London 91.

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Stimulated by Fox's criticisms, Manson over a period of nine month s collected a series of six patients who were in a transitional state or who had a combination of elephantiasis of the limb and lymph scrotum. He noted tha t inguinal lymphadenopathy was prominent in all these patients, and succeeded in aspirating microfilariae from the glands, even in patients with elephantiasis of the legs and normal genitals who had no microfilariae detectable in th e blood159. On two occasions, he recov ered ova rather than microfilariae from the lymph nodes. This observation caused him to evolve the theory that adul t worms live in the lymphatic vessels distal to the draining nodes and that they sometimes expelled ova prematurely. He postula ted that the ova are then caught in the nodes where they cause stasis, regurgitation of lymph, anastomosis o f lymph vessels, and hypertrophy of the tissues, sometimes going on to produce lymphorrhoea or chyluria, depending upon the si te of the obstructed lymphatics. Moreover, Manson believed that the parent worms may sometimes die, giving rise to an abscess, usually in the scrotum or thigh 162. The flaw in his argument, of course, was the idea that fe male worms "miscarried" with release of ova, but in many other respects he was right in his interpretation of the sequence o f events. Many of the sceptics were silenced (Fox having died in the interim) when in 1882 MacKenzie presented the post-mortem findings in the patient in whom he had succeeded in reversing filarial periodicity once before. The young man had died from an abscess near the clavicle, pneumonia and pyelonephritis . Autopsy revealed that the thoracic duct was obliterated and embedded i n inflammatory tissue, and that the ly mphatics below the obstruction were dilated enormously, thus confirming t hat the habitat of mature filariae in humans is the lymphatic system, and suggesting that chyluria was due to rupture of distended lymphatics146. There is little doubt that Manson himself would have advanced the understanding of the pathology of filariasis much more rapidly if he had had the opportunity. He was hampered, however, by the bitter antipathy which the Chinese had to examination of the body after death. An illustration of th e difficulties he went through in this cause is recounted in chapter 11 where his accidental discovery of Sparganum mansoni while looking for adult filariae is described. On an earlier occasion, Manson and his brother David had paid a widow 200 dollars in return for permission to make a limited examination of a man with elephantiasis and microfilaraemia. While they were engaged in the autopsy, a mob gathered outside shouting death to the foreign devils, and they had to flee for their lives 174. Despite all these evidences, Prout in 190 8 forcefully advanced the view that filariae were not the cause of either the inflammatory disorders (lymphangitis and abscess) or obstructive lesions (lymph varices, lymph scrotum, hydrocele and elephantiasis) that had been associated with filariasis 196. He based his arguments upon epidemiological observations that filariae were not alway s found even though the vector was present, the fact that these lesions had no t

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been produced experimentally, and the record by Maxwell in 1901 177 that he had found remains of adult filariae in only one of 23 abscesses, despit e microfilaraemia being present in almost al l of the patients. Prout postulated that bacteria produced the acute inflammatory lesions and that recurrent attack s caused the obstruction of lymphatics. Despite formidable opposition fro m Manson170 and others including Low and Manson-Bahr 143, this concept slowly gained ground. Indeed, in 1915, Dutcher and Whitmarsh announced th e "discovery" of a bacterium similar to Bacillus subtilis which they called B. lymphangiticus and which they believed was "the cause of those disease s grouped under the designation of 'filariasis'" 77. Meanwhile, Wise and Minett in British Guiana (Guyana) had studied carefully 28 abscesses and had found evidence in favour of both helminthic an d bacterial causation. Complete worms or pieces of adult filariae were found in the advanced pus in 22 patients, and 21 abscesses grew streptococci in pur e culture, four grew Staphylococcus aureus, and three were sterile 238. In contrast, Anderson and his colleagues working in the same country a few years late r found adult worms in only one of 48 abscesses, streptococci in 41 patients, and staphylococci in 22 cases 1. Consequently, the Royal Society and the London School of Tropica l Medicine in 1926 launched an investigation into the bacterial complications of filariasis in British Guiana. The report published a few years later concluded that a "filarial attack" was really lymphangitis, the usual cause of which was a beta haemolytic streptococcus. It was opined, however, that neithe r lymphangitis nor elephantiasis occurred to any great extent in the absence of W. bancrofti 98. The role of the worm was thus relegated to that of a foreign body which acted as a focus for the opera tion of bacteria. In the 1930's, however, the pendulum began to swing back in favour of the parasitic cause of the problem. In 1931 McKinley reported the results of a study designed to answer th e question: "Can we have acute filarial lymphangitis without bacteria l infection?"148. He investigated 39 cases of acute filarial inflammation and found that blood cultures and microbiological studies of aspirates from inflame d tissue were uniformly negative whereas bacteria were always isolated from a control group of non-filarial abscesses 148. FW O'Connor then re-emphasized the correlation between the presence of insect vectors of W. bancrofti and these complaints, the lack of correlation between chronic filariasis and bacteria l infections, the failure of McKinley to aspirate streptococci in filaria l lymphangitis, and his own pathological studies in which serial sections o f involved tissues revealed large numbers of parasites but no evidence o f bacteria. He concluded that adult worms and their larvae were entirel y responsible for the acute inflammation and chronic obstructive changes see n in filariasis. More importantly, he believed that living worms produced n o serious pathology but that the tissue reactions were usually in response to death of the worms and were probably allergic in nature 185. This belief in an

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immunological reaction was supported when large numbers of early , inflammatory filarial lesions in Ame rican troops were biopsied and histological examination revealed a typical picture of granulomatous lymphangitis 107,232. The prepatent period of filarial infections in humans has not been defined well. As mentioned earlier, microfilaraemia developed 84 days after infection of a human volunteer with B. pahangi 80. An attempt to infect a human similarly with B. malayi was unsuccessful, but a prepatent period of between 67 and 98 days has been found in experimental monk eys188. Such an experiment has never been undertaken with W. bancrofti in humans, but recently Cross and hi s colleagues have infected Taiwan monkey s (Macaca cyclopis) with this parasite and obtained prepatent periods ranging between eight and eighteen months 66. The life span of the adult worms is also unclear. Jachowski and hi s colleagues studied filariasis in Samoans in Samoa (the endemic area) and i n Samoans in Hawaii (a non-endemic area), and calculated that W. bancrofti microfilariae disappeared from the blood in a little over five years 114. This is presumed, but has not been proven, to be when the adult worms had died . Similar deductions have been made by other investigators, although there has been a report of microfilaraemia in the blood of a Frenchwoman who had not lived in an endemic area (Tahiti) for 40 years 49.

DEVELOPMENT OF DIAGNOSTIC METHODS Ways of diagnosing filariasis became evident with the discovery of parasites in various tissue fluids or excretions as has been recounted in the preceding pages. Thus, Demarquay found microfilariae in hydrocele fluid 73 then Bancroft recovered adult worms from the same source 20. Wucherer demonstrate d embryos in the urine 239, Lewis discovered microfilariae in the periphera l blood131 and Manson found them in lymph node aspirates 159 . Nevertheless, it rapidly became evident that not only were adult worms hard to find, but als o that microfilariae could often not be demonstrated in the bloodstream o f infected persons, especially in patients with gross obstructive disease. A number of approaches were therefo re used to enhance diagnostic ability. These included the assessment of immunodiagnostic tests, biopsy of affecte d lymphatics, and the development of techniques for the concentration o f microfilariae from the blood. A clue may be given to the diagnosis by finding an eosinophilia, a n observation that was first made by Gulland in 1902 102. It was soon realized, however, that this was a very nonspecific finding, being seen not only in other tissue helminthiases, but also in a variety of unrelated conditions. Rarely , calcified worms have been noted to produce opacities on X-ray examination, particularly in the thigh and groin 186, but this does not provide an aetiological diagnosis.

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Somewhat more specific were the immunologic al tests that were developed, beginning with skin testing using Dirofilaria immitis antigen, as described by Taliaferro and Hoffman in 1930 225, and the independent development of th e same test as well as an assay for c omplement fixing antibodies by Fairley in the following year82. Much effort was made to improve the sensitivity an d specificity of these assays by fractionating Dirofilaria antigens213,214 and by using W. bancrofti 113 and B. malayi 101 antigens. More promising, since they differentiate between past and present infection and may provide an index of intensity of infection, have been recent attempts to measure filarial antigens in tissue fluids or circulating in the peripheral blood 105,199. Morphological demonstration of the worms, however, is the most definitive means of proving a diagnosis. Experience of early, inflammatory filariasis i n American troops during World War II indicated that the diagnosis could b e made in many patients by biopsy of inflamed lymphatics 76,107,119,232. The commonest practice over the years, however, has been to examine for th e presence of microfilariae in one or more drops (20 µl) of blood smeared on a glass slide. The development of concentration techniques has assisted greatly in the demonstration of microfi lariae in the peripheral blood. One of the first of these techniques used in filariasis was that of de Beaurepaire Aragão who i n 1919 described mixing 0.5 ml of blood with 5 m l of a solution containing acetic acid (which haemolysed the erythr ocytes) then inspecting the centrifuged pellet for parasites32. This technique had, in fact, been used five years earlier in both loiasis and filariasis by Smith and Rivas as is described in chapter 24. Possibly independently, Suganumu in Japan described essentially the same method i n 1921224. The same principle was employed by Haga in Indonesia 103; he used a preparation of the locally available soap fruit ( Sapindus rarak, which contains saponine) to haemolyse red blood cells. This was also the basis for the much publicized "Knott's technique" which did not require (in his origina l description) centrifugation: 1 ml of blood was added to 10 ml of 2% standard aqueous formalin in a measuring flask and was allowed to stand for 12-2 4 hours - a compact pellet containing microfilariae formed under the action o f gravity121. More recently, filtration of venous blood through variou s microscopic filters has become popular in view of its simplicity an d effectiveness 33,74.

THE SEARCH FOR EFFECTIVE TREATMENT The treatment of the obstructive complications of filariasis has long exercised the mind of surgeons. Operative removal of diseased scrotal tissue has bee n practised for at least 150 years. The surgical treatment in 1853 of Moodoo sudun Das (referred to earlier) who was "anaesthetized" with laudanum an d brandy was recorded as follows:

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Professor Raleigh.....made two parallel incisions over each spermatic cord, commencing over the pubes, and extending down the tumour about 14 inches in length; after dissecting up each testicle, a semilunar-shaped incision was made transversely across the pubes, uniting the two former incisions. The penis was next dissected up, and the whole tumour removed by making two small lateral flaps, with a long catlin; the haemorrhage was mostly venous, and not great; two small arteries only required ligature.4

Remarkably, the patient recovered, as did 13 of the next such 15 patients . Similar operations were described by a number of surgeons 95,96,154. Dreadful as are the problems with enlargement of the genitalia , elephantiasis of the limb has proven almost unassailable. Compression of the limb was tried but found to be of only temporary benefit 87, although Knott 70 years later was more impressed with its usefulness 120. Carnochan in 1851 introduced the operation of deligation, or tying of the main artery to the limb 50. This procedure sometimes had disastrous consequences and was roundl y condemned 87,151. Surgical removal of the adult worms was investigated b y Maitland152, but since the procedure involved excision of the involved tissues, it had the manifest disadvantage of exacerbating lymphatic obstruction . Maitland's operation was criticized by a number of surgeons, and despite his plea that it was safe and effective 153, failed to find a solid place in the surgical armamentarium. Near the turn of the present century, Handley proposed an operation o f lymphangioplasty for the cure of elephantiasis, but he himself was doubtful as to its value106 and others were distinctly unimpressed 149. Kondoléon in Athens believed that lymph stasis occurred chiefly in the fascia in the non-tropica l cases that he studied, so he devised an operation in which a strip of fascia was removed in order to make a broad communication between the disease d subcutaneous tissues and the lymphatics in the muscles 122. In 1930, Auchincloss described another operation which was intended to lighte n elephantoid legs and remove focal tender spots by excision of large slabs o f skin, subcutaneous tissues and fascia 17, then a similar operation was described by Gorter97. These operations, however, were major procedures in gross cases (when they were most necessary), and at best gave only partially satisfactor y results. From time to time, various unorthodox therapeutic modes, including radiotherapy115,231 and protein shock therapy 142 have been tried to cure filariasis, but they have been valueless or even dangerous. The medical treatment of filariasis has proved almost as depressing as the surgical management. As early as 1846, Bonyun claimed to cure chyluria with the bark of the mangrove tree, but his account hardly makes convincin g reading36. Myers experimented with the effects of quinine, salicylic acid , arsenic and santonin on microfilariae in vitro, but concluded that the amount of drug required to kill the wo rms would be sufficient to kill the host as well 180. Lawrie in India in 1891 considered that chyluria could be removed wit h

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thymol129, but subsequent investigators were unable to confirm his observ ations. Similar evanescent claims were made for methylene blue 89, salvarsan (arsenic) 39, pepper201, antimony 202, hectine226, anthiomaline 40and arsphenamine227. A vast number of other drugs were also tried and found wanting. For example, Chopra and Rao reported in 1919 that they had assessed 72 different drugs without finding any worthwhile filaricidal activity 52. Sulphonamides, however, were shown to be of some value in acute inflammatory filariasis , presumably because of their action on secondary bacterial infections 78. In 1947, Hewitt and his colleagues reported that a new piperazin e derivative, diethylcarbamazine, produced a rapi d disappearance of microfilariae from the blood of cotton rats infected with Litomosoides carinii and in dogs with Dirofilaria immitis infections, although there was little effect on the adult worms themselves 111. Clinical trials were then carried out in the West Indies by Santiago-Stevenson and colleagues : 26 patients with filariasis were treated and a striking reduction in the level of microfilaraemia was observed and toxi c effects were tolerable 209. Subsequent studies showed that the drug and it s metabolites did not have a direct effect on microfilariae in vitro or on microfilariae in hydrocele fluid. Hawking and his colleagues concluded that the drug modified the microfilariae in some way so that they were removed by the reticulo-endothelial system109,110. Despite the high hopes held initially for this drug, it has not revolutionized the treatment of filariasis, often having only a transient effect on microfilaraemia and sometimes precipitating acut e inflammatory reactions, especially in malayan filariasis, which may merel y accelerate the natural history of the disease.

UNDERSTANDING THE EPIDEMIOLOGY The distribution and prevalence of filariasis was quite inexplicable unti l Manson discovered that microfilariae developed in mosquitoes. Even then , another 20 years were to pass before the method of transference back t o humans was understood. In 1908, George Low wrote a paper entitled "Th e unequal distribution of filariasis in the tropics" 141 as a result of his experiences of that condition in the West Indies. He emphasized that the dicta "N o Anopheles, no malaria" or "No Stegomyia fasciata [= Aedes aegypti], no yellow fever" could be extended to "No Culex fatigans or suitable mosquito, no Filaria nocturna"141. Low remarked, however, that what was more difficult to explain was why the disease should remain localized in certain parts of the world although the intermediate hosts were much more widely distributed. He noted that filariasis was perhaps the most tedious of all the tropical diseases of which to study the epidemiology, for: the only way to arrive at a conclusion of how many individuals in a given district are infected is to make exhaustive night blood examinations of the population generally.141

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Nevertheless, countless inve stigators have burnt the midnight oil and hundreds of papers describing the distributio n and intensity of filarial infection in various communities have appeared since Low's time. These have all given rise to the same general conclusions, namely that human s are the only significant reservoir of W. bancrofti but that subperiodic B. malayi is a zoonosis, the prevalence of microfilaraemia in endemic areas increases with age or plateaus in adult life, the prevalence of disease with chronic lymphatic obstruction increases wit h age, and that vectors of filariae in clude species of Aedes, Anopheles, Culex and Mansonia. There are a number of physiological forms within the W. bancrofti complex, however, which differ in their capacity for development in variou s mosquito vectors211. Furthermore, it became clear that the transmission o f infection is remarkably inefficient. Hairston and de Meillon 104 first drew attention to this in 1968 when they showed that bites by an average of 15,500 mosquitoes carrying infective larvae were necessary for the production of each new case of microfilaraemia i n Rangoon, Burma. Furthermore, less than 1% of mosquitoes carried infective larvae. Infection only occurred because th e average person was bitten by around 100,000 mosquitoes per year. The distribution of filariasis is not static. The infection was probabl y brought to the Western Hemisphere by the transportation of infected slave s from Africa 212 and was introduced into the sugar canefields of Queensland by infected labourers from the south Pacific islands. With improving standards of living, the worm has disappeared from some developed countries such as in the southeastern USA212 and northeastern Australia147 . On the other hand, rapi d urbanization and industrialization without concurrent provision of wast e disposal systems has lead to an increased breeding of culicine moquitoe s (especially Culex quinquefasciatus) which, when coupled with immigration of infected persons from endemic areas, has resulted in the inception of, or a n increase in, transmission of the infection 200.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Means of preventing the exit of microfilariae from the host became obviou s when the uptake of microfilariae by mosquitoes was shown by Manson. These ways were either the eradication of the mosquitoes or the prevention of interaction between the insect and the human. The first was frequently impossible but there was hope for the latter with the us e of mosquito nets and the screening of houses. It was not obvious, however, that the same measures would prevent infection until it was discovered that infective larvae entered the host directly from the biting mosquito rather than by being ingested in water. Fortunately, these same measures were effective in the prevention of malaria and yello w fever, and it was fear of the latter devastating infections that usually stimulated the installation of antimosquito measures. Nevertheless, filariasis in its ow n right has also been the subject of control efforts. As early as 1900, an attempt

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was made to institute a campaign against filariasis in Barbados, but although considerable attention was given to educational measures, little was achieved. This resulted in 1912 in a particularly ill-informed and racist editorial which compared the prospects for control in white Australia versus the black Wes t Indies: of course, the difficulty, even for Brisbane, would be finding the carriers....and this difficulty for native populations, such as the negroes in the West Indies would be almost insurmountable. In the same way, having found that a negro was a carrier, it would be practically impossible to make him sleep under a mosquito net, or to explain to him the danger he was to other people. This will always be the difference in dealing prophylactically with white and native populations. 13

and concluded that the destruction of the int ermediate host was the only feasible proposition. Nevertheless, attempts to control breeding of mosquitoe s (particularly those that were specifically transmitters of infection, a procedure known as "species sanitation") and obstructions to contact between man an d mosquito remained the mainstays of filariasis control until the introduction of the powerful chlorinated hydroca rbon insecticides (e.g. DDT) after World War II and the discovery of diethylcarbamazine in 1947. Modifications to the physical environment, in cluding elimination of polluted water in urban areas (C. quinquefasciatus) 68, water containers in Tahit i (An. polynesiensis) 176, and drainage of swamps (Mansonia) 187, have been tried with variable success. Insecticides, including chlorinated hydrocarbons an d organophosphate compounds, have been used to control larvae and adul t worms, but their expense and the evolution of resistance to these agents i s creating increasing problems 68. In areas where Anopheles species are the major vectors, house spraying with residual insecticides has resulted in the welcome byproduct of filariasis control 234. Major efforts to control filariasis with either mass or selective administration of diethylcarbamazine have met with littl e effect except in circumscribed island communities 100. Limitations of human-mosquito contact with flyscreens and the humble mosquito net offe r perhaps the most promising prospects for control. Despite pockets of success, more people are infected now than whe n Manson discovered the vector over 100 years ago, but the prevalence an d severity of filariasis would be even worse were it not for: the efforts of a devoted but largely anonymous band of health officers, entomologists and their assistants which have been responsible for mosquito control in all the major cities, towns and even many small townships of the tropics. These measures were rarely aimed specifically against the vectors of filariasis but more against the vectors of malaria and arboviruses. In many cities, the original purpose is forgotten and mosquito control remains an exercise in aesthetics which makes life more tolerable by removing 'nuisance' mosquitoes.182

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TROPICAL EOSINOPHILIA In 1939, Meyers and Kouwenaar described a series of seven Javanese men who had lymphadenopathy and a marked eosinophilia. When the lymph nodes were biopsied, eosinophilic granulomas surrounding microfilariae were found . Nevertheless, observation for as long as three years failed to reveal an y microfilariae in the peripheral blood, n or were any adult filariae seen in excised glands. The patients had no evidence of lymphatic obstruction but two ha d asthma and two had haemorrhag ic nephritis so the authors suggested that these syndromes were possibly allergic reactions to filariae 178. In the paper immediately following this report, Bonne, in the same journal, describe d finding extraordinary eosinophilic granulomas with giant cells around microfilariae in the spleen of a Javanese man killed in a motor vehicle accident . Bonne thought that this condition was similar to that described by Meyers and Kouwenaar and suggested that the finding represented either an undescribe d phase in the life cycle of one of the common filarial species or a manifestation of an unusual filarial parasite 34. In 1942, Dhayagude and Amin in Bomba y reported a further 11 cases of microfilarial granuloma 75. Meanwhile, in 1940, Frimodt-Möller and Barton had described a series of 175 patients with what they termed a "pseudo-tuberculous condition" characterized by dyspnoea, eosinophilia a nd extensive, persistent mottling of the lungs on chest X-ray92. In 1943, Weingarten reported a condition which he had seen in 81 cases, and which he believed to be a new disease entity, that he calle d tropical eosinophilia. The illness was characterized by fever, paroxysma l cough, dyspnoea, wheezing, splenomegaly and eosinophilia while chest X-ray examination of the lungs disclosed a distinctive, disseminated mottling. I n contrast to Löffler's syndrome, the illness persisted for weeks or months an d responded to treatment with arsenicals 235. Weingarten could find no cause for the condition but noted that it was common in coastal regions. The relationship with the conditions described by Meyers and Kouwenaar and by Bonne was not immediately apparent and there was considerable speculation to its cause , although a parasitic aetiology seeme d likely. In 1944, Carter and his colleagues postulated that the cause was the cheese mite 51. In 1955, Winter suggested that tropical eosinophilia may be regarded as an accentuated state of sensitivity in persons infected with filariae 237. In 1957, Gault and Webb reported that liver biopsies in four children with tropical eosinophilia (including the typical pulmonary symptoms) showed a striking eosinophilic infiltration in the portal triads, then found similar changes together with granulomatous foci around nematode larvae in a surgical biopsy from a further patient with hepatomegaly 94. In the following year, Danaraj and his colleagues in Singapore noted that W. bancrofti microfilariae occurred in Chinese, Indians and Malays, but that eosinophilic lung was virtually confined to Indians. Furthermore, these latter patients had high titres of antibodies to D. immitis antigen and responded well to tr eatment with diethylcarbamazine. They

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postulated, therefore, that the illne ss was due to infection with a filarial parasite of animal origin which could n ot complete its development in humans 69,70. This view seemed to be supported when Buckley reported that the condition wa s evoked in a human volunteer infected with Brugia malayi then B. pahangi 44. In 1960, Webb and his colleagues demonstrated the presence of microfilarial granulomas in lung biopsies of patients wi th tropical pulmonary eosinophilia 233. In 1979, Ottesen and his colleagues reported that patients with this condition had evidence of immediate hypersensitity reactions to filarial antigens 189. Although it remains unproven, the consensus of opinion now is that W. bancrofti and B. malayi are the most probable causes of the affliction, th e differences from the usual manifestations of filariasis resulting from a failure of microfilariae to evade the host's immune responses so that the parasites are screened out in the lungs, spleen and liver.

REFERENCES 1. ANDERSON J et al. Filariasis in British Guiana (A report of the Filariasis Commission, 1921). London School of Tropical Medicine Research Memoir Series, Number 7, pp 122, 1921 2. ANDREWS EW. Dzibilchaltun; lost city of the Maya. National Geographic Magazine 115: 90-119, 1959 3. ANNETT HE, DUTTON JE, ELLIOTT JH. Report of the malaria expedition to Nigeria of the Liverpool School of Tropical Medicine and Medical Parasitology. Part II. Filariasis. Thompson Yates Laboratory Reports, volume 4, 1901 4. ANONYMOUS. Elephantiasis scroti. Lancet ii: 43-44, 1844 5. ANONYMOUS. Worms in urine and blood. Lancet ii: 310, 1872 6. ANONYMOUS. Haematozoa and chyluria. British Medical Journal i: 147-148, 1873 7. ANONYMOUS. The newly-discovered haematozoon inhabiting human blood. Lancet ii: 889-890, 1872; i:56-57, 1873 8. ANONYMOUS. Is the mosquito the intermediate host of the Filaria sanguinis hominis? British Medical Journal i: 904, 1878 9. ANONYMOUS. Discussion of 160 10. ANONYMOUS. The Veterinarian, 1883 11. ANONYMOUS. The life-history of Filaria sanguinis hominis. British Medical Journal i: 1073, 1888 12. ANONYMOUS. British Medical Journal ii: 443, 682, 1900 13. ANONYMOUS. The prevention of filariasis. Journal of Tropical Medicine and Hygiene 15: 91-92, 1912 14. ANONYMOUS. Filarial periodicity. Lancet ii: 270-271, 1937 15. ASH LR, LITTLE MD. Brugia beaveri sp. n. (Nematoidea: Filarioidea) from the raccoon (Procyon lotor) in Louisiana. Journal of Parasitology 57: 1043-1051, 1971 16. ASHBURN PM, CRAIG CF. A new blood filaria of man: Filaria philippinensis. American Journal of Medical Science 132: 435-443, 1905 17. AUCHINCLOSS H. A new operation for elephantiasis. Porto Rico Journal of Public Health and Tropical Medicine 6: 149-150, 1930 18. BABIONE RN. Mumu. A few facts about filariasis for folks who fear that filaria-infected fellows will fetch filariae from the front. Hawaii Medical Journal 5: 69-71, 1945 19. BAHR PH. Filariasis and elephantiasis in Fiji. Report to the London School of Tropical Medicine, Witherby and Co., London, pp 192, 1912 20. BANCROFT J. Cases of filarious disease. Transactions of the Pathological Society o f

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London 29: 407-417, 1878 21. BANCROFT J. On filaria. Transactions of the Intercolonial Medical Congress of Australasia, pp 49-54, 1889 22. BANCROFT J. Cited in 56 23. BANCROFT J. Cited in 57 24. BANCROFT J. Cited in 59 25. BANCROFT TL. Filarial metamorphosis in the mosquito. Australasian Medical Gazette 18: 20, 1899 26. BANCROFT TL. On the metamorphosis of the young form of Filaria bancrofti, Cobb (Filaria sanguinis hominis, Lewis; Filaria nocturna, Manson) in the body of Culex ciliaris, Linn., the "house mosquito" of Australia. Journal and Proceedings of the Royal Society of New South Wales 33: 48-62, 1899. Reprinted in the Journal of Tropical Medicine and Hygiene 2: 90-94, 1899; 2: 149-153, 1900 27. BANCROFT TL. Preliminary notes on the intermediary host of Filaria immitis, Leidy. Journal and Proceedings of the Royal Society of New South Wales 35: 44-46, 1901 28. BANCROFT TL. On some further observations on the life-history ofFilaria immitis, Leidy. Journal and Proceedings of the Royal Society of New South Wales 37: 254-257, 1903. Reprinted in British Medical Journal i: 822-823, 1904 29. BARBOT J. A description of the coasts of North- and South Guinea and of Ethiopia inferior etc, London, six volumes, 1732 30. BASCOME E. On elephantiasis. Lancet i: 435-436, 1846 31. BASTIAN H, HARLEY J. Cited in 191 32. de BEAUREPAIRE ARAGÃO H. Novo methodo para facilitar o diagnostico e a coservação dos embryos de filarias no sangue e de parasitas nas fézes. Brazil Medico 33: 1-2, 1919 33. BELL D. Membrane filters and microfilariae: a new diagnostic technique. Annals of Tropical Medicine and Parasitology 61: 220-223, 1967 34. BONNE C. Over hypereosinophilie in de milt gecombineerd met een filaria-infectie. Geneeskundig Tijdschrift voor Nederlandsch-Indië 79: 874-876, 1939 35. BONNE C, LIE KJ, MOLENKAMP WJ, MYEREN FW. Wuchereria malayi, de Macrofilaria behoorende bij de Microfilaria malayi. Geneeskundig Tijdschrift voor Nederlandsch-Indië 81: 1487-1501, 1941 36. BONYUN GR. Report of a case of chylous urine successfully treated with the bark of Rhizopus racemosa, or mangrove, a tree indigenous to British Guiana. Lancet i: 95-96, 1846 37. BOURNE AG. A note on Filaria sanguinis hominis: with a description of the male specimen. British Medical Journal i: 1050-1051, 1888 38. BOURNE AG. Transactions of the South Indian Branch of the British Medical Association 2: 396-398, 1888 39. BRANCH ER. Salvarsan in filariasis. Journal of Tropical Medicine and Hygiene 16: 364-365, 1913 40. BROWN HW. The treatment of filariasis (Wuchereria bancrofti) with lithium antimony thiomalate. Journal of the American Medical Association 125: 952-958, 1944 41. BRUG SL. Een nieuwe Filaria-soort (Filaria malayi) parasiteerendi bij den mensch (voorloopige mededeeling). Geneeskundig Tijdschrift voor Nederlandsch-Indië 67: 750-754, 1927 42. BRUG SL. Filariasis in Nederlandsch-Indië. Geneeskundig Tijdschrift voor Nederlandsch-Indië 68: 681-704, 1928 43. BRUG SL, de ROOK H. Filariasis in Nederlandsch-Indië. II. Deoverbrenging van Filaria malayi. Geneeskundig Tijdschrift voor Nederlandsch-Indië 70: 451-472, 1930 44. BUCKLEY JJ. Tropical pulmonary eosinophilia in relation to filarial infections (Wuchereria spp.) of animals. Preliminary note. Transactions of the Royal Society of Tropical Medicine and Hygiene 52: 335-336, 1958 45. BUCKLEY JJ. A new genus, Brugia, for Wuchereria spp. of the malayi group. Abstract of Papers, Sixth International Congress of Tropical Medicine and Malaria, Lisbon, p 35, 1958 46. BUCKLEY JJ. On Brugia gen. nov. for Wuchereria spp. of the "malayi" group i.e. W. malayi Brug, 1927, W. pahangi Buckley and Edeson, 1956, and W. patei Buckley, Nelson and Heisch, 1958. Annals of Tropical Medicine and Parasitology 54: 75-77, 1960

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47. BUCKLEY JJ, EDESON JF. On the adult morphology ofWuchereria sp. (malayi?) from a monkey (Macaca irus) and from cats in Malaya, and on Wuchereria pahangi n. sp. from a dog and a cat. Journal of Helminthology 30: 1-20, 1956 48. BURNELL AC. The voyage of John Hughen van Linschoten to the East Indies, Hakluyt Society, London, volume 1, pp 307, 1885 49. CARME B, LAIGRET J. Longevity of Wuchereria bancrofti var. pacifica in mosquito infection acquired from a patient with low level parasitemia. AmericanJournal of Tropical Medicine and Hygiene 28: 53-55, 1979 50. CARNOCHAN. Cited in 151 51. CARTER HF, WEDD G, D'ABRERA V. The occurrence of mites (Acarina) in human sputum and their possible significance. Indian Medical Gazette 79: 163-168, 1944 52. CHOPRA RN, RAO SS. Chemotherapy of filarial infection. Indian Journal of Medical Research 27: 549-592, 1939 53. CILENTO R. Tropical diseases in Australia, second edition, W R Smith and Paterson, Brisbane, pp 461, 1942 54. COBBOLD TS. On the development of Bilharzia haematobia; together with remarks on the ova of another urinary parasite (the so-called Trichina cystica of Dr. Salisbury) occurring in a case of haematuria from Natal. British Medical Journal ii: 89-92, 1872 55. COBBOLD TS. Cited in 191 56. COBBOLD TS. Verification of recent haematozoal discoveries in Australia and Egypt. British Medical Journal ii: 780-781, 1876 57. COBBOLD TS. Discovery of the adult representative of microscopic filariae. Lancet ii: 70-71, 1877 58. COBBOLD TS. On Filaria Bancrofti. Lancet ii: 495-496, 1877 59. COBBOLD TS. Discovery of the intermediary host of Filaria sanguinis hominis (F. Bancrofti). Lancet i: 69, 1878 60. COBBOLD TS. The life-history of Filaria bancrofti, as explained by the discoveries of Wucherer, Lewis, Bancroft, Manson, Sonsino, myself and others. Journal of the Linnean Society (Zoology) 14: 356-370, 1878 61. COBBOLD TS. Parasites: a treatise on the entozoa of man and animals including some account of the ectozoa, J&A Churchill, London, pp 508, 1879 62. COBBOLD TS. Introduction to observations on filariae by Drs. Patrick Manson, John R. Somerville, Joseph Bancroft, J.F. da Silva Lima, J.L. Paterson, Pedro S. de Magalhaes and J. Mortimer-Granville, communicated, with an introduction by the President. Journal of the Quekett Microscopical Club 6: 58-60, 1880 63. CORRE A. Note sur l'helminthe rencontré dans les urines hématochyleuses. Revue des Sciences Naturelles, 1872 64. CORTESÃO A. The Suma Oriental of Tomé Pires, Hakluyt Society, London, pp 578, 1944 65. CREVAUX J. De l'hématurie chyleuse ou graisseuse des pays chauds, Thèse de Paris, pp 64, 1872 66. CROSS JH, PARTONO F, HSU MK, ASH LR, OEMIJATI S. Experimental transmission of Wuchereria bancrofti to monkeys. American Journal of Tropical Medicine and Hygiene 28: 56-66, 1979 67. CUNNINGHAM DD. The haematozoon; notes on its discovery and its relation to the canine filaria. Lancet i: 835-837, 1873 68. CURTIS CF, FEACHEM RG. Sanitation and Culex pipiens mosquitoes: a brief review. Journal of Tropical Medicine and Hygiene 84: 17-25, 1981 69. DANARAJ T. The treatment of eosinophilic lung (tropical eosinophilia) with diethylcarbamazine. Quarterly Journal of Medicine 27: 243-263, 1958 70. DANARAJ TJ, da SILVA LS, SCHACHER JF. The serological diagnosis of eosinophilic lung (tropical eosinophilia) and its etiological implications. American Journal of Tropical Medicine and Hygiene 8: 151-159, 1959 71. DANIELS CW. Discovery of the parental form of a British Guiana blood worm. British Medical Journal i: 1011-1012, 1898 72. DAVID HL, EDESON JF. Filariasis in Portuguese Timor, with observations on a new microfilaria found in man. Annals of Tropical Medicine and Parasitology 59: 193-204, 1965

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226. TANON L, GIRAUD G. Traitement des filarioses sanguines par les injections sous-cutanées d'hectine. Revue de Médecine et Hygiene Tropicale 12: 82-86, 1920 227. THETFORD ND, OTTO GF, BROWN HW, MAREN TH. The use of phenyl arsenoxide in the treatment of Wuchereria bancrofti infection. American Journal of Tropical Medicine 28: 577-583, 1948 228. THORPE VG. Filaria sanguinis hominis in the South Sea Islands, with photomicrographs from Tonga and the Friendly Islands. British Medical Journal ii: 922-924, 1896 229. TRENT SC. Re-evaluation of World War II veterans with filariasis acquired in the Pacific. American Journal of Tropical Medicine and Hygiene 12: 877-887, 1963 230. TURNER LH, EDESON JF. Studies on filariasis in Malaya; the periodicity of the microfilariae of Wuchereria malayi. Annals of Tropical Medicine and Parasitology 51: 271-277, 1957 231. WARDEN AA. Note on the treatment by radium of lymphatic obstruction (cervical, submaxillary and axillary) in a patient suffering from Filaria nocturna. Lancet ii: 224-225, 1909 232. WARTMAN WB. Lesions of the lymphatic system in early filariasis. American Journal of Tropical Medicine and Hygiene 24: 299-313, 1944 233. WEBB JK, JOB CK, GAULT EW. Tropical eosinophilia; demonstration of microfilariae in lung, liver and lymph nodes. Lancet i: 835-842, 1960 234. WEBBER RH. Eradication of Wuchereria bancrofti infection through vector control. Transactions of the Royal Society of Tropical Medicine and Hygiene 73: 722-724, 1979 235. WEINGARTEN RJ. Tropical eosinophilia. Lancet i: 103-105, 1943 236. WILSON T, EDESON JF, WHARTON RH, REID JA, TURNER LH, LAINGAB. The occurrence of two forms of Wuchereria malayi in man. Transactions of the Royal Society of Tropical Medicine and Hygiene 52: 480-481, 1958 237. WINTER H. "Tropische Eosinophilie" als symptomarme Filariasis. Zeitschrift für Tropenmedizin und Parasitologie 6: 99-105, 1955 238. WISE KS, MINETT EP. Report of tropical diseases research in the Government Bacteriological Laboratory, British Guiana, for the six months October 1911 to March 1912. Report of the Advisory Committee of the Tropical Diseases Research Fund for the Year 1912. H.M. Stationery Office, London, pp 108-114, 1913. Abstracted in Tropical Diseases Bulletin 2: 93-94, 1913 239. WUCHERER OE. Noticia preliminar sobre vermes de una especie ainda não descripta, encontrados na urina de doentes de hematuria intertropical no Brazil. Gazeta Medica da Bahia 3: 97-99, 1868. Translated in 117

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Table 23.1. Landmarks in filariasis ___________________________________________________________________ BC 1863 1866 1872 1876 1877

Elephantiasis recognized from antiquity Demarquay and colleagues discovered microfilariae in hydrocele fluid Wucherer found microfilariae in chylous urine Lewis observed microfilariae in blood Joseph Bancroft discovered a female adult worm Manson found microfilariae in the stomach of a mosquito and observed their subsequent development 1879 Manson discovered the nocturnal periodicity of W. bancrofti microfilaraemia in China 1880 Manson reported finding microfilariae in aspirates of lymph nodes 1888 Sibthorpe isolated and Bourne described a male adult worm 1896 Thorpe reported the diurnal subperiodicity of the Pacific form of W. bancrofti 1899 Thomas Bancroft suggested that infection may be acquired via the proboscis of a biting mosquito 1900 Low demonstrated infective larvae in the proboscis of filariated mosquitoes prepared by Thomas Bancroft 1927 Lichtenstein and Brug described a different microfilaria which was named microfilaria malayi 1939 Meyers and Kouwenaar described a syndrome of marked eosinophilia and lymphadenopathy with eosinophilic granulomas around microfilariae in the lymph nodes 1940 Rao and Maplestone described the parental form of B. malayi 1947 Hewitt and colleagues showed that diethylcarbamazine caused a rapid disappearance of Litomosoides carinii microfilariae from the blood of cotton rats 1948 Santiago-Stevenson and co-workers demonstrated a similar effect in humans with bancroftian microfilaraemia 1958 Danaraj showed that tropical pulmonary eosinophilia responded to treatment with diethylcarbamazine 1960 Webb and colleagues demonstrated the presence of microfilarial granulomas in lung biopsies from patients with tropical pulmonary eosinophilia 1965 David and Edeson described the Timor microfilaria 1977 Partono and colleagues described Brugia timori, the parental form of the Timor microfilaria ___________________________________________________________________

Chapter 24

Loa loa and LOIASIS

SYNOPSIS Common name: eyeworm causing Calabar swellings Major synonyms: Dracunculus loa, Filaria lacrymalis, F. loa, F. oculi humani, F. subconjunctivalis, microfilaria diurna Distribution: West and Central Africa Life cycle: The adult worms, 30-70 mm long by 0.35-0.5 mm wide, migrate throughout the connective tissues. Microfilariae are produced and released into the bloodstream; they appear only during the day, a phenomenon known as diurnal periodicity. When microfilariae are ingested by tabanid flies of the genus Chrysops, they develop over 10-14 days into infective larvae which pass to the proboscis and infect the host at the next blood meal Definitive host: humans, (subhuman primates) Major clinical features: recurrent, transient, urticarial, subcutaneous swellings (Calabar swellings). Occasionally adult worms are seen migrating through the subconjunctiva Diagnosis: clinical (obervation of Calabar swellings); observation of the adult worm in the eye; demonstration of microfilariae in the blood Treatment: diethylcarbamazine, suramin

AWARENESS OF THE ADULT WORM Since the adult Loa loa is several centimetres in length and moves from time to time through the subconjunctival tissues of the eye, this worm must hav e been recognized by people living in endemic areas for many centuries past. The name of the first European to see and describe this worm, however, has been a matter of some dispute. When the Frenchman, Guyon, described a case i n 1864, he reviewed the literature and believed that the first recorded evidence of this parasite was a certain copper engr aving which he interpreted as showing the extraction of Loa loa from the eye48. This engraving, which had been drawn by the engraver and publisher, JT de Bry, appeared in 1598 in the secon d volume of a two volume work called Collectiones peregrinationum in Indiam orientalem et occidentalem (known as India Orientalis for short) 14. The text was concerned in part with the travels to Asia of the Dutchman, Huighen van Linschoten, and included, amongst other things, his description o f dracunculiasis on Hormuz island in the Persian Gulf (see chapter 26), an d recounted how the king blinded his relatives to prevent assassination an d rebellion. The first volume, which had appeared in 1597 in German and was 641

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then issued in 1598 in Latin, contained an account about Africa by th e Portuguese, E Lopez; the reco rd of Lopez had been translated from Portuguese into Italian by Phillip Pigafetta in 1593 then into German by A Cassiodo r Reinus. Its Latin title began: " Vera descriptio regni Africani quod tamabincolis quam Lusitanis Congus appellatur per Phillipum Pigafettam ....MDXCVIII". Guyon connected the words Congo and 1598 in the title of volume 1 with the engraving in volume 2 and concluded that the engraving was indicatin g pictorially the removal of Loa from the eye. This view was accepted b y Blanchard9, who believed that Pigafetta was the author of this publication, and by many other writers. In fact, there is no loiasis in the Persian Gulf, an d Ward91 and Grüntzig and Jennes46 have shown that there was no reference to this parasite in these accounts. Indeed, the latter authors have argue d convincingly that these engravings were not scientific reproductions, but were fashioned with the aid of de Bry's fertile imagination, for his primary purpose was not to serve science but to offer entertaining literature to the educate d general public. The first definitive account of the worm was published in 1770 by Mongin, a French surgeon who saw the para site at Santo Domingo in the Caribbean. He was called by the Count of Cockburn to see one of his black female servant s who had been complaining of a severe stabbing pain in the eye of 24 hours ' duration. Mongin wrote that there was no inflammation, but he: saw a worm which seemed to crawl superficially on the eye, but when I tried to catch it with forceps, I realized that it was between the conjunctiva and the cornea. When it approached the transparent cornea, the pains became more severe....it was one and a half inches long, the width of a violin string, and dark colored. One end was bigger than the other, although both ends were very pointed. 75

Although Mongin was the first t o publish an account of the worm, his compatriot, Bajon in Cayenne, saw and removed one earlier in July 1768. A ship's captain from Guadeloupe brought him a young African girl six to seven years old in whose eye he saw: a motile small worm the size of a small thread; I examined it and observed a small animal almost two thumbs in length; it moved around the eyeball in the cellular tissue which unites the conjunctiva with the sclera. On stimulating it to move, I saw that its movements were not straight but tortuous and oblique; the colour of the eye never changed and the small negress complained of no pain even though the worm moved in the way it did; she did, however, have an almost continuous small watering of the eyes.8

Bajon saw another case, again in a negress, in 1771. In this patient, however, the conjunctiva was inflamed. He reported his experiences with this condition in 1777 8 . Further cases were seen by Guyot in Angola (1778) 49 , Clot Bey in Egypt (1838)18, Blot10 then Guyon47 in Martinique, and Loney in West Africa 62. This last-named author, who was a surgeon on Her Majesty's brigantin e Dolphin, gave the first account in English. He saw two patients in 1848: They applied to me....with itching, and a sensation as if something was moving around in the eye. On examination, I observed a worm moving round and round the

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cornea, beneath the conjunctiva, causing very little if any, irritation....neither of the dracunculi when extracted were found to exceed two inches in length. 62

Worms were encountered by many surgeons subsequently, but it was not until 1895 that the British ophthalmologist, Argyll-Robertson, in collaboration with Manson, provided the first detailed descriptions of the male and femal e parasites5. Further detailed descriptions were then provided by Looss 63 and by Huffman and Wherry 51. Many of the early French writers referred to the worm as a "dragonneau " (i.e. dracunculus or guinea worm), but it soon became clear this parasite was a different creature from Dracunculus medinensis . In 1845, Dujardin placed the worm in the genus Filaria of Müller78 and named it Filaria oculi humani 26, then Dubini called it Filaria lacrymalis 25, Gervais and van Beneden designated it Filaria oculi 40, and Guyon labelled it Filaria subconjunctivalis48 . The French naval surgeon, Guyot, who had seen several cases while cruising off the coast of Angola in 1778 mentioned, in his description of the parasite man y years later, that the local native name for the parasite was "loa" meanin g "worm"49. This term was adopted by Cobbold who combined it wit h Dracunculus to name the worm Dracunculus loa 19. Nevertheless, many other authors retained it in the genus Filaria and following the lead of Aitken i n 18661, the worm was known as Filaria loa for many years. In 1905, Stiles and Hassall placed the parasite in the subgenus Loa of the genus Filaria 89, then Castellani and Chambers in 1913 erected the genus Loa to house the worm which has since that time been known as Loa loa 16.

DISCOVERY OF THE MICROFILARIA AND DETERMINATION OF ITS RELATIONSHIP WITH THE ADULT LOA LOA In 1890, Stephen Mackenzie of the London Hospital found microfilariae in the blood of an African from the Con go named Mandombi who was suffering from sleeping sickness (trypanosomiasis); the aetiology of this condition was no t understood at that time. Mackenzie noticed that the microfilariae differed i n several respects from the well-known forms now called Wuchereria bancrofti. In particular, the parasites did not have nocturnal periodicity and could thus be found by day and by night, and secondly, the microfilariae did not all appear to be of the same size. In view of these pecularities, Mackenzie invited Partrick Manson to see the patient. When Manson examined Mandombi's blood on the evening of 2 December 1890, he confirmed that the parasites were of two sizes. One of them resembled the microfilariae of W. bancrofti and at that time, Manson had no doubts that that was precisely what it was. The other form was about two thirds of the size and had more active motions. The patient died the next day, but no adult worms could be found at autopsy. A few days later , Manson had the opportunity of seeing another patient of Mackenzie's; he also came from the Congo and had been placed in a lunatic asylum because of a

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mental disorder. On examination of this patient's blood, only the smaller forms were found, thus proving that one type of microfilaria was not a transitiona l form of the other. Manson then examined the blood of two blacks from Ol d Calabar who were patients of Dr Grattan Guiness. In one, he found the small forms, but in the other he saw bot h of the types that he had seen in Mandombi's blood. As with that patient, microfilariae were circulating in the blood during the day. Manson scrutinized parasites from this patient very carefully, looking for differences from those of microfilaria bancrofti (this was before the introduction of Romanowsky stains) but found only minor variations, bot h forms being of the same size and provided with a sheath. However, Manso n now thought that the large microfilariae from the African subjects wer e different from those of microfilaria bancrofti in that the sheath was mor e delicate, the oral movements were more marked, and that there was an absence of granular material around the middle of the body. He examined the periodicity of these microfilariae in detail. In both patients, the smaller worm could b e found throughout the 24 hours, but in the patient with the large microfilariae, these parasites reached a peak in the middle o f the day and were absent at night. Manson wrote: the law of periodicity for the appearance of the major embryo is just the reverse of that which has hitherto been found to apply to the filaria sanguinis hominis of Lewis.67

As a result of all these observations, he concluded that "man is liable to be the host of at least two, if not three, distinct species of filarial haematozoa" 67. Manson may not have been quite so definite in his remarks, however, if these observations had been made after the discovery of the diurnal periodicity of W. bancrofti in the Pacific by Thorpe in 1896. In order to differentiate these new microfilariae from the Filaria sanguinis hominis of Lewis, Manson called them Filaria sanguinis hominis major (i.e. bigger) and Filaria sanguinis hominis minor (i.e. smaller)67. Later that year at the Seventh International Congress on Hygiene and Demography held in London he renamed these parasites on th e basis of their periodicity. Filaria sanguinis hominis became Filaria sanguinis hominis nocturna, Filaria sanguinis hominis major became Filaria sanguinis hominis diurna, and Filaria sanguinis hominis minor became Filaria sanguinis hominis perstans to reflect night-time periodicity, daytim e periodicity, and persistence of microfilaria throughout the 24 hours , respectively 68. These names subsequently became shortened to Filaria nocturna, F. diurna and F. perstans. Although it was apparent that there was at least one and probably two new species of microfilariae, the nature of the parent worms was not immediately clear. With the perspicacity of a true savant, Manson suggested that Loa loa was a likely candidate, although he made one important error initially. Afte r recalling that the subcutaneous and subconjunct ival migrations of this worm did not seem propitious for transfer of t he parasite to a new host and noting that the embryos in the circulation might have a much greater opportunity of migrating

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via a blood-sucking insect in a fashion analogous to W. bancrofti in mosquitoes, and perhaps misled by Leuckart's observation that adult Loa loa contained embryos which had a general resemblance to those of W. bancrofti except that they were smaller, he wrote: "Might it not be that the smaller o f these new haematozoa is the embryo of the filaria loa?" 67. Manson's error, of course, was in thinking that it was the smaller microfilaria which was th e embryo of Loa loa (this is now known to be the embryo of Mansonella perstans). Later, however, when it became apparent that F. perstans was endemic in both Africa and South America whereas the acquisition of F. loa was restricted to Africa, he corrected this mistake and related F. diurna to F. loa 69. Two ways of confirming this hypothesis were to compare the embryo s within an adult Loa loa with microfilariae of F. diurna in the bloodstream, and to look for F. diurna in the bloodstream of patients with clinical evidence o f infection with the adult Loa loa. An opportunity for undertaking both of these options presented itself to Argyll-Robertson in 1894-1895. He removed a female Loa loa from the eye of a patient and s ent it to Manson but unfortunately the investigation was not conclusive, with Manson writing: The uterine tubes are stuffed with embryos at all stages of development. The more mature embryos resemble in size and shape those of F. nocturna and F. diurna, but in consequence of the method of mounting, it is impossible to say if they are possessed of a sheath or not. If they are possessed of a sheath, I should say that they are practically indistinguishable from the parasites mentioned. 71

Similarly, examination of the pat ient's blood failed to reveal microfilariae 5. The absence of F. diurna from the blood of a patient with adult Loa loa infection had also been documented previously by Dr. Logan in Liverpool. Occasional patients were noted in whom both F. loa were recovered from the eye an d microfilaria diurna were seen in the blood 11,15, but since many more patient s had had only one or the other, the association remained uncertain. Indeed , Annett, Dutton and Elliot studied microfilaria diurna in its natural habitat in West Africa and concluded in 1901 that Manson's hypothesis that thes e microfilariae were the embryos of F. loa was erroneous. Rather, they contended that microfilaria diurna was none other than microfilaria bancrofti, and that the normal periodicity had been disturbed by the peculiar habits of West African negroes who, they claimed, spent their nights in orgies 2. Eventually, however, examination of more adult worms revealed that th e enclosed embryos were sheathed and seemed very similar to both microfilaria nocturna (= W. bancrofti) and microfilaria diurna. George Low then made careful measurements of microfilaria nocturna and microfilaria diurna and concluded that the former measured 0.21-0.28 mm in length whereas the latter were 0.29-0.32 mm long, and that the location of the V spot (excretory pore) in these two forms was different. Furthermore, he made measurements on 30 embryos expressed from an adult Loa loa that had been sent to him by D r Currie in Lagos and found that they were the same as those of microfilari a

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diurna. Finally, in contrast to nocturnally periodic microfilaria bancrofti, Low was unable to reverse the diu rnal periodicity by inverting the sleep habits of an infected patient. He believed, therefore, that there was no question of th e identity of Loa loa and microfilaria diurna and declared that the time had come for abolishing the name microfilaria diurna and substituting in its place th e term microfilaria loa 64. Low's views were supported by Huffman who studied in detail the embryos in a living Loa loa 50 and by Foley who found simila r differences in the measurements of microfilaria bancrofti and microfilaria diurna in the peripheral blood 36. In 1912, Fülleborn clinched the matter when he reported that in microfilariae stained with haematoxylin or Azur II, nuclei extended to the extreme end of the tail in the case of microfilaria diurna, but only for 95% of the length of the worm in the case of microfilaria bancrofti. Furthermore, this characteristic was identical in microfilaria diurna and in microfilariae obtained from adult Loa loa 37,39. Fülleborn's observations were confirmed soon afterwards by Fol ey36 and then by Meinhof 74. A few years later, Dyce Sharp reported characteristic differences among microfilaria loa, microfilaria bancrofti and microfilaria perstans when stained with supravital dyes and when fixed organisms were examined after different stainin g preparations 33.

FURTHER OBSERVATIONS ON DIURNAL PERIODICITY Sensitized by their previous interest in the nocturnal periodicity of microfilaria bancrofti, Mackenzie and Manson showed from the very beginning that Loa loa microfilaraemia had a peak in the middle of the day. Indeed, this was one of the means by which Manson differentiated the new species and provided the basis of his name for it. Mackenzie, then others, had shown that microfilari a bancrofti nocturnal periodicity could be reversed by inverting the sleepin g habits of a patient. As already indicated, Low mentioned in 1910 that in 1904 he had been unable to achieve such a reversal in a patient with Loa loa microfilaraemia 64. He repeated this experiment in 1921 on a 28 year old man who had acquired loiasis in Nigeria and confirmed this observation by having him sleep by day and remain awake at night for six days and nights 66. The mechanism of diurnal periodicity in Loa microfilaraemia was and remains as much of a mystery as does the nocturnal periodicity of W. bancrofti microfilaraemia. One theory which had been put forward by Lane was that W. bancrofti female adult worms released microfilariae in a cyclical fashion (see chapter 23). This theory, in loiasis at least, was negated by a potentiall y disastrous experience undertaken by Gönnert in 1941 (disastrous in the sense that Gonnert could have given himself a fatal transfusion reaction or infected himself with, for example, hepatitis B virus). In 1912, Fülleborn had reported that he had injected Loa microfilariae into mice and monkeys but had failed to

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recover any worms from either the peripheral or lung blood 38. Gönnert in Hamburg took this idea and collected 160 ml of blood from a patient from the Cameroon with a heavy Loa microfilaraemia and injected it intravenously into his own bloodstream almost immediately. He calculated that he transferre d 1,640,000 microfilaria loa and 112,000 microfilaria perstans. He suffered from an unanticipated transfusion reaction but examined his blood at intervals and found that a definite diurnal periodicity persisted over the next few days . Clearly, the periodicity was dependent upon the microfilariae themselves, o r upon an interaction between them and the host rather than upon the adul t worm41.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE TABANID INTERMEDIATE HOST The manner of transmission of Loa loa was a complete mystery to the earl y observers who saw the adult worm. When Manson first described the microfilariae that eventually turned out to be those of Loa loa, he predicted that the vector would be a blood-sucking insect of limited distribution in Africa an d with day-biting habits. He wrote: "Some naturalists may be able, even at this early stage of the investigation, to indicate these animals" 67. The failure to find microfilariae in the blood of many such patients , however, misled other investigators into thinking that some other mode o f transmission must be operative. Thus, Argyll-Robertson postulated tha t embryos may be ingested in contaminated water, although he cautioned that: the chief difficulty consists in determining how these embryo filariae escape from the bodies of those affected with the disease, and get deposited in the impure water and thus propagate the disease....Possibly the embryo parasites may be discharged along with some of the excreta from the body, and from faulty sanitary arrangements find their way into drinking water. 5

Argyll-Robertson must have later changed his mind, possibly after conversation with Manson, however, for he recorded in a subsequent report that his patient, who had returned to Old Calabar, had sent specimens of mosquitoes an d sandflies which he and Manson had examined but had failed to detect an y developing filarial larvae 6. Subsequently, Manson 72 then Sambon 84 suggested that the intermediate host of Loa loa should be looked for amongst the larg e blood-sucking flies of the family Tabanidae which bite by day and were known popularly as mangrove flies or horse flies. Fülleborn reported in 1912 that he had tried to infect mosquitoes with Loa loa but to no avail 38. In the latter part of that year, Robert Leiper, funded by a bequest to the London School o f Tropical Medicine by the late Lord Wandsworth, went to West Africa an d undertook a series of studies designed to identify the vector of Loa loa. He fed the bedbug, Cimex rotundatus, the flea, Pulex irritans, many species of mosquitoes, and various other flies including Stomoxys calcitrans, S. migrans,

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Glossina palpalis, Tabanus par, T. socialis, T. fasciatus and T. secundus on a patient with Loa loa microfilaraemia but with negative results. A sligh t degree of infection was observed with Haematopota cordigera and Hippocentrum trimaculatum , but the development was slow and asynchronous. In Chrysops dimidiata and C. silacea, however, development was rapid an d uniform60. Leiper sent a telegram from Calabar to the London School o f Tropical Medicine on 27 December 1912 which was reported in The Times and the British Medical Journal of the following week: "The metamorphosis of Filaria loa has been proved to take place in the salivary glands in a fl y belonging to the genus Chrysops"61. Leiper had to abort his studies in January 1913, however, because of a lack of f lies with which to work. He was informed that Chrysops had a marked seasonal incidence at Calabar in Nigeria and that they would not reappear in abundant numbers until June. Perhaps because he intended to extend his studies later, Leiper does not appear to have published details of his observations on the development of microfilariae in Chrysops. Nevertheless, his discovery was confirmed and this omission rectified by a number of subsequent investigators. In 1915, Kleine reported the results of his investigations in a heavil y endemic area at Eseka in the German Cameroons (now called Cameroon). He examined 600 wild-caught female flies (500 C. dimidiata and 100 C. silacea) and found that 5.3% were infected, with fully mature infective larvae bein g present in nine flies. Kleine considered that microfilariae perforated the gu t wall, then development took place in the fatty tissue surrounding the tracheae in the abdominal cavity. Later, they migrated to the cephalic end of the body of the insect, and in two cases he was abl e to demonstrate emergence of the larvae from the proboscis 57. This work was criticised by Cockin, however, on th e grounds that the nature of the hosts o n which the flies had fed was unknown, no illustrations or descriptions of the larvae were provided, and no attempt wa s made to transmit infection by means of infected flies 20. While the first criticism was valid, the second could also have been levelled at Leiper, and the third was manifestly unfair in view of its impracticability and the doubtful ethics of such a procedure. This was, of course, at the height of World War I, a time which was not propitious for extended investigations on Kleine's part, and perhaps a little xenophobia coloured C ockin's comments. These criticisms were certainly not applied by an editorial writer in The Lancet 4 commenting on the report in 1921 by Dr. A. Connal in which he described the findings on more than 2,000 Chrysops which were caught over eight months in 1917 near Lagos and then were dissected by his wife. She observed that 0.8% of 2,255 C. silacea and 2.4% of 249 C. dimidiata were infected; the larvae were usually present in the muscles - in one insect, 427 worms were present 21. Subsequently, the Connals conducted many feeding experiments on cases of loiasis with large numbers of flies. They reported that the majority of embryos reached the abdomina l muscles within 24 hours of feeding, although others proceeded to the head and thorax. Growth was rapid so that by the fifth day they were seen coiled i n

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whorls in the musculature, particularly of the abdomen. Ten to twelve days after infection, larvae migrated towards the head, accumulated at the root of th e proboscis and the labium and exited via the labella. Finally, evidence wa s procured which indicated that flies could remain infective for five to si x days22,23. Soon afterwards, however, they had to modify these comments since histological sections of infected flies prepared by Dr AC Stevenson had made it clear that most of the larvae were not in muscles but in fatty tissue, th e so-called "fat body". Connal and his wife concluded that the forms found b y Kleine in abdominal fatty tissue were almost certainly, as he presumed, stages in the development of Loa loa 24. This question was re-investigated many years later by Lavoipierre and by Lebied. The former author considered that the young larvae invaded the cells of the fat body then, after bursting o ut of them, migrated to the thorax, neck and head58, while the latter believed that fatty cells in the haemocoele surrounded the larvae and fused to form a syncitium 59. Gordon and Crewe studied the mechanism of feeding of C. silacea and C. dimidiata and concluded that they fed from a pool of blood formed in th e deeper layers of the skin as a result of several thrusts of the fascicle, durin g which action the anticoagulant in the insect's saliva prevented clotting. The y showed that the infective larvae escaped from the proboscis during the act of feeding44 then Lavoipierre indicated later that the infective larvae escape d through a rupture in the delicate labio-hypo-pharyngeal membrane 58. Gordon and Crewe also reported that the infective larvae could not penetrate the intact skin, and presumably entered through the wound made by the biting fly. Although Loa loa has never been transferred to humans experimentally , Orihel and Moore in 1975 infected two patas monkeys ( Erythrocebus patas) and a baboon (Papio anubis). They used infective larvae obtained fro m C. silacea that had fed on a patient in the British Cameroons and found a prepatent period of 146 days in the baboon and 135 and 148 days in th e monkeys. Microfilaraemia persisted for more than 40 weeks in the monkeys but began to decline after three months in the baboon 80.

RECOGNITION OF THE CLINICAL FEATURES The most dramatic clinical manifestations of loiasis were attended by th e appearance of a worm in the eye. Sometimes the parasite caused little trouble except perhaps a minor irritation or watering, whereas on other occasions i t produced a severe stabbing pain or overt conjunctivitis 8,62,75. A detailed description was provided in 1895 by Argyll-Robertson who recounted th e symptomatology in a 32 year old English lady who had spent eight years at Old Calabar in Nigeria on the West Coast of Africa. She told him that: the worm frequented both eyes, but showed a preference for the left one, sometimes coursing over the surface of the eye under the conjunctiva, sometimes wriggling under the skin of the eyelids - causing a tickling, irritating sensation but not real

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pain, occasionally causing the eye to become bloodshot, and the eyelids to swell and blacken slightly.5

Furthermore, the patient noticed that she was troubled much more when sh e was febrile (from malaria) or remained indoors in a warm room or sat near a fire, and that the worm seemed to disappear to the deeper parts when her face was exposed to the cold. Finally, Argyll -Robertson was able to observe a worm in the eye after the application of a warm cloth to her orbit: I observed the worm moving in a tortuous, wriggling manner under the conjunctiva, the surface of which became slightly elevated as it moved along. It passed with a pretty quick movement over the surface of the sclerotic at the distance of about 5mm from the outer margin of the cornea. There was increased lachrymation and slightly increased injection of the conjunctiva.5

Argyll-Robertson also drew attention to the other characteristic feature of loiasis which came to be known as "fugitive swellings" or "Calabar swellings". He remarked that his patient complained of: ill-defined swellings under the skin of the forearm a little above the wrists, over the dorsal surface of the radius, more marked generally in the right arm. The surface of the swellings was not quite uniform, but did not give one the idea of being produced by a coiled-up worm. The swellings measured about half an inch in diameter. They were not painful, but occasioned a feeling of stiffness....The swellings occurred at irregular intervals.5

Moreover, his patient told him that the natives of Calabar and others who had been resident there for some time were also subject to these swellings on the forearms and wrists; they were termed " ndi tot" meaning "swelling" by the local populace5. The pathogenesis of these lesions was a matter of considerable debate . Argyll-Robertson managed to extract an adult Loa from deep within the tissues of a similar swelling in the temple of a patient 5. Manson (1910) thought i t unlikely that the mere presence and movement of worms caused these lesions for he cited a patient whose blood was teeming with microfilaria loa and who amused himself by harpooning adult worms with a needle as they wriggled their way under the skin of his chest or abdomen, yet who rarely suffered fro m Calabar swellings. Manson postulated that the oedema might be caused b y lymphatic obstruction, the secretion of irritating glandular products, th e excretion of faecal material by the worm, or the periodical emptying of th e contents of the uterus of a gravid female worm into the connective tissues of the host. Of these various hypotheses, he favoured the last, and supported thi s thesis by instancing his discovery of microfilariae in an aspirate of one of these lesions70. This could not be confirmed by Low, however; he aspirated swellings of two patients who, in contrast to Manson's case, did not have a microfil araemia, and failed to find any embryos; he thought it more likely that th e lesions were due to a toxic reaction to the worms, possibly dead ones 65. Less definite were the suggestions of an association between Loa infection and cerebral disease. The patient in whom Manson first observed the micro filariae died of sleeping sickness and the second patient was insane, so Manson

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canvassed the possibility that the two conditions were connected 68. Later authors12,87 described a variety of neurological problems in patients with Loa infections, but these turned out to be coincidental, while trypanosomes wer e shown to be the cause of sleeping sickness. Other conditions which have been associated with loiasis include endomyocardial fibrosis 52 and nephrotic syndrome93. Several reports have been given by physicians of their own, personal , naturally-acquired infections. Rogers described fugitive swellings, especially around the joints, which were painless yet occasioned stiffness, and recounted the migratory habits of the adult worm 82. Similarly, Johnstone recorded his own experiences: I first noted the gradual onset of a swelling above the right wrist. This was pronounced to be a sprain, but the swelling gradually spread to involve the whole of the right hand, and writing for more than a few minutes caused cramp....playing any games which involved holding a handle was impossible. At this stage, and lasting about ten days, a severe neuralgia in the distribution of the right median nerve came on every night and at no time....did I manage to sleep more than 20 minutes at a time....The swelling of the wrists and hand persisted for at least 6-8 weeks. Within a few weeks of the appearance of the first swelling, a regular crop of swellings kept coming and going. In one week....I had 16 swellings, 3 coming on in one day. At times they were irritating and the overlying skin red; at other times they appeared to be situated more deeply, causing an ache which usually felt like a bruise and lasted 24 hours. By far the greatest number developed on the forearms, but few parts of my body have so far escaped.54

Johnstone then went on to recount the removal of an adult worm from his eye on four separate occasions 54. It was noted that the natural history of this infection may occupy man y years. A number of months usually passed after exposure before the first sign of infection appeared. Meinhof reported the case of a female German missionary who went to the German Cameroons in 1903 and developed Calaba r swellings two years later. These recurred, together with headaches, for another six years until an adult Loa was first seen 74. On the other hand, Dyce Shar p demonstrated that clinical manifestations (Calabar swellings) could appea r soon after exposure, for he recounted a case in which such problems began 61 days after the earliest conceivabl e date of infection and one week after the most probable infective date 34. The adult worms may be very long-lived fo r instances have been recorded in which adult worms have persisted for at least 17 years73,95.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of loiasis is obvious when a worm is seen moving around th e subconjunctival tissues of the eye. Neverthel ess, there have been countless tales of sceptical but ill-informed doctors who found the story that their patient told

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them too incredible. An alternative method of diagnosis was apparent whe n Manson and Mackenzie discovered microfilaria loa and means were evolved for differentiating them from other filarial parasites, as has already bee n discussed. The chances of making the diagnosis in this way were improved by various concentration techniques. The methods used in W. bancrofti infections were equally efficacious in loiasis, and are discussed in chapter 23. It needs to be remarked, however, that the first concentration technique was applied i n cases of loiasis and filariasis by Smith and Rivas. They reported in 1914 that the diagnosis could be enhanced by mixing 0.1-1.0 ml of blood in 5 ml of 2% acetic acid, shaking and centrifuging the mixture, then finding microfilariae in the sediment87. Rarely, Loa microfilariae have been recovered from urine , sputum and cerebrospinal fluid 53. It was realized gradually, however, that many patients with a history o f eyeworm had no microfilaraemia and, vice versa, that many patients with Loa microfilaraemia had no such history. Worse, many patients with Calaba r swellings had neither evidence of an adult worm nor the presence of micro filariae in the bloodstream. Although these lesions were very puzzling initially (even Rogers, a doctor with experience himself in the endemic area, wa s misdiagnosed in 1907), clinicians began to recognize them as characteristic, if not pathognomonic, of Loa infection, and realized that parasitological con firmation of the diagnosis was likely if the patient was followed for lon g enough. In such circumstances, reliance had to be placed upon pointers t o infection with Loa loa. Eosinophilia was a characteristic finding 74 but although it tended to be higher than in other helminthiases, was too non-specific to be diagnostic. Slightly more specific were immunoassays. Fairley 35 and Rodhain and Dubois81 showed that intradermal injection of Dirofilaria antigen produced an immediate hypersensitivity reaction in patients with loiasis, but noted that this test did not differentiate among the various filariases; immunologica l reactions to Dirofilaria have also been seen, for example, in Mansonella perstans 85 and Wuchereria bancrofti 13 infections.

THE SEARCH FOR EFFECTIVE TREATMENT The management of loiasis is essentially s urgical when the opportunity presents itself. The French naval surgeons, Mongin and Bajon, were among the firs t Europeans to report surgical extraction of the parasite, although witch-doctors and their kin had been performing suc h procedures for centuries. Mongin made it appear simple, merely remarking: "In order to remove it, I opened th e conjunctiva and extracted the worm through that incision" 75. Bajon was more expansive in detailing the problems he encountered: After reflecting upon the ways in which I could extract it, I believed that by making a small opening in the conjunctiva near the side of the head of the small animal, then after stimulating it to move, it would come out by itself. I put this plan to

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action, but instead of coming out through the aperture I had made, it passed to the side and went to the region opposite the incision. Seeing that this tentative method was not of any use, I grabbed hold of it at the middle of its body with small forceps as well as the conjunctiva; I then made a small hole at the side of its body with the point of a lancet, and with an ordinary needle, I pulled it out; after this operation, the negress was well within 24 hours.8

A century later, when local anaesthesia was available, Argyll-Robertso n recounted his technique: I at once placed my finger on the surface of the globe in such a manner as to prevent the parasite passing backwards until the conjunctiva was pretty well anaesthetised by the application of cocaine. I then got my friend Dr. Maddox, who was present, to apply his finger while the necessary preparations were hastily made for an operation. She was placed on a couch and the speculum applied, when the pressure of the finger having been removed the wriggling movements of the worm resumed, as briskly as before application of the cocaine. I now grasped with a pair of toothed fixing forceps a good fold of conjunctiva over the centre of the wriggling worm, taking care to include in the fold all the structures superficial to the sclerotic. I next made with a pair of scissors an incision through the conjunctiva a little nearer the cornea, in such a manner as to lift up a small flap of conjunctiva, and after a little careful separation of the tissues, found one extremity of the worm, which I seized with a pair of iris forceps. On now relaxing the fixing forceps, the parasite came away readily.5

In the following year, Roth told of his unfortunate experiences. He tried many times to remove a worm from the eye of a 15 year old girl, but never succeeded in catching the elusive creature. The same sequence befell his next tw o patients, and he remarked rather optimistically that they had probably bee n cured by his application of cocaine 83. Roth noted in passing that it was a common practice amongst the local inha bitants to treat the infection by packing small pieces of onions around the eye; this was said to either retain the worm on the sclera where it could be picked off with a needle, or drive it away (and he postulated that it passed through the nasal duct and was then eithe r swallowed or spat out!). A number of drugs were tried in loiasis. Aubert and Heckenroth (1913 ) investigated the actions of aniline, vari ous arsenicals and tartar emetic in loiasis but found them to be useless7. Although most authors agreed that there was no effective drug for the medical treatment of this infection, evanescent claim s were made for salvarsan (arsenic) 76, anthiomaline (antimony) 17 and picric acid77. In 1947, diethylcarbamazine was introduced for the treatment of bancroftian filariasis (see chapter 23), then this drug was soon tried in loiasis. A number of investigators reported clinical improvement in many but not all patients with loiasis79,86,88,90. Some patients developed an itchy morbilliform or urticarial rash after treatment (possibly due to concurrent occult infection with Onchocerca). Most of these patients had no Loa microfilaraemia. In Murgatroyd and Woodruff's series, for example, only three of the 17 patients had microfilariae in the bloodstream, and no mention was made of the longterm effects of the drugs on

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the microfilaraemia 79. Woodruff later reported the liver biopsy finding in a patient in whom diethylcarbamazine treatment had caused the parasites t o disappear from the peripheral blood; microfilariae in the biopsy wer e surrounded by phagocytes, thus suggesting that the action of the drug was t o sensitize the microfilariae which were then destroyed by the cells of th e reticulo-endothelial system 94. Subsequent experience has shown that although this drug may be useful in patients with loiasis, it cannot be relied upon t o eradicate the infection.

UNDERSTANDING THE EPIDEMIOLOGY Although cases of loiasis were described initially from both Africa and fro m South America, its universal occurrence in black slaves in the latter area and its spontaneous disappearance from that regi on indicated that Loa infection was endemic only in parts of West and Central Africa. The factors influencing the distribution and intensity of infection could b e ascertained only when the central role of Chrysops flies in the transmission of infection had been ascertained . Sporadic attempts were made over the next few decades to both define th e prevalence and severity of disease in infected populations, and to study th e habits of the vectors, but the most intensive efforts were made during the late 1940's and the 1950's. Gordon and his colleagues reported their investigations in a town in th e British Cameroons in which a quarter of the population were infected . C. siliacea and C. dimidiata were both found, though the former was muc h more common. They observed that the female flies bit once every two weeks or so, usually between the hours of 8.30 a.m. and 4.30 p.m., were found indoors as well as outdoors, hunted probably by sight, preferring the well-lighte d houses of Europeans to the d ark houses of the Africans, and had infection rates of up to 12%. Chrysops larvae were found in densely-shaded streams, localized in the stagnant parts and in mud beneath decaying vegetation 43,45. It became clear that infection was limited chiefly to the rain forest or its immediat e environs56 with the adult flies occupying the canopy of the forest. Furthermore, monkeys in those forests were infected with a strain of Loa loa which, although it had certain morphological differences and had nocturnal periodicity, wa s possibly transmissible to man 27,42. Duke then showed that smoke from woo d fires increased greatly the biting rate and may be an important factor i n attracting flies from the forest to feed in houses28, and also suggested that the flies were attracted by movement 29.

655

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THE DEVELOPMENT MEASURES

OF

PREVENTIVE

AND

CONTRO L

Attempts to control loiasis became feasible with discovery of the tabani d vector, but such measures have not proved very satisfactory. Persona l prophylaxis is dependent upon wearing long-sleeved and long-legged clothes and the use of insect repellents to inhibit biting when outdoors, as well as the screening of houses to prevent biting indoors. Control of the vector itself i s usually impractical although clearing of vegetation to eliminate resting places for adult flies and canalization of streams to enhance the free flow of water or the use of insecticides in streams to reduce breeding larvae have bee n advocated43,92. Control by mass treatment with diethylcarbamazine to reduc e microfilaraemia and repeated prophylactic administration of the drug have been proposed32. This latter idea was suggested by the demonstration by Duke i n monkeys30 and in humans 31 that diethylcarbamazine appeared to kill infective larvae. The main difficulty wi th these approaches, however, has been to ensure the cooperation of the population. This has proved almost impossible in areas where concurrent onchocerciasis increased greatly the incidence and severity of toxic reactions to the drug.

REFERENCES 1. AITKEN W. Parasitic diseases. In, Science and practice of medicine, London, volume 1, pp 799-900, 1866 2. ANNETT HE, DUTTON JE, ELLIOT JH. Report of the malaria expedition to Nigeria of the Liverpool School of Tropical M edicine and Medical Parasitology. Part II. Filariasis. Thompson Yates Laboratory Reports, volume 4, 1901. Abstracted in Journal of Tropical Medicine and Hygiene 5: 111-112, 1902 3. ANONYMOUS. Filaria loa. British Medical Journal i: 39-40, 1913 4. ANONYMOUS. Filaria loa and its insect host. Lancet i: 606, 1921 5. ARGYLL-ROBERTSON DM. Case of Filaria loa in which the parasite was remove d from under the conjunctiva. Transactions of the Ophthalmological Society of the United Kingdom 15: 137-167, 1895 6. ARGYLL-ROBERTSON DM. Note of the further history of the case of Filaria loa previously reported to the Society. Transactions of the Ophthalmological Society of the United Kingdom 17: 227-232, 1897 7. AUBERT P, HECKENROTH F. Action de divers médicaments sur les Microfilari a perstans et diurna. Bulletins de la Société de Pathologie Exotique et de ses Filiales 6 : 457-459, 1913 8. BAJON B. Mémoires pour servir à l'histoire de Cayenne et de la Guyane française etc., Paris, two volumes, pp 878, 1777-1778. Partly translated by DI Grove 9. BLANCHARD R. La filaire sous-conjonctivale ( Filaria loa Guyot). Progrès Médical , Paris, series 2, 4: 591-593, 611-612, 1886 10. BLOT. Cited in 47 11. BRUMPT EJ. La Filaria loa Guyot est la forme adulte de la microfilaire désignée sous le nom de Filaria diurna Manson. Comptes Rendus Hebdomadaires de la Société d e Biologie 56: 630-632, 1904

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12. BRUNETIERE. La filaire de l'oeil (Filaria loa) peut-elle déterminer des complications cérébrales? Gazette Hebdomadaire des Sci ences Médicale de Bordeaux 34: 351-353, 1913 13. BRUYNOGHE G. Recherches sur les propriétés antigeniques des microfilaires d e Dirofilaria immitis. Annales de la Société Belge de Médecine Tropicale 19: 335-353 . 1939 14. de BRY D, de BRY J. India orientalis, two volumes, Frankfurt, 1597-1598 15. BURROWS D. The relationship of microfilaria diurna to Filaria loa. Journal of Tropical Medicine and Hygiene 13: 49-50, 1910 16. CASTELLANI A, CHALMERS AJ. Manual of tropical medicine, second edition . Bailliere, Tindall and Cox, London, pp 1747, 1913 17. de CHOISY H. Observation d'un cas de microfilariose Loa traité par l'antimonio-thiomalate de lithium. Revue de Médecine et Hygiene Tropicale 29: 294-296, 1937 18. CLOT A. Dragonneau. Archives Générales de Médecine 30: 573, 1832 19. COBBOLD TS. An introduction to the study of helminthology with reference, mor e particularly, to the internal parasites of man, Groombridge and Sons, London, pp 480 , 1864 20. COCKIN RP. Commentary on 57. Tropical Diseases Bulletin 7: 362, 1916 21. CONNAL A. Observations on filaria in Chrysops from West Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 14: 108-109, 1921 22. CONNAL A, CONNAL SL. A preliminary note on the development of Loa loa (Guyot) in Chrysops silacea (Austen). Transactions of the Royal Society of Tropical Medicine and Hygiene 15: 131-134, 1921 23. CONNAL A, CONNAL SL. The development of Loa loa (Guyot) in Chrysops silacea (Austen) and in Chrysops dimidiata (Van der Wulp). Transactions of the Royal Society of Tropical Medicine and Hygiene 16: 64-89, 1922 24. CONNAL A, CONNAL S L. (The development of Loa loa [Guyot] in Chrysops silacea [Austen] and in Chrysops dimidiata [Van der Wulp].) Correspondence. Transactions of the Royal Society of Tropical Medicine and Hygiene 16: 437, 1923 25. DUBINI A. Entozoografia umana per servire di complemento agli studii di anatomi a patologia etc. Annali Universali di Medicina gia Compilati dai Dottore Annibale Omodei, Milano, 35: 502-578, 1850 26. DUJARDIN F. Histoire naturelle des helminthes ou vers intestinaux, Librairi e Encyclopédique de Roret, Paris, pp 652, 1845 27. DUKE BO. The development of Loa in flies of the genus Chrysops and the probable significance of the different species in the transmission of loiasis. Transactions of th e Royal Society of Tropical Medicine and Hygiene 49: 115-121, 1955 28. DUKE BO. Studies on the biting habits of Chrysops. II. The effect of wood fires on the biting density of Chrysops silacea in the rain-forest at Kumba, British Cameroons. Annals of Tropical Medicine and Parasitology 49: 260-272, 1955 29. DUKE BO. Studies on the biting habits of Chrysops. III. The effect of groups of persons, stationary and moving, on the biting density of Chrysops silacea at ground level in the rain-forest at Kumba, British Cameroons. Annals of Tropical Medicine and Parasitology 49: 362-367, 1955 30. DUKE BO. Studies on the chemoprophylaxis of loiasis. I. Experiments on monkeys with special reference to diethylcarbamazine (Banocide). Annals of Tropical Medicine an d Parasitology 55: 447-451, 1961 31. DUKE BO. Studies on the chemoprophylaxis of loiasis. II. Observations o n diethylcarbamazine citrate (Banocide) as a prophylactic in man. Annals of Tropica l Medicine and Parasitology 57: 82-96, 1963 32. DUKE BO, MOORE PH. A trial of Banocide as a means of controlling the transmission of loiasis on a rubber estate in Nigeria. Annals of Tropical Medicine and Parasitology 55: 263-277, 1961 33. DYCE SHARP N A. Filaria bancrofti and Loa loa. A note on some methods o f

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34. 35. 36.

37. 38. 39. 40.

41. 42.

43.

44.

45.

46. 47.

48.

49.

50. 51. 52. 53.

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differentiation of their embryos. Transactions of the Royal Society of Tropical Medicine and Hygiene 17: 177-191, 1923 DYCE SHARP N A. Loa loa infections. A case with rapid onset of symptoms. Lancet ii: 765-766, 1929 FAIRLEY NH. Serological and intradermal tests in filariasis. A preliminary report . Transactions of the Royal Society of Tropical Medicine and Hygiene 24: 635-648, 1931 FOLEY H. Études morphologiques sur les microfilaires à Gaine (Mf. bancrofti et Mf. diurna). Observations faites chez les tirailleurs Sénégalais d'Algérie. Annales de l'Institut Pasteur 27: 50-68, 1913 FÜLLEBORN F. Untersuchu ngen über Filarien. Archiv für Schiffs- und Tropen-Hygiene 16: 439-440, 1912 FÜLLEBORN F. Beiträge zur Biologie der Filarien. Centralblatt für Bacteriologie , Parasitenkunde und Infektionskrankheiten, Abteilung originale 66: 255-267, 1912 FÜLLEBORN F. Beiträge zur Morphologie und Differentialdiagnose der Microfilarien. Archiv für Schiffs- und Tropen-Hygiene 17: 7-72, 1913 GERVAIS P, van BENEDEN PJ. Zoologie médicale. Exposé méthodique du règn e animal, basé sur l'anatomie, l'embryogénie, et la paléontologie; comprenant la description des espèces employées en médecine, de celles quie sont vermineuses et de celles qui sont parasites de l'homme et des animaux, Paris, two volumes, pp 959, 1859 GÖNNERT R. Zur Lebensdauer omenschlicher Mikrofilarien. Zentralblatt fü r Bakteriologie 149: 75-81, 1942 GORDON RM. A brief review of recent advances in our knowledge of loiasis and o f some of the still outstanding problems. Transactions of the Royal Society of Tropica l Medicine and Hygiene 49: 98-105, 1955 GORDON RM. CHWATT LJ, JONES CM. The results of a preliminary entomological survey of loiasis at Kumba, Britis h Cameroons, together with a description of the breeding places of the vector and suggestions for future research and possible methods of control. Annals of Tropical Medicine and Parasitology 42: 364-376, 1948 GORDON RM, CREWE W. The deposition of the infective stage of Loa loa by Chrysops silacea, and the early stages of its migration to the deeper tissues of the mammalian host. Annals of Tropical Medicine and Parasitology 47: 74-85, 1953 GORDON RM, KERSHAW WE, CREWE W, OLDROYD H. The problem of loiasis in West Africa with special reference to recent investigations at Kumba in the Britis h Cameroons and at Sapele in southern Nigeria. Transactions of the Royal Society o f Tropical Medicine and Hygiene 44: 11-41, 1950 GRUNTZIG J, JENNES B. Historical note on Loa loa: a reinterpretation. America n Journal of Tropical Medicine and Hygiene 26: 679-683, 1977 GUYON. Note sur des vers observés entre la sclérotique et la conjonctive, chez un e négresse de Guinée, habitant l a Martinique. Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences 7: 755-756, 1838 GUYON. Sur un nouveau cas de filaire sous-conjonctival, ou Filaria oculi des auteurs observé au Gabon (côte occidentale d'Afrique). Comptes Rendus Hebdomadaires de s Séances de l'Académie des Sciences 59: 743-748, 1864 GUYOT. Ophthalmie produite par des vers dans les yeux à la côte d'Angole. Abstracted in J N Arrachart's Mémoires, Dissertations et Observations de Chirurgie, Paris, p p 228-233, 1805. (Originally presented to the Academy of Surgery in Paris in 1778) HUFFMAN OV. The embryos of Filaria loa. Parasitology 4: 75-82, 1911 HUFFMAN OV, WHERRY B. A description of four Filaria loa from the same patient. Parasitology 4: 7-18, 1911 IVE FA, WILLIS AJ, IKEME AC, BROCKINGTON IF. Endomyocardial fibrosis and filariasis. Quarterly Journal of Medicine 36: 495-516, 1967 JANSSENS PG, van BOGAERT L, TVERDY G, WANSON M. Réflexions sur le sort des microfilaires de Loa loa l'organisme humain parasite. Manifestations viscérale s provoquées par leur infiltration dans les tissus. Bulletin de la Société de Pathologi e

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Exotique 51: 632-645, 1958 54. JOHNSTONE RD. Loiasis. Lancet i: 250-252, 1947 55. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, pp 677, 1978 56. KERSHAW WE, KEAY RW, NICHOLAS WL, ZAHRA A. Studies on th e epidemiology of Loa loa and Acanthocheilonema perstans in West Africa, with special reference to the British Cameroons and the Niger Delta. Annals of Tropical Medicine and Parasitology 47: 406-425, 1953 57. KLEINE FK. Die Uebertragung vo n Filarien durch Chrysops. Zeitschrift für Hygiene und Infektionskrankheiten 80: 345-349, 1915 58. LAVOIPIERRE MM. Studies on the host-parasite relationships of filarial nematodes and their arthropod hosts. I. The sites of devel opment and the migration of Loa loa in Chrysops silacea, the escape of the infective forms from the head of the fly, and the effect of th e worm on its insect host. Ann als of Tropical Medicine and Parasitology 52: 103-121, 1958 59. LEBIED B. Iconographie de l'évolution intrasyncitiale de Loa loa chez Chrysops. (Note préliminaires sur les facteurs, interne et externe, déterminants du cycle évolutif de s Filariata (Scrjabin) chez leurs hôtes intermédaires. Annales de la Société Belge d e Médecine Tropicale 37: 641-645, 1957 60. LEIPER RT. Report of the helminthologist, London School of Tropical Medicine, for the half-year ending April 30th 1913. Report to the Advisory Committee of the Tropica l Diseases Research Fund, Colonial Office, 1913. Abstracted in Tropical Diseases Bulletin 2: 195-196, 1913 61. LEIPER RT. Cited in 3 62. LONEY W. Extirpation of dracunculi from the eye. Lancet i: 308, 1844 63. LOOSS A. Zur Kenntnis des Baues der Filaria loa Guyot. Zoologischer Jahrbücher . Abteilung für Systematik, Oekologie und Geologie der Tiere, Jena 20: 549-574, 1904 64. LOW GC. Discussion of 70. Transactions of the Royal Society of Tropical Medicine and Hygiene 4: 251-253, 1910 65. LOW GC. The aetiological relationship of Loa loa to Calabar swellings. Journal o f Helminthology 1: 191-192, 1923 66. LOW GC, O'DRISCOLL EJ. Observations upon a case of Filaria (Loa) loa infection. Lancet i: 798-800, 1921 67. MANSON P. The Filaria sanguinis hominis major and minor, two new species of haematozoa. Lancet i: 4-8, 1891 68. MANSON P. The geographical distribution, pathological relations and life history o f Filaria sanguinis hominis diurna and Filaria sanguinis hominis perstans in connexion with preventive medicine. Transactions of the Seventh International Congress on Hygiene and Demography, London, August 10-17, 1891, 1: 79-97, 1892. Abstracted in Medical Press and Circular 103, new series 52: 202-205, 1891 and Semaine Médecine 11: 342 , 1891 69. MANSON P. Tropical diseases. A manual of the diseases of warm climates, Cassell and Co., London, pp 607, 1898 70. MANSON P. On the nature and origin of Calabar swellings. Transactions of the Society of Tropical Medicine and Hygiene 3: 244-251, 1910 71. MANSON P. Cited in 5 72. MANSON P. Cited in 84 73. MANSON-BAHR P. On the longevity of the Loa loa and some hitherto undescribe d manifestions of this infection. Archiv für Schiffs- und Tropen-Hygiene 29: 222-224, 1925 74. MEINHOF H. Zur Klinik und Morphologie der Filaria und Mikrofilaria loa (diurna) . Archiv für Schiffs- und Tropen-Hygiene 17: 77-130, 1913 75. MONGIN. Sur un ver trouvé sous la conjonctive, à Maribarou, isle Saint-Domingue . Journal de Médecine, Chirurgie, Pharmacie etc. 32: 338-339, 1770. Translated in 55 76. MORLOT, ZUBER. Neosalvarsan et Filaria loa. Comptes Rendus Hebdomadaires des Séances de la Société de Biologie 77: 475-476, 1914

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77. MÜHLENS. Zur Behandlung der Filariasis. Archiv für Schiffs- und Tropen-Hygiene 25: 247-248, 1921 78. MÜLLER OF. Verzeichniss der bisher entdeckten Eingeweidewürmer, der Thiere, i n welchen sie gefunden Worden, und besten Schriften, die derselben erwähnen . Naturforscher, Halle 22: 33-86, 1787 79. MURGATROYD F, WOODRUFF AW. Loiaisis treated with Hetrazan (Banocide) . Lancet ii: 147-149, 1949 80. ORIHEL TC, MOORE PJ. Loa loa: Experimental infection in two species of Africa n primates. American Journal of Tropical Medicine and Hygiene 24: 606-609, 1975 81. RODHAIN J, DUBOIS A. A contribution to the study of intradermal reactions in human filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 25 : 377-382, 1932 82. ROGERS W. A note on a cas e of Loa loa. Annals of Tropical Medicine and Parasitology 7: 363-365, 1913 83. ROTH F. Filaria loa. Lancet i: 764-765, 1896 84. SAMBON LW. Remarks on the individuality of Filaria diurna. Journal of Tropical Medicine and Hygiene 6: 26, 1903 85. SCHOFIELD FD. The complement-fixation reaction in loiasis and Acanthocheilonema perstans infections. Journal of Tropical Medicine and Hygiene 60: 170-172, 1957 86. SHOOKHOFF HB, DWORK KG. Treatment of Loa loa infections with Hetrazan . American Journal of Tropical Medicine 29: 589-593, 1949 87. SMITH AJ, RIVAS D. Notes upon human filariasis ( Filaria loa Guyot, and Filaria bancrofti Cobbold). American Journal of Tropical Diseases and Preventive Medicine 2: 361-377, 1914 88. STEFANOPOULO GJ, SCHNEIDER J. Essais de traitement de la filariose à F. loa par la 1-diéthyl-carbamyl 4-methylpipérazine. Comptes Rendus Hebdomadaires des Séances de l'Académie de Biologie 142: 930-931, 1948 89. STILES CW, HASSALL A. The determination of generic types, and a list of roundworm genera, with their original and type species. Bureau of Animal Industry, United State s Department of Agriculture, Bulletin 79, pp 1-150, 1905 90. WANSON M. Essai de traitement avatif de la filariose à Loa loa et de la filariose apériodique par les dérivés de la pipérazine. Annales de la Société Belge de Médecin e Tropicale 29: 73-80, 1949 91. WARD H B. The earliest record of Filaria loa. Zoologische Annalen 1: 376-384, 1905 92. WILLIAMS P, CREWE W. Studies on the control of vectors of loiasis in West Africa. V. The effects of DDT, dieldrin, aldrin and gamma-BHC in the mud of natural tabani d breeding-sites in the rain-forest of the Cameroons. Annals of Tropical Medicine an d Parasitology 57: 300-306, 1963 93. WILLIS AJ. Adult nephrotic syndrome at Ibadan; aetiological considerations. Journal of Tropical Medicine and Hygiene 71: 513-517, 1968 94. WOODRUFF AW. Destruction of microfilariae of Loa loa in the liver in loiasis treated with Banocide (Hetrazan). Transactions of the Royal Society of Tropical Medicine and Hygiene 44: 479-480, 1951 95. ZIEMANN H. Ein Fall von Filaria-loa-I nfektion mit mindestens 17 jähriger Dauer. Archiv für Schiffs- und Tropen-Hygiene 30: 626-628, 1926

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Table 24.1. Landmarks in loiasis ___________________________________________________________________ BC

Adult worms migrating through the eye were recognized by inhabitants of West and Central Africa and were removed by local practitioners 1768 Bajon removed an adult worm from the eye of a girl 1770 Mongin published an account of the adult worm and the clinical features it caused 1890 McKenzie found unusual microfilariae in the blood of a patient with sleeping sickness 1891 Manson investigated several patients and differentiated a microfilaria of the same size as microfilaria bancrofti but which had diurnal periodicity and ill-defined morphological changes (= microfilaria loa) and a smaller microfilaria with no periodicity (= microfilaria perstans) 1895 Argyll-Robertson in collaboration with Manson gave a detailed description of the morphology of male and female adult worms Manson suggested that microfilaria diurna may be the embryo of L. loa 1912 Leiper discovered that microfilariae developed in flies of the genus Chrysops 1914 Smith and Rivas described a concentration technique for the demonstration of microfilariae in the blood 1921-3 Connal and Connal described in detail the development of larvae in Chrysops 1948 Stefanopoulos and Schneider described the results of treatment with diethylcarbamazine 1975 Orihel and Moore infected two monkeys and a baboon experimentally using infective larvae developed in a fly fed on a human with loiasis __________________________________________________________________

Chapter 25

Onchocerca volvulus and ONCHOCERCIASIS

SYNOPSIS Common name: the convoluted filaria causing river blindness Major synonyms: Filaria volvulus, Filaria volvulxus, Onchocerca caecutiens Distribution: West, Central and East Africa, Central and northern South America Life cycle: the adult worms, 20-50 cm long by 0.15-0.40 mm in diameter, mostly live coiled tightly in subcutaneous nodules. Microfilariae are produced and migrate through the dermis and into the cornea, anterior chamber and uveal tract of the eye. When microfilariae are ingested by blackflies of the genus Simulium, they develop over a week or so into infective larvae which pass to the mouthparts and infect the next host at the following blood meal Definitive host: humans (gorilla, spider monkey) Major clinical features: subcutaneous nodules, dermatitis, keratitis, iridocyclitis, choroidoretinitis, leading to blindness Diagnosis: observation of microfilariae in the cornea or anterior chamber (best with a slit lamp), finding microfilariae on skin biopsy, demonstration of worms in excised nodules Treatment: diethylcarbamazine, ivermectin, suramin

DISCOVERY OF THE MICROFILARIA In 1874, John O'Neill, a British n aval surgeon attached to HMS Decoy at Cape Coast Castle in the Gold Coast (Ghana) became intrigued by an irritating and intractable skin disease somewhat resembling scabies which afflicted man y people living in parts of the West Coast of Afr ica. He determined to look for the cause of this peculiar condition, which was known locally as "craw-craw", by studying a number of patients in Addah Fort Hospital under the care of D r Thompson of the Glover Expedition. The condition was characterized b y papules, vesicles and pustules. O'Neill examined the contents of pustules and vesicles under a microscope but found nothing other than leucocytes. When he turned his attention to papules, success attended his efforts for he found a n organism which he had no doubt was the cause of the complaint. He reported in 1875: I was induced to bestow much time on its microscopic examination, and succeeded at length in discovering a filaria which I believe to be the immediate cause of the complaint.102

When specimens were examined in a drop of water under a microscope , microfilariae that were easily detectable by virtue of their violent contortions 661

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were often seen: Thread-like in form, at one time undulating, and now twisted as if into an inexplicable knot, then, having rapidly untwined itself, it curls up into many loops.... measuring it now we find its length about 1/100 inch, and its breadth about 1/2000 inch, and with the exception of the abruptly pointed tail the filaria is of nearly equal breadth throughout its entire length. At the head, or blunted extremity, two small dots are noticed, but their nature could not be determined. 102

It is possible that the same parasites were also seen in 1875 by Dr da Silva Araujo in a negro in Bahia, Brazil. This patient had been troubled wit h recurrent attacks of a skin complaint, also labelled "craw-craw". This term, of course, was imprecise and does not necessarily indicate the same affliction as that described by O'Neill. Nevertheless, da Silva Araujo recovered from th e skin of this patient microfilariae which he named Filaria dermathemica 129. Whether the microfilariae found by da Silva Araujo were in fact O. volvulus or blood-borne embryos of another species which had contaminated the ski n biospsies is uncertain; if they were, then a case could be made for designating the worm now known as Onchocerca volvulus as Onchocerca dermathemica .

DISCOVERY OF THE ADULT WORM The discovery and publication of the finding of the adult O. volvulus was a strange and tortuous affair. It 1890, an unnamed German doctor working in the Gold Coast (Ghana), West Africa, removed two tumours, each about the size of a pigeon's eggs, one from the scalp and the other from the chest, from two of the local inhabitants. On examining the specimens, he found that the y contained worms and sent them to Rudolf Leuckart in Germany for identification. Both tumours contained several female and male worms, the forme r being about 6-70 mm in length and the latter about half that size; they wer e coiled together to form a ball which was very difficult to unravel. This mass of worms was situated in a cavity which contained fluid laden with embryos . Leuckart did not publish news of this discovery, but informed Patrick Manson in a personal communication 82. It was left to Manson to publish a skimpy notice of the parasite, with due to acknowledgem ent to Leuckart, in a chapter he wrote on skin diseases in the tropics for Davidson's book Hygiene and disease o f warm climates89. The section on this parasite was labelled Filaria volvulxus, the latter apparently being a mistranscription of "volvulus" (from the Lati n "volvo volvere" = to roll or turn round ); whether this was Leuckart's or Manson designation was not indicated in the text, but was presumably intended to draw attention to the twisted and coiled intertwining of the worms. Leuckart had also sent Manson an histological section containing a fragment of the uterus of one of the worms. Manson remarked: It was stuffed with outstretched embryos, resembling in shape and dimensions F. diurna and F. nocturna. Possibly, compared to these parasites, the embryo of

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F. volvulxus was somewhat shorter, and also somewhat broader proportionately, and more abruptly truncated at the cephalic end....One important feature of F. diurna and F. nocturna I did not see represented in the embryo of F. volvulxus, viz., the sheath. Professor Leuckart makes the same remark. 89

On the basis of the absence of a sheath, Manson concluded that these worms were not the parental forms of microfilaria diurna (i.e. loa), and were certainly not the mature W. bancrofti. He made no mention of the micro-filaria e discovered in skin by O'Neill nearly 20 years earlier, and may well have been unaware of the report. Somewhat wistfully, he concluded: beyond the facts just stated, we possess very little information on the subject. Observations on this and allied matters are very much wanted. From the numerous discoveries, notwithstanding very limited opportunities, made in recent years in African pathology and helminthology, it is evident that many novelties await the investigator of diseases in that country.89

Six years later (1899), Labadie-Lagrave and Deguy described a youn g female worm found in a nodule removed from a French soldier who had been on an expedition to Dahomey in West Africa; they called the parasite F. volvulus 78. In 1901 Prout described the worms recovered from tumour s removed from two frontier policemen by Dr Hood, District Surgeon in Sierra Leone. Prout examined the blood and aspirates from a lymph node of th e second of these patients, but was unable to find any microfilariae. Concerning the tumour, he wrote: The tumour was about 1 in. in length by about 3/4 in. in breadth. On making an incision, a greenish, semipurulent-looking fluid about the consistency of cream escaped from the cyst. This, on microscopical examination, was found to contain numerous filarial embryos. The capsule of the cyst consisted of dense fibrous tissue, lined internally by a layer of soft, caseous-looking material, which could be easily scraped off. This was composed of granular material, flat nucleated epithelial cells, and contained free embryos. The interior of the cyst was filled with adult filariae, lying in loops twisted up in the most confusing fashion, entering the cyst wall, running along shallow tunnels, and re-entering the cyst. Owing to this and the softness and brittleness of the worm, it was a matter of the greatest difficulty to dissect it out, and I found it impossible to do so without breaking it. Eventually, however, I succeeded in isolating a complete unbroken adult male, and the head, tail and intermediate fragments of a female. These two worms formed the whole contents of the cyst.108

Prout then went on to give the first detailed description of the male and female adult worms, and described t he microfilariae. Further examples of onchocercal infection with recovery of adult worms were reported by Brumpt (1904) 25, Fülleborn (1908) 52 and Parsons (1908) 107. Parsons had in fact seen five patients and wrote: very little was known or taught of this particular nematode when (in 1903)....I became a government official in Northern Nigeria. While other members of the Filaridae have received a good deal of attention during the present decade, Filaria volvulus seems to have been comparatively ignored. I am inclined to think, however, that this Filaria is far more common in certain parts of Africa than is generally

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supposed.107

In 1910, Railliet and Henry111 transferred the worm from the genus Filaria of Müller98 to the genus Onchocerca which had been erected by Diesing i n 1841 to house O. reticulata, a parasite of the horse, donkey and mule i n Europe42. The name Onchocerca was derived from a combination of the Greek words (ONCHOS) meaning "hook" and (KERKOS, CERCOS) meaning "tail". In 1916, Rodolfo Robles in Guatemala removed a tumour from the forehead of a boy and on opening it found that it contained: a fine worm, white and ball-shaped, with the characteristics of a filaria....The dissection of the parasite was extremely difficult because it seemed to be sewn into the tumor itself. Extremely fragile, it broke at the slightest pull. However, after a laborious effort, I extracted a whole piece that measured almost 30 cm (sic)....The thick cuticle and the very obvious transverse striations made me think it was of the genus Onchocerca; however, not having the head, the tail, or a male, I was unable to identify the parasite fully.114

Subsequently, Robles removed other cysts and obtained isolated worms b y digesting them in a dog's stomach for five hours. Although he thought that the worm resembled O. volvulus, he thought that some characteristics did no t coincide exactly. His discovery was first reported in a newspaper, La Republica, on 29 December 1916, then the formal description appeared in La Juventud Médica in 1917114. Most of the copies of the issue were destroyed in an earthquake, but the article was republished in French in 1919 115. In an accompanying article, Brumpt gave a detailed description of the parasite, and after comparing it with the specimens collected by him in the Congo, decided that it was a different species which h e named O. caecutiens to indicate that the parasite caused blindness (from the Latin "caecus" = blind) 26. Calderón 34 concurred with this opinion. Fülleborn believed that O. volvulus and O. caecutiens were morphologically indistinguishable, but considered that there were differences in the clinical manifestations caused by the two parasites 54,55. Subsequent studies by Sandground 125 in which more material was examined, however, showed that there were considerable variations among the specimens and that no consistent differences existed between the American and African forms of the worm. An editorial in the British Medical Journal in 1935 describing the latter's work, undertaken as part of the Harvard Department of Tropical Medicine expedition to Guatemala, accepted this opinion: Another important result of the expedition has been the final decision, after careful examination of numerous adult filariae removed from the tumours, that the Central American form does not differ in any way from the long-known type from the old world, a conclusion which means that the name O. caecutiens is merely a synomym of O. volvulus.3

CORRELATION OF O'NEILL'S MICROFILARIA WITH THE ADULT

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O. VOLVULUS AND ONCHOCERCAL DERMATITIS When O'Neill in 1875 first described microfilariae in the skin of patients with craw-craw, the microfilariae of Wuchereria bancrofti had been discovered only 13 years before, Lewis had de monstrated their presence in the blood only three years earlier, and the parent worm of microfilaria bancrofti was still unknown. Furthermore, none of the other microfilariae which may be found in human s (Loa loa, Mansonella perstans etc.) had at that time been discovered. Th e microscopical facilities and staining techniques available during that perio d were not advanced sufficiently to permit a detailed description of th e morphology of these parasites. The major difference between the microfilaria described by O'Neill and that found by Lewis was the presence of a sheath in the latter's case. O'Neill's omi ssion of any mention of the absence of this sheath in the skin microfilariae that he saw 102 implies that he had not seen Lewis' s paper and may well have bee n unaware of it. This is not particularly surprising since he was a naval surgeon on the high seas and away from current librar y facilities. Leuckart and Manson 89 were the first to recognize this characteristic absence of a sheath in O. volvulus microfilariae, but failed to speculate on the relationship between O. volvulus and the parasite described by O'Neill. Many years were to pass before such a relationship was established definitely. When Prout described the morphology of adult O. volvulus in 1901, he also compared in tabular form the salient diagnostic features of microfilaria diurna (= loa), microfilaria nocturna (= bancrofti), microfilaria perstans and the Onchocerca microfilaria; he showed that they were all distinct from each other in one respect or another 108. Like Manson, however, Prout did not relate these worms to the microfilariae of craw-craw that had been described by O'Neill. In 1913, Ouzilleau reported that in the re gion of Mbomu, French Equatorial Africa, O. volvulus infections were very common (as were Loa loa and Mansonella perstans, but Wuchereria bancrofti was absent). This provided an opportunity for examining a large number of patients with onchocerciasis . Ouzilleau confirmed Prout's observation that microfilariae were not present in the blood; he found a microfilaria similar to those aspirated from a n onchocercal cyst only once in 200 blood examinations, but did find them o n many occasions in lymph node aspirates 103. This finding was criticized by Low who felt that they must have been W. bancrofti microfilariae 83, but Ouzilleau was supported later that year by Fülleborn and Simon56. Simon had found large, unsheathed microfilariae in the inguinal lymph nodes and in the blood of a patient with large onchocercal nodules on the superior iliac spine. He believed that they might be microfilariae of O. volvulus so submitted them to Fülleborn who could discern no differences between them and those prepared from O. volvulus adult worms. This observation was confirmed when Simon the n obtained lymph nodes from another patient with onchocerciasis who wa s operated upon for a femoral hernia. Careful measurements of the size an d

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location of various landmarks on the microfilariae proved conclusively that the microfilariae from the lymph nodes and from O. volvulus were identical, and were different from those of W. bancrofti and Loa loa. Finally, Simon also showed that although the blood contained no microfilariae, O. volvulus-type microfilariae could be obtained in blood specimens if excessive pressure was applied to the skin, perhaps squeezing them out in the lymph. Thes e observations satisfied Low who now wrote: it is at once seen that the embryos found in the lymph glands and blood of the native infected with volvulus cysts correspond with - or one might say, are the same as the real embryos of O. volvulus.84

Ouzilleau's views were again confirmed in 1916 by Rodhain and van de n Branden in Leopoldville, Belgian Congo (Zaire) and by Dubois in the Well e (Uele) district of the same country, by Robles in Guatemala, and later b y Montpellier and colleagues 97. Despite repeated and intensive investigations , including the use of concentrating techniques, Rodhain and van den Branden failed to find any microfilariae in the blood of 29 patients with clinica l onchocerciasis yet were able to find microfilariae in 11 of 28 patients after the single puncture of a femoral or inguina l lymph node 119. Similarly, Dubois wrote that microfilaria volvulus was present in inguinal lymph nodes and stated that he had never succeeded in finding them in the blood 43 and Robles in Guatemala only once observed an infection when he pricked skin near a nodule 114. Nevertheless, it was still not realized that these microfilariae were also found commonly in the integument and were the same as O'Neill's parasites. Montpellier and Lacroix in 1920 were first to put forward this view. They reported that many native troops from Africa complained of a skin affection or itch which was most marked on the buttocks, flanks and lumbar regions, and was associated with inguinal lymp hadenopathy and an eosinophilia. Systematic examination of these lesions resulted in the discovery of the constant presence of microfilariae in the dermal layer of the skin, independent of the vascula r system. Montpellier and Lacroix considered the microfilariae to be embryos of O. volvulus or a very closely related species. Further investigation, moreover, revealed the presence of fibrous cysts in some patients, one of which upo n excision yielded a male and female O. volvulus. These investigators regarded the condition as identical with the craw-craw described by O'Neill in 1875 and concluded that this condition, which they called gale filarienne (filarial itch) , was a dermal manifestation of onchocerciasis 95. At the conclusion of their paper which they presented to La Société d e Pathologie Exotique in France, however, Brumpt challenged Montpellier and Lacroix's proposition on the grounds that the distribution of craw-craw an d onchocerciasis were different27. Not to be outdone, Montpellier and colleagues reaffirmed their views in another paper pub lished later that year, remarking that craw-craw or filarial itch used in the restricted sense of O'Neill corresponded in geographical distribution with O. volvulus and reported that, except in rare

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instances, all their patients with filarial itch had onchocercal tumours, and that all persons with one of these nodules had the eruption characteristic of filarial itch94. This failed to convince Brumpt who again asserted that any role for O. volvulus in the causation of filarial itch was doubtful 28. In the following year, Ouzilleau and colleagues in the Congo (Brazzaville), studied a village in which 16 of the 27 inhabitants were afflicted wit h onchocercal nodules, with five having cutaneous lesions in addition. Thes e investigators examined the skin lesions and concluded that subjects infecte d with O. volvulus nodules always had microfilaria volvulus in the dermis, and that these parasites elicited an inflammatory reaction which caused th e cutaneous lesions, yet unaccountably, they did not consider that "craw-craw " was connected with onchocerciasis 105. This elicited another response fro m Montpellier and Lacroix 96 who discussed the advisability or otherwise o f retaining the term craw-craw as a dis tinct condition. They reiterated their belief that the skin lesions were due to itching whereas Ouzilleau and colleagues had ascribed the skin reactions directly to the action of the microfilariae. In fact , both groups of investigators were probably partly right, with microfilaria e stimulating an inflammatory reaction which, amongst other things, cause d itching and scratching which in turn exacerbated the condition. Th e observations of the French workers were confirmed by Macfie and Corson in Accra, Ghana. They found that not only were O. volvulus microfilariae present in the skin of patients with Onchocerca nodules, but that examination of skin biopsies taken from 50 health y men selected at random revealed larvae in 34% of them. Finally, MacFie and Corson showed at autopsy of three infecte d individuals that parasites were p resent in widely separated areas of the skin but were absent from the mucous membranes and internal organs 86. Thus, by the middle of the 1920's, it was becoming clear that th e unsheathed microfilariae in lymph node aspirates which looked the same a s those obtained from O. volvulus adults were indeed derived from that parasite, as were the same microfilariae seen in th e skin. Finally, despite the reservations of some sceptics such as Brumpt, it seemed c ertain in retrospect that the filariae seen in the skin 50 years earlier by O'Neill were indeed O. volvulus microfilariae.

ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE BLACKFLY INTERMEDIATE HOST When Manson first described O. volvulus, he wrote that "Judging also from the absence of sheath, it may be that the life history of this parasite is somewha t different in character from that of F. diurna or F. nocturna" 89. Nevertheless, Manson probably had in mind the likelihood that infection was transmitted by some blood-sucking insect in the same way as he had shown with W. bancrofti.

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When MacFadden and Leiper in 1911 reported on the contamination wit h Onchocerca gibsoni of Australian beef imported into Britain (when , incidentally, they first coined the term onchocerciasis to describe the diseas e caused by infection with Onchocerca), they speculated that the vector wa s probably a blood-sucking muscid fly such as Stomoxys, Hipposbosca or a tabanid, or an ixodid tick 85. In the same year, Breinl in Australia reported that he had been unable to infect Stomoxys calcitrans, the mosquitoes Culex fatigans (= quinquefasciatus), Stegomyia fasciata (= Aedes aegypti) and Mansonia uniformis, the leech Hirudo medicinalis, or the copepod (crustacean) Cyclops pallidus with O. gibsoni 24. In 1913, Leiper tried to infect the flies Stomoxys nigra and S. calcitans with the human parasite, O. volvulus, when he was in Nigeria. He fed them upon the juice of onchocercal nodules and although there was food initially in the stomach contents, dissection at late r dates provided no evidence of i nfection of the flies 81. Similar experiments were tried unsuccessfully by a numb er of subsequent investigators: Rodhain and van den Branden (1916) with the mosquito Aedes aegypti and the bedbug Cimex rotundatus 119, Calderón (1920) with lice, mosquitoes and various flies34 , Macfie and Corson (1922) with the tse-tse fly Glossina palpalis 86, and Blanchard and Laigret (1924) with the tick Ornithodorus moubata and the bedbug C. lectularis 22. Meanwhile, Robles in Guatemal a, by a masterly series of observations, had come very close to the truth as early as 1917. He ruled out transmission o f infection via water by showing that the disease was common in plantation s above 2,000 feet but not in people living at lower altitudes who drank the same water which had flowed through the infection areas. Further, he noted that in one farm which had two ranches, one situated at 2,000 feet (610 metres) and the other at 2,300 feet, all the inhabitants of the higher site were infected, but among the people living at the lower village, only those workers who picked coffee by day at heights varying between 2,300 and 2,500 feet were infected. These individuals slept at home at the lower ranch and their wives, wh o remained there, were never infected. He also observed that with tw o exceptions, the same blood-sucking insects were found above and below 2,000 feet, and they were present in considerable numbers at both locations. Th e exceptions were two flies (which he erronously called mosquitoes): From a careful investigation, we deduce that only two mosquitoes of the genus Simulium: the S. samboni and the S. dinelli, exist between 2,000 and 4,000 feet above sea level. In the places where these insects were numerous, the largest number of ill patients was found....they bite for five minutes, sucking blood to the point where you can see the abdomen fill progressively, giving them a red coloration. When they are completely full, they become so heavy they can hardly fly, and many times fall to the earth.114

On one of the farms where the flies abounded in great numbers, Roble s exposed two largely naked children at 10 a.m. and watched the insects bite. The majority rested on the ears, cheek and neck with the occasional one on th e

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forehead and chest. Unfortunately, Robles did not catch and dissect these flies, but he wrote: "I believe I can hypothesize that these are the intermediate hosts. At any rate, it is necessary to demonstrate this, and it has not been done" 114. In 1923, the Briton, Donald Blacklock, began to investigate the mode o f transmission of onchocerciasis in Sierra Leone. Since the microfilariae were not in the blood but in the skin, he postulated that any arthropod capable o f transmitting the worms must be able to da mage the skin and dislodge the larvae in its efforts to reach blood. Accordingly, he first looked at the Congo floo r maggot, Auchmeromyia luteola , which was common in the houses, but n o signs of the parasite were found. In December 1923 and January 1924, h e observed that the blackfly prophetically named Simulium damnosum was biting viciously and in great numbers near the streams supplying several of th e villages in an endemic area. Furthermore, he noticed that the insect was slow in drawing blood, which reinforced his idea that it must be inflicting sever e damage. He therefore caught 100 specimens and examined them for larvae in the gut, but finding nothing, abandoned the search temporarily. In 1925, h e resumed this operation at another vill age, this time with success. 780 flies were captured while biting randomly selected boys and 2.6% of the insects contained larvae morphologically identical with O. volvulus microfilariae in their gut . Thereupon, he submitted two men who were known to have O. volvulus microfilariae in their skin, bu t were not infected with any other filarial parasite, to the flies and found that 17% of Simulium contained microfilariae in thei r intestinal tract. When flies were then permitted to bite only on a 4 inch ban d around the patients' body, this area in cluding nodules near the trochanters, 80% of the insects became infected. Meanwhile, 1,320 wild Simulium were dissected and 1.1% were found to contain developmental forms of som e nematode, which was in all probability the larva of O. volvulus, in the thorax. Wild flies were then fed upon infected persons and kept alive for as long a s possible, with the result that up to 82% were found harbouring larvae in th e thorax, although only one worm was found in the head. In 1926, he undertook a further series of experiments to study the development of filariae within the flies. He found that development took about ten days to complete an d summarized his findings: The skin forms taken into the gut of Simulium accumulate at the margin of the blood coagulum lying between this and the gut wall. They are very active and the majority pass out of the gut within 24 hours and may be found in the posterior part of the thoracic muscles in 48 hours. They have altered completely in shape....they have also lost a great deal of their mobility. Several moults appear to occur before the form is reached which is capable of invading the head. 20

Blacklock found that when worms reached the proboscis they entered th e labium where they remained coiled up waiting for an opportunity to emerge. He then inoculated two monkeys with infective larvae, one intradermally and the other subcutaneously, the first in the flank and the second in the head, but was unsuccessful in transmitting infection. Details of Blacklock's work wer e

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published in 192618,19 and summarized in the British Medical Journal in 192720. Blacklock's findings were confirmed by other workers in Africa. Bequaert (1928) described the insect carrier of O. volvulus in Liberia14, then Gibbons and Loewenthal investigated S. damnosum and onchocerciasis in Uganda 61. Van den Berghe (1941) showed that S. damnosum was an important vector in the Belgian Congo (Zaire) 16. Earlier (1932), Hisette had shown that in certain regions of the same country, S. neavei was the vector 69, then this was confirmed in 1940 by McMahon in Kenya 87. Eventually, Wanson, Henrard and Peel 141 in 1945 successfully infected laboratory-bred S. damnosum with O. volvulus. In the Americas, Hoffman in Mexico reported in 1930 that although tw o blackflies, S. mooseri (= callidum) and S. ochraceum ingested microfilariae, development proceeded only in the latter 71. On the other hand, Strong i n Guatemala showed in the next year that S. mooseri, S. ochraceum and S. avidum were all vectors131. Giaquinto Mira believed that S. ochraceum was the most important species in view of its preference for biting man 60 then Vargas studied the development of O. volvulus larvae in S. callidum 137. O. volvulus has not been transmitted experimentally to humans by infected flies, but epidemiological evidence suggests that the prepatent period i s between three to 18 months. The adult worms may live for 15 years and ar e capable of producing microfilariae for up to ten years 113, while microfilariae may persist for from 6 months to 3 years 46.

RECOGNITION OF THE CLINICAL FEATURES AND DESCRIPTION OF THE PATHOLOGY SKIN DISEASE Once the adult onchocercal worms were recognized within subcutaneou s nodules, it was obvious that these lesions were a cardinal manifestation o f onchocerciasis. Nevertheless, only scattered reports describing this condition in one or several patients appear ed during the twenty years following Manson's first description. The first person to record a large series of patients wit h nodules was Ouzilleau in 1913. He noted that the cysts, which varied in siz e from very small to as large as an apple, were generally superficial in location. Although the skin could usually be moved over them, they were often tethered to the underlying muscles or bones. Nearly 80% of the cysts were situated on the lateral aspects of the chest, while the remainder were usually seen ove r bony surfaces or joints, especially the iliac crest, greater trochanter, knee , olecranon, and frontal, parieta l and occipital regions of the scalp 103. Ouzilleau's findings were largely confirmed several years later by Dubois who collected an enormous series of 1,449 patients. He did f ind, however, a different distribution

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of nodules in the body with 30% being locate d over the trochanters, 29% on the iliac crests, 21% on the sides of the thorax and 19% either on different or two or more sites 43. Similar findings were then found by many investigators, with the distribution of nodules tending to follow more the pattern described b y Dubois. Desoil and Benoit studied the histological appearances of an excise d onchocercal nodule and found a granulomatous inflammatory reaction around the adult worms and microfilariae migrating throughout the tissues of th e "tumour"40. Similar observations, with the addition of oedema, eosinophili c infiltration, endothelial proliferation and fibrosis were noted by subsequen t investigators90,101. From time to time, nodules became infected secondarily with bacteria and presented as abscesses, the original problem being realized only when onchocercae were recovered from the abscess contents 77,122. While the relationship of O. volvulus to nodules was clear, considerabl e controversy surrounded the role of O. volvulus microfilariae in producing other skin lesions. As has already been recounted, it was not until 1920 that O' Neill's description of filarial worms in craw-craw was exhumed from the librar y archives and equated with O. volvulus by Montpellier and Lacroix. O'Neil l described craw-craw as an itchy, papulo-vesiculo-pustular eruption which was most marked in the clefts of the fingers, front of the wrists, and back of th e elbows. This distribution is classical of scabies as he himself remarked, and it may well be that he was dealing with a dua l infection. O'Neill discoursed on the natural history of the condition: The papules arise singly and at irregular intervals, increase to the size of a pin's head, feel firm to the touch, and appear of the same colour as the surrounding integument. In some cases, the papules arrange themselves in a crescentic form, like ringworm.....In about two days' time the papule becomes converted into the vesicle, with very little increase in size, and in the course of a couple of days the pustule is developed, rapidly enlarging, and uniting with those in its immediate neighbourhood. In the height of his suffering the patient tears the pustules, and their liberated and dessicated contents produce large and unsightly crusts. 102

It was the itching and consequent scratching which led to the rediscovery b y Montpellier and Lacroix of microfilariae in the tegument 95. In addition to the papules, vesicles and pustules, Ouzilleau and his colleagues in 1921 recognised thickening of the skin variously described as pseudo-ichthyosis, ichthyosi s simplex and lichenization. Their histological studies of these lesions revealed the presence of microfilaria volvulus in the dermis and subdermal tissues , infiltration with mononuclear cells, hyperkeratosis of the epidermis, often with infiltration of the basal layers by leucocytes, enlarged dome-like papillae i n lichenoid zones and in pruriginous regions with the addition in the latte r location of blisters and ulceration. In leucodermic areas, the pigment wa s lacking, the horny layers of skin were thinner than usual and there was a n increase in fibrous tissue with an absence of blood vessels and glands 105. In contrast, Montpellier and Lacroix 95 did not emphasize the inflammator y

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reaction, nor did Dyce Sharp who found that microfilariae were not usuall y associated with inflammation, although there was sometimes a layer of definite inflammatory change49. These differences in severity were probably due t o biopsies being taken from areas of skin with differing severities of disease . Harris summarized the natural history of the skin lesions by remarking that the first skin affection was an itching rash which then either became elephantoid, often with enlarged lymph nodes, or became atrophic 65. One of the major objections which Brumpt had raised about th e onchocercal nature of these lesions was the frequent absence of onchocerca l nodules. Although these criticisms were no longer tenable when man y investigators demonstrated the unequivocal presence of microfilariae identical with those of O. volvulus in the skin, explanations were furnished by th e discovery in autopsies of two humans of clinically occult adult worms whic h were free in the tissues unencumbered by a fibrous, nodular reactions15, then the realization that nodules might be located in the deep, inaccessible tissues. Another problem which was the subject of some controversy was whether or not onchocercal infection caused elephantiasis. Ouzilleau (1913) had found that up to 3% of the populati on he surveyed had this condition, yet Wuchereria bancrofti was absent, only O. volvulus, M. perstans and L. loa being present. Since he had found O. volvulus microfilariae in aspirates from enlarged lymph nodes, he suggested that this parasite may be the cause of elephantiasis 103. Ouzilleau was supported by Dubois who proved onchocercal infection in over 90% of 53 patients with elephantiasis 43. Ouzilleau returned to this theme i n 1923104, then was echoed by Dyce Sharp who found O. volvulus microfilariae in hydrocele fluid 49. In order to explain the pathogenesis of elephantiasis i n Onchocerca infection, Rodhain put forward the hypothesis that obstruction to lymph flow was caused by microfilariae in the lymphatic capillaries 118. On the other hand, Dubois eventually modified his views and concluded that while O. volvulus favoured the appearance of elephanti asis, W. bancrofti was its primary cause44. Nevertheless, Kirk (1947) found that hydrocele and scrota l elephantiasis were very common in patients with onchocerciasis in the Sudan in an area where bancroftian filariasis was rare 76, so that the matter is not yet completely resolved. Finally, a form of pseudoelephantiasis called "hangin g groin", in which a sac of atrophic skin containing sclerosed glands in a matrix of connective tissue and lymph exudate, was described by Nelson as bein g frequent in persons heavily infected with Onchocerca in Uganda99. Variations on these themes were seen in onc hocerciasis in Central America, perhaps partly due to the light skin colour of many of the infected persons and the biting habits of the vectors. In Guatemala, there was a condition known as "Erisipela de la Costa" (erysipelas, i.e. red skin inflammation of the coast). In 1915, Robles was consulted by a woma n concerning recurrent erysipelas of the face which was accompanied by fever, a burning sensation, pruritus and poor vision, but he did not know the cause. Afterwards he saw a boy with the same features:

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There was edema of the eyelids, the forehead, and the superior lip. The cheeks were puffed up with shiny, dry, scaly lesions that resembled chronic eczema; also there was a greenish coloration of both cheeks as you would see in ecchymosis of several days' duration. When touched, the edema was hard leaving no digital impression. The ears were much increased in size with the external ear pushed forward; the lobe was edematous, scaly, dry and whitish.114

On his forehead was a tumour the size of a cherry; it was this nodule tha t Robles excised and first discovered the adult Onchocerca in the Americas and later remarked: "I understood then that the 'erysipelas' lesions surely were due to the presence of this parasite" 114. Robles collected a large series of patients and noted that the nodules were found most commonly on the head. They were generally situated in the sub cutaneous tissues but were occasionally tethered to underlying structures . Indeed, in four of 500 patients on whom he operated, the nodules ha d perforated the cranium and were resting on the meninges. He noted too, that the adult worms could be long-lived, for he found living worms in a cyst which he removed from a patient who had been living out of an endemic area for seven years. Apart from the skin nodules, Robles observed two forms of skin disease . Some patients developed acute inflammation in which the skin became: smoothy, shiny, red, tense and warm simulating erysipelas....After three to four days the fever falls slowly and the patient enters a chronic stage. The swellings persist much longer, for days, up to months in the same stage; but usually at the end of 20 days they diminish notably.114 In the chronic stage, however, he wrote that when the face was involved: the cheeks are always indurated, the skin eczematous, pigmented and lustrous, with an absolutely typical greenish livid color; elephantiasis of the ears, which are doubled in size, bent forward with skin wrinkled and scaly.....On the limbs of the body there is a uniform swelling with induration as seen in the elephantiasis of the Arabs. However, the typical greenish color suggests the diagnosis instantaneously.114

Robles observations were confirmed by Calderón 34 and by Strong 131,132. A few years late, Goldman and Ortiz classified the dermatitis into three forms : pigmentation dermatitis or "mal de morado" (= purple disease) in which th e skin became purplish in colour, a lic henoid form, and an eczematous dermatitis in which the lesions were papulo-vesicular, excoriated, papillomatous an d hyperkeratotic62. Although Robles had commented upon elephantiasis of th e limbs, subsequent investigat ors were agreed that this condition was very rarely seen in American onchocerciasis.

EYE DISEASE The early investigators of onchocerciasis in Africa made no mention at all of eye disease. This is not altogether surprising as the most obvious feature was the presence of nodules, which were not usually situated on the head. Bein g

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aware of microfilariae in lymph nodes, they were more concerned with th e possibility of the organism causing elephantiasis. Furthermore, they were not aware of onchocercal microfilarial skin disease which, had they known of it , might have sensitized them to look for other manifestations of illness caused by microfilariae. Finally, they were devoid of the technical equipment necessary for a full recognition of onchocercal eye disease; it is doubtful if any of the m even had a simple ophthalmoscope. In contrast, the clinical presentation t o Robles in Guatemala was completely different. Nodules were common on the head and produced a distinctive sk in disease, often located on the face. Further, the patients often complained of an associated eye trouble. Robles' first, bu t undiagnosed, patient complained o f losing her sight, and ophthalmic symptoms and signs were marked in the boy from whom he first recovered an adul t Onchocerca: The ocular symptoms consisted of redness of the conjunctiva and iritis; the usually brilliant and transparent corneas were now dull and without glossiness; there were scattered small leucomas as if the patient had suffered from an ulcerative keratitis; there were periorbital pains....and very notable diminution of visual acuity. The boy complained of cloudy vision. Photophobia was so intense that the little boy always walked with the brim of the hat pulled down to shade his eyes from the light; at midday he experienced burning and pruritis (sic) in the eyes which felt as though they were full of sand.114

What really convinced Robles of the relationship between the eye disease and infection was the remarkable resolution following removal of onchocerca l nodules from his forehead: the child's appearance the following day was completely different; the edema as well as redness of the conjunctiva had disappeared. . The clouding of his vision had disappeared so that now he could see perfectly; the light did not bother him any longer; the pruritis (sic) and gritty sensation were no longer present. 114

As with the skin disease, Robles recognized two forms of eye involvement. In acute ophthalmic onchocerciasis, he described periorbital pain, sensations of having foreign bodies in the eyes, and wrote that "the cornea has the char acteristics of a punctate keratitis" 114. Further, he noted that a dangerous iriti s could complicate the picture, but remarked that examination of the fundus by Dr Pachecho Luna had not revealed any abnormality of that part of the eye. In chronic cases, Robles found photophobia, pte rygia, punctate keratitis, a dull iris with a deformed and constricted pupil, and progressive loss of visual acuity . These features were echoed by Pachecho Luna who thought that the punctate keratitis was due to a microfilarial toxin as eyesight improved rapidly whe n nodules were removed: For this reason, it is presumed that all the symptoms are due to the secretion from a parasite in the human organism, of a toxic substance, which produces at times appreciable lesions in the eyes.106

Pachecho Luna never saw any microfilariae in the eye itself. Similarly , Calderón commented upon punctate keratitis, corneal leucoma, acute o r chronic iritis, photophobia, pigmentation of the sclera, and considerabl e

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impairment of vision34. A number of other authors also remarked upon th e rapid disappearance of acute symptoms after removal of a nodule, althoug h such statements were criticiz ed by Guerrero (1922) on the ground that patients were not followed up to see if the problems recurred and he contended that a "post hoc propter hoc" interpretation of the relationship could be fallacious 64. Doubts were also expressed by Fülleborn, who together with Zschukke, found nodules in 70% of labourers on one Guatemala plantation yet found objective evidence of diminution of vision in only two. He concluded that the carriers of Onchocerca that they had seen were perfectly healthy individuals and h e deprecated the prophylactic removal of parasitic cysts which had bee n proposed recently54,55. His view did not endure, however, and many author s confirmed the relationship between O. volvulus infection and eye disease 36,80. The first persons to mention onchocerciasis of the eye in Africa wer e Ouzilleau and his colleagues who recorded that one of the 16 infected persons they had found in a village of 27 inhabitants had keratitis 105. Publication of the observations in Central America stimulated a search for eye disease in African onchocerciasis but it seemed to be largely absent; thus, Blacklock in 192 7 reported that he could find no evidence of eye disease in patients wit h onchocerciasis in Sierra Leone 20. It was not until 1931 that Hisette reported that in a focus of onchocerciasis in the Belgian Congo (Zaire), 20% of the patients with onchocerciasis were blind and that 50% of the population suffered from eye troubles. The disease differed from onchocerciasis as generally described in Africa in that large numbers of cysts were located on the head, although there was no erysipelas-like lesions. Further, he found that removal of the nodule s often ameliorated the symptoms 68. Hisette amplified his findings in a long paper published in the following year where, in addition to a description of anterior eye disease, he drew attention to an association with choroidoretinitis 69. His findings prompted renewed efforts to find ocular complications o f onchocerciasis in other parts of Africa and in 1935 Bryant reported tha t blindness was appallingly common in a part of the Sudan where the infection was endemic. Some of this was due to anterior eye disease with onchocerca l punctate keratitis and corneal sclerosis, but most people were blind because of a gross choroidoretinitis with optic atrophy. Whereas the first condition wa s clearly due to Onchocerca infection, there was some doubt about the second, for microfilariae could not be found in histologically-sectioned eyes, but h e provided statistical and epidemiological evidence to support his thesis 29. In 1945, Ridley showed that slightly more than one third of patients wit h onchocerciasis in a region of the Gold Coast (Ghana) had evidence of eithe r anterior or posterior disease, with nearly half of them being blind or nearl y blind. He concluded on the basis of slit lamp examinations and a review of the literature of the pathology of the disease that living microfilariae caused n o tissue reaction but that the lesions were a response to dead microfilariae 112. In the same year, Puig Solanes and his colleagues in Mexico came to the sam e conclusion 109.

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Histological studies of infected eyes were slow in coming because o f difficulties in obtaining material. In 1928 and again in 1930, Ochoteren a described the findings in an eye excised from a blind man. The eye was fixed entire and serial sections made; microfil ariae were seen particularly in the outer one third of the cornea and in the optic nerve 100. Silva (1932) found microfilariae in the choroid and posterior two thirds of the cornea in sections of eyes128 and Hisette in the same year found microfilariae throughout the eye 69. Giaquinto Mira in 1934 also described microfilariae in the optic nerve 59 then in the same year, Strong and his colleagues indicated that in a study of 11 eyes removed at operation, microfilariae were found in the cornea, iris, ciliary body and choroid132. Bryant (1935) then showed that in patients with anterio r onchocerciasis, microfilariae could be found throughout the anterior eye, th e cornea was vascularized, the ciliary body inflamed and fibrotic, and the sclera and choroid were infiltrated with plasma cells although he could no t demonstrate microfilariae therein 29. Most investigators have agreed that whether or not eye disease is likely to occur depends, at least in part, on the distribution and density of microfilariae in the body. It was realized e arly that the propensity of flies in Central America to bite near the head and for nodules to form there increased the relativ e frequency of eye disease in that region compared with Africa. Kershaw and his colleagues working in Africa described in 1954 a technique for quantifying the microfilarial density in various parts of the body. They showed that there was a clear relationship between heavy microfilarial counts in the skin, particularly of the upper parts of the body, and eye lesions with blindness: The occurrence of anterior segment lesions is related to the presence of microfilariae in the anterior chamber and the head region consequent upon a spread of microfilariae from the lower parts of the body. This spread is associated with a high intensity of infection in the human host and this in turn probably reflects the duration and intensity of the exposure to which the host has been subjected throughout his life....Blindness due to anterior-segment lesions, when expressed as a percentage of infected persons, is 23 times higher in these heavily infected communities than in lightly infected ones....the incidence of blindness due to choroido-retinal lesions amongst infected persons is only six times higher. 75

These observations were then confirmed by Rodger and Brown 116. While the vast majority of observers accepted that onchocercal infectio n could cause devastating eye disease, there were still some sceptics. Choyc e (1958) considered that there was no good evidence that posterior lesion s (retinal degeneration and optic atrophy) were due to onchocerciasis and, on the basis of his experience in the Cameroons, believed that the anterior diseas e (keratitis commonly, iritis mor e rarely), although admittedly due to O. volvulus infection, did not often lead to more than a slight interference with vision 38. In reviewing this opinion, a commentator in The Lancet wrote: "If this is correct, there is little to justify the growing reputation of onchocerciasis as a blinding affection"4. Woodruff and his colleagues therefore investigated the questio n further in Uganda and concluded that many other factors than the mer e

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presence of microfilariae were necessary for the production of eye disease 142. At this point, so much uncertainty and controversy surrounded the question of onchocercal eye disease, that a reviewer in The Lancet in 1963 wrote: The relation between infection with these worms and damage to the eyes is by no means straightforward....Everyone agrees that microfilariae invading the cornea may cause conjunctivitis and keratitis, both punctate and sclerosing; but such lesions rarely cause complete blindness. Blindness is likelier to be due to lesions in the posterior part of the eye, but opinions differ as to whether such lesions are really caused by microfilariae or whether they arise from genetic effects and excessive inbreeding.5

Choyce in 1964 then compared the ocular manifestations of onchocerciasis in endemic areas in Central America, in Africa, and in expatriates in Britain. He now concluded that in American onchocerciasis blindness was due to anterior lesions, posterior lesions being rare, while in the African form of the disease choroidoretinal lesions were present as well as anterior eye involvement . Nevertheless, Choyce still held that the posterior eye lesions were due to other factors such as vitamin B deficiency or inheritance 39. On the other hand, Quere and his colleagues in Africa, from observations of a large series of patients , concluded that both anterior and posterior regions of the eye were involved in a typical sequence of inflammatory processes caused by the microfilariae 110. This view is now generally accepted.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of onchocerciasis can be established by finding the parasite in a number of ways. The most obvious of these is excision of the nodule an d finding the adult worms therein, as was done in Africa by the medica l missionary who sent the original specimens to Leuckart, and by Robles i n Central America. Alternatively, a nod ule can be aspirated with a needle and the contents examined 103. Van den Berghe used this technique in a large series of 405 nodules and found eggs liberated by damage to the female worm by th e needle in 60%, a few larvae but no eggs in 30%, and neither eggs nor larvae in the remaining 10% 17. Microfilariae may also be aspirated from draining lymph nodes as was shown by Ouzilleau 103. Another way of demonstrating the presence of microfilariae was described by O'Neill in 1875 but was forgotten until the technique was resurrected b y Montpellier and Lacroix in 1920. O'Neill wrote: I find the readiest way to procure the filaria is to take between the finger and thumb a fold of the skin, so that the papule will be the highest point, then with a very sharp scalpel slice off the epidermis, which may be discarded; now take another slice, which will remove the base of the papule and the cutis vera. This film, moistened with a drop of water, and magnified about 100 diameters, will very likely contain at least one filaria, easily detected in the field by its violent contortions. 102

Fülleborn and Simon then showed that the diagnostic morphological features

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of O. volvulus microfilariae could be demonstrated by staining them wit h Romanowsky stains 56. The presence of microfilariae in the eye can be discerned in a number o f ways. Silva in 1925, merely by illuminating the fundus with a flat mirror, saw a very mobile, refringent body with a golden reflection which he believed was a filaria in the vitreous; with the Gullstrand ophthalmoscope he saw its shadow on the retinal surface 128. Subsequently, Torroella first used the slit lamp an d saw microfilariae migrating along the corneal surface and moving in a spira l fashion through the anterior chamber 135. Torroella's observations wer e confirmed in 1932 in the Congo (Zaire) by Hisette 69 and also in Uganda by Boase (1935). The latter described his slit lamp findings: prolonged examination revealed many of these organisms....The manner in which they propelled themselves through the aqueous immediately suggested to my mind the well-known antics of the mosquito larvae, though I think a better description of their movements would be to say that they tied themselves into knots and untied themselves with amazing rapidity....their length....is about a third of a millimetre. 23

In the same year, Bryant reported that microfilariae could be found in aqueous fluid obtained by puncture of the anterior chamber under local anaesthetic with a syringe, but this method clearly has its disadvantages and dangers 29. A few years later, Torres Estrada compared vari ous means of visualizing microfilariae in the eye with different types of ophthalmic equipment and emphasized that the parasite seemed to be more abundant in the vitreous than in the anterio r chamber and could be seen in the former site early in the disease 134. A number of observers noted that blood eosinophil levels were increased in onchocerciasis, but this was clearly a nonspecific finding. Many attempt s were therefore made to develop more specific immumoassays. Rodhain and van den Branden in 1916 looked for complement fixing antibodies using a n O. volvulus antigen preparation but found them in only 18% of patients 119. Fifteen years later, Rodhain together with Dubois described a skin test using a similar antigen but found cross-reactivity with other nematodes 120, then reported the same phenomenon with Fairley's preparation of Dirofilaria immitis antigen121. Greater specificity was claimed by van Hoof usin g O. volvulus antigen prepared in a different manner in an assay to detec t complement fixing antibodies 72. Finally, Mazzotti in 1948 drew attention to the fact that a presumptiv e diagnosis of onchocerciasis could be made if pruritus with or without a ras h appeared following the administration of diethylcarbamazine (the Mazzott i reaction - see section on treatment) for this was almost invariable i n onchocerciasis but was absent in filariasis 91. The usefulness of this phenomenon was then emphasized by Burch 32.

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THE SEARCH FOR EFFECTIVE TREATMENT The management of onchocerciasis has been approached from both surgica l and medical standpoints. The surgical excision of nodules containing adul t worms was shown to be effective 69,114, but its feasibility depended upon th e availability of facilities and the number and locations of the nodules to b e removed. Many attempts have been made to improve the medical therapy o f onchocerciasis since O'Neill first tried sulphur (which was often useful i n scabies) and found it ineffective. He also noted that "the nostrums of the native 'medical man' have frequently failed to bring relief after six months ' application"102. The same might be said for the modern medical man whos e therapeutic armamentarium is not that much m ore effective. Dyce Sharp (1926) tried a Bayer preparation, B1916, in a single case and claimed excellen t results49. Certain antimony compounds and plasmochin were found to have an effect on microfilariae but were discarded as they had no action on the adul t worms which rapidly replenished the supply of microfilariae 1. Enzer (1942) in a preliminary paper investiga ted euflavine, tryparsemide (arsenic) and suramin (the latter two being anti-trypanosomal compounds) and thought that they may be of some value if combined with protein shock (T.A.B.) therapy 50. In 1947, van Hoof and his colleagues took up the further investigation of suramin which had first been u sed in the treatment of trypanosomiasis in 1921. They gave 1 gram a week for seven to ten weeks and considered that it wa s always successful73. On the other hand, Ruiz Reyes tried the same drug bu t without appreciable benefit 123. Burch tried suramin with some success bu t experienced troublesome side-effects 31 then Ashburn and colleagues showed that suramin had a definite lethal effect on adult worms 8. At around the same time as these re sults were reported, diethylcarbamazine was introduced for the treatment of filariasis (see chapter 24) then was soo n tried in onchocerciasis. The first results were reported in 1948 by Mazzotti and Hewitt who found some reduction in the numbers of microfilariae in the skin, but in contrast to when suramin was used, nodules extirpated subsequently still contained living adult worms and microfilariae 93. This was followed by th e observation of Mazzotti that although the numbers of skin microfilaria e decreased initially, they often increased again a few months later 92. These effects, i.e. a failure to kill adult Onchocerca and only a transient reduction in microfilarial numbers were confirmed by many investigators 8,31,33,45,66,138. Mazzotti had earlier noted that allergic attacks with fever and local induration of the skin may occur in onchocerciasis, then found that such reactions wer e commonly precipitated by the administration of diethylcarbamazine, th e severity of the reaction being dependent upon the intensity of infection 91. This phenomenon came to be known as the Mazzotti reaction. Hawking and Laurie described it graphically, even when small doses of the drug were given: even a single dose of 50 mg hetrazan citrate almost always produced a violent

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reaction which was well marked in 16 hours. There was usually swelling, oedema and tenderness of the skin, especially of the buttocks and thighs. Sometimes the prepuce, penis and scrotum were swollen. Intense itching was always widespread. Sometimes there was a thick papular rash over the trunk and limbs. The lymph-glands were generally enlarged and tender....There was always pyrexia. 66

The initial encouraging reports with suramin and with diethylcarbamazine were followed by comparative trials 33 and with the combination of the tw o drugs37,126. Although each drug has had its advocates, suramin has largely been abandoned because of its occasional severe toxicity, especially on the kidneys, even though it kills adult worms, while diethylcarbamazine suffers from th e twin disadvantages of having only a transitory effect and producing unpleasant side-effects associated with killing of the microfilariae. Attempts have bee n made to improve the effectiveness of the latter drug, for example, b y administering the drug in a skin lotion 6, but these efforts have bee n unrewarding. Duke in 1981 summarized the difficulties: The outstanding problem in onchocerciasis remains in the treatment of patients, particularly those whose eyes are at risk. We are still dependent upon two drugs, DEC-C (diethylcarbamazine citrate) and suramin whose actions were discovered more than 30 years ago and which are far from satisfactory in use....What is now needed above all is a non-toxic drug, which has a convenient dosage schedule and which can kill or permanently sterilise the adult worms of O. volvulus without producing a microfilaricidal reaction.48

Duke then remarked that towards this end, The United Nations Development Fund/World Bank/World Health Organization Spec ial Programme for Research and Training in Tropical Diseases has set in train a programme to develop new filaricidal drugs effective against O. volvulus, which: Given adequate funds, sufficient brains, patience, and some luck, it is hoped...may pay off within the next 10-15 years developing a new drug to improve the prospects of treatment of those threatened with or suffering from ocular onchocerciasis. 48

While these words were being written, a promising drug was bein g developed. In 1978, Blair and Campbell had reported that ivermectin, a macrocyclic lactone derived from a new species of actinomycete, Streptomyces avermitilis, had exceptional potency against the nematodes Ancylostoma caninum 21 and Dirofilaria immitis 35. In 1982, Aziz and his colleagues showed that the density of skin microfilari ae was greatly reduced in Senegalese patients treated with ivermectin 12. Subsequent double-blind studies in West Africa have compared ivermectin with diethylcarbamazine and placebo in patients wit h high skin microfilarial density, most of whom had ocular involvement . Ivermectin was shown to be superior to diethylcarbamazine in both safety and efficacy; ivermectin resulted in a more sustained microfilaricidal effect, wit h skin microfilarial levels 12 months after treatment being 2-10% o f pre-treatment levels compared with a value of 10-45% for patients treated with diethylcarbamazine 9,63,79.

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UNDERSTANDING THE EPIDEMIOLOGY Early workers in Africa observed an association between onchocerciasi s and rivers, particularly smaller waterways. Thus, Ouzilleau found that the infection was common around the headwaters of the Ubangi 103. Dubois observed onchocerciasis around waterways in the lower Welle (Uele ) district43 and Rodhain showed that the condition was prevalent along other tributaries of the Congo117. Similar terrain was present in the Konno district of Sierra Leone where Blacklock first demonstrated transmission by S. damnosum: It is a hilly region drained by several large rivers and a multiplicity of small streams; the hills are in most cases clothed with dense bush right to the summit. Each village has in its immediate vicinity several streams; swampy areas produced by silting up and overflow of the streams are numerous and biting insects are plentiful. 20

This association was explained when the vector was discovered and its breeding habits discerned. Robles in Guatemala had earlier described some aspects of the biting behaviour of Simulium in Guatemala, showing that those species preferred to bite by day and around the head (see earlier). After Blackloc k proved that S. damnosum was the intermediate host, he began to study it s behaviour. He demonstrated that the flies were present in the bush in th e vicinity of water, that female flies bit by da y, usually from the waist downwards, and preferred shade and humidity. Like Robles, Blacklock observed that they took from one to five minutes to feed then became so distended that they had difficulty in flying 20. Similar observations were made by van den Berghe in the Congo16. Wanson and Henrard, also in that country, later showed that female worms commonly migrated several miles (even up to 45 miles) along rapidly flowing sections of rivers. They found that breeding took place in these rivers, with larvae and pupae attached to submerged stones, plants and various other impedimenta submerged in fast-moving water. They determined that the period for development from egg to adult took about nine days, and that the adul t females lived for about three weeks 140. Studies of the behaviour of simuliid flies in Central America gave broadly similar results. In East Africa (Kenya), McMahon reported in 1940 that S. neavei was the vector 87 then he and van Someren showed that the larva of this specie s developed on the carapace of a freshwater crab 130. Both Dubois43 and Rodhain117 in the early part of this century noted that the distribution of onchocerciasis was very p atchy, with the frequency varying from one location to another. Subsequent studies showed that in some regions, up to 100% of the population was infected. In general, the frequency of infection was observed to rise with increasing age. In West Africa, onchocerciasis wa s present in parts of both the northern arid savannah and in the southern rai n forest, but eye disease was much less common in the latter location. Duke and his colleagues then showed that this difference may be due to the presence of

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different strains of both parasite and vector in those two regions 47. In many parts of Central America, onchocerciasis is often associated with the growing of coffee. The infection was first described in Guatemala, as has already been recounted. In 1923, Fülleborn suggested that onchocerciasis may also be present in Mexico 53, then this was confirmed by Larumbe80 . Subsequently, foci of infection were reported in other parts of northern South America. Two hypotheses have been promulgated concerning the origins of onchocerciasis in America 70. The first postulates that the infection did not exist in the Western Hemisphere prior to its introduction by infected persons from Africa. The most obvious source of such infection is among the negro slaves carried from West Africa124, but other suggestions have been made. For example , Torroella considered that the infection may have been introduced into Mexico by a battalion of Sudanese troops sent to assist the French invasion troops of Napoleon III in 1862 136. The alternative hypothesis is that onchocerciasis i s autochthonous to the Americas. This seeme d quite tenable when Brumpt's view that O. caecutiens was different to O. volvulus was accepted. This idea wa s supported by Diaz who found a small number of pre-Columbian skulls wit h erosions and perforations which he attributed to onchocercal nodules 41. This, of course, was a non-specific finding, as are the various examples of earl y Spanish literature citing regions where blindness was common, that have been quoted by Figueroa Marroquin in support of this latter thesis 51. Although natural infections with O. volvulus have been found in the gorilla in the Congo and in the spider monkey in Me xico, there is no evidence that they are a significant reservoir of zoonotic onchocerciasis.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES When Gibbins and Loewenthal reported their own studies of onchocerciasis in Uganda in 1933, they wrote that since huge tracts of extremely fertile country had been rendered uninhabitable through the ravages of Simulium flies, and as the lives of those still living there had been made miserable by irritation from their bites, the question of suppression of these insects was urgent . Interestingly, they were concerned only with skin disease and made thi s judgement without any consideration of the ophthalmic complications of th e infection. They were not sanguine about the prospects, however, remarking that it was futile to attempt to attack the flies in their breeding grounds, bu t suggested that trapping may prove feasible 61. A few years later, Buckley found in Kenya that discriminative clearing of bush along the banks of two infected rivers, together with removal of surrounding undergrowth, greatly reduced fly numbers30. The outlook was changed drastically, however, with the discovery in 1941

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by Müller and his team at Geigy in Switzerland of the insecticide, DDT . Garnham and McMahon in 1949 used this ne w chemical to attack the fly in one of the three areas in Kenya endemic for onchocerciasis where S. naevei bred in limited stretches of two rivers. They app lied emulsions of DDT in oil and water at 10-14 day intervals for six to seven months and succeeded in eradicating the flies57. Seven years later they reported that the flies were still absent and that although transmission of onchocerciasis had ceased, the disease still lingered on58. Eighteen years after eradication of the flies, Roberts and colleague s reported that all the adult O. volvulus had disappeared by about the sixteenth year113. A similar result was obtained following a campaign of sprayin g vegetation along the river banks with DDT from the air in the Congo 139. In 1967, McMahon reviewed the information available about the control o f Simulium vectors of onchocerciasis. He concluded that larviciding was th e most efficient means of control and indicated that intermittent control of S. damnosum had been achieved in various parts of West Africa and that S. naevei had been eradicated from Kenya and parts of Uganda 88. These results encouraged the World Health Organization in collaboration with the Food and Agriculture Organization, the United Nations Development Programme and the World Bank to embark upon a multi-million dollar programme in the Volt a River Basin of West Africa with the objective of eradicating blackflies wit h larvicides. Since 1974, the biodegradable organophosphate insecticide , temephos, has been applied from the air repeatedly to 14,000 km of river s covering an area of nearly one million square kilometres and encompassin g seven countries (Benin, Burkina Faso [Upper V olta], Ghana, Ivory Coast, Mali, Niger and Togo) with a popul ation of ten million people. This programme was based upon the premise that by keeping S. damnosum out of the control area for 10-15 years, transmission will be interrupted for long enough for th e infection to die out. The initial two phases of the Onchocerciasis Contro l Programme carried out between 1974 and 1985 cost US $162 million. A third phase, at an estimated cost of US $133 million, is to be undertaken betwee n 1986 and 1991, and will be extended westwards into Guinea, Guinea-Bissau, Senegal and Sierra Leone; it is thus hoped to prevent reintroduction of th e disease into treated areas by migratory blackflies and provide protection to an additional eight million people 7. In contrast to the experience in Africa, the breeding places of Simulium in Central America are largely inaccessible and McMahon concluded that control by larviciding was difficult 88. A different approach has been taken in that area for many years, however. Mass campaigns for the removal of head nodule s have been mounted with a considerable reduction in microfilarial density , morbidity and onchocercal transmission 131,133. An alternative approach which has been tried in both Africa and th e Americas has been the repeated administration of diethylcarbamazine; this has met with little success because the frequency of side-effects has ensured poor

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cooperation by the populace6. Nevertheless, the introduction of ivermectin has provided new hope. As already mentioned, this drug is less toxic and mor e effective, and may be better tolerated than diethylcarbamazine when given as a mass prophylactic in endemic areas 11.

OTHER SPECIES OF ONCHOCERCA In 1965. Siegenthaler and Gübler reported finding an Onchocerca (probably O. gutturosa) in a nodule removed from the knee of a 25 year old Swis s woman127. In the same year, Azarova and colleagues described the recovery of an Onchocerca from the conjunctiva and cornea of a 15 year old girl in th e Crimea (USSR) 10. In 1973, Ali-Khan and Meerovitch reported the removal of an Onchocerca from a wrist swelling of a middle-aged woman from Ontario, Canada2, then Beaver and his colleagues discu ssed another such worm removed from a similar site in a woman in Illinois, USA 13.

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McLEAN DS. Onchocerciasis and the eye in Western Uganda. Transactions of the Royal Society of Tropical Medicine and Hygiene 57: 50-63, 1963

Table 25.1. Landmarks in onchocerciasis ___________________________________________________________________ 1875

O'Neill discovered microfilariae in skin biopsies in West Africans with a skin condition known as "craw-craw" 1893 Manson reported the personal communication to him by Leuckart of the discovery by a German doctor in Ghana of adult worms in nodules removed from the subcutaneous tissues 1916 Robles discovered Onchocerca infection in Guatemala 1917 Robles postulated on epidemiological grounds that Simulium flies may be the vector of Onchocerca in Guatemala, and suggested a relationship between this infection and eye disease 1920 Montpellier and Lacroix in Africa once more drew attention to the presence of microfilaria volvulus in the skin and related this infection to dermatitis 1925 Silva observed a microfilaria in the eye with an ophthalmoscope 1926 Blacklock in Africa described the development of microfilaria volvulus into infective larvae in S. damnosum, but failed to transmit infection experimentally to monkeys 1928 Ochoterena demonstrated histologically the presence of microfilariae in the eye and optic nerve 1930 Torroella observed microfilariae in the cornea and anterior chamber with a slit lamp 1930 Hoffman showed that species of Simulium were the vectors in Central America 1931 Hisette emphasized the ocular manifestations of onchocerciasis in Africa 1947 Van Hoof and his colleagues showed that suramin killed adult worms but various workers found this drug to be very toxic 1948 Mazzotti and Hewitt reported that skin microfilarial density fell after treatment with diethylcarbamazine, although adult worms were not killed 1948 Mazzotti suggested that the precipitation of a rash by diethylcarbamazine could be used as a diagnostic method 1949 Garnham and McMahon eradicated flies from a limited focus in Kenya by applying DDT to streams 1982 Aziz and his colleagues indicated that ivermectin greatly reduced the density of skin microfilariae ___________________________________________________________________

Chapter 26

Dracunculus medinensis and GUINEA WOR M DISEASE

SYNOPSIS Common names: Guinea worm, Medina worm, dragonneau, causing dracunculiasis, dracontiasis Major synonyms: Filaria medinensis, Fuellebornius medinensis, Gordius medinensis Distribution: West, North and East Africa, Middle East, Indian subcontinent Life cycle: First-stage larvae released from gravid female worms into water are ingested by small crustaceans (Cyclops) in the body cavity of which they moult twice to become infective forms. When humans ingest water containing infected Cyclops, the larvae escape from the crustacean and migrate through the duodenal wall into the retroperitoneal connective tissues. There they mature and mate. The female worms migrate through the connective tissues, usually to the lower limbs, and the female worm, about 1 metre long, appears in the base of an ulcer approximately one year after ingestion of the parasite Definitive hosts: humans (dogs, cats, monkeys, raccoons) Major clinical features: ulcer, secondary infection Diagnosis: macroscopic appearance, larvae in discharged fluid Treatment: metronidazole, niridazole, thiabendazole suppress inflammation and aid in mechanical extraction of the worm

AWARENESS OF THE ADULT WORM Guinea worms have been known since antiquity in parts of Africa and th e Middle East. The parasite is probably mentioned in the Egyptian Papyrus Ebers (c.1550 B.C.) 99. Thus, Hoeppli49 believed that the following selectio n from this papyrus is possibly a description of the treatment of an infection with Guinea worm; "-----" represents the lesion and cannot be translated wit h certainty: If thou examinest a swelling of ----- in any limb of a man, then thou shalt apply a bandage to it. If thou findes that it goes and comes, piercing through the flesh which is under it, then thou shalt say concerning it; ----- has entered (?). Thou shalt perform an operation for it, the same being split with a....knife and seized with an ....instrument (forceps); that which is in its interior is seized with a forceps and then thou shalt remove it....That which is like the head is seized. 29

It is certainly true that dracunculiasis was endemic in Egypt at the time for the calcified remains of a Dracunculus have been identified in the mummy of a 693

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teenage girl entombed around 1,000 BC 22. The theory was advanced in 1855 by Küchenmeister 59 that the "fiery serpents" which attacked the children of Israel in the desert during their exodu s from Egypt (c.1250 BC) were in reality Dracunculus medinensis , thus making the Mosaic passage in Numbers 21: 6 (th ought to be written in 8th century BC) one of the earliest recorded references to the worm: "Then the Lord sent fiery serpents among the people, and they bit the people, so that many people o f Israel died" (Revised Standard Version). Küchenmeister's postulate has been accepted with enthusiasm by some but rejected by others 5,6,124. The affliction was mentioned by Agatharchides of Cnidus (2nd quarter of the 2nd century BC), a geographer and teacher of one of the sons of Alexander Ptolemy VII. The original manuscript has now been lost but Plutarch (c.46-120 AD) refers to him in the eight book of his Symposiacon (Table talk) where he makes him narrate: The people who live near the Red Sea are tormented by an extraordinary and hitherto unheard of disease. Small worms issue from their bodies in the form of serpents which gnaw their arms and legs; when these creatures are touched they withdraw themselves and insinuating themselves between the muscles give rise to horrible sufferings.1

The condition was also known, either by experience of as a result of hearsay, to a number of other Greek and Roman writers including Pliny (23-79 AD) , Soranus of Ephesus (c.100), Julius Pollux (c.185), Galen (129-c.200), Aetius of Amida (c.550) and Paulus Aegineta of Alexandria (c.840). It was described by a number of Persian-Arab physicians including Rhazes (died 928) an d Avicenna (980-1037). Among the first Europeans from non-endemic areas to come in contact with the worm were Amatus Lusitanius, van Linschoten , Alexei de Abreu, Edward Wotton, Thomas de Veiga, Joh. Gorraeus, Mercurialis and Ingrassia, all in the sixteenth century. Considerable uncertainty surrounded the nature of the affliction. Som e authors including Aetius, Paulus Aegineta, Rhazes, Amatus Lusitanius, Alexei de Abreu, Wotton and de Veiga apparently regarded it as a worm. Others , however, thought it was a corrupt nervous substance (Soranus, Pollux, Galen, Paré), a tumour or abscess (Gorraeus, Aldrovandi, Montranus), an elongated vein (Guy de Chauliac), black bile (Tagentiu s), fibrous concretions (Richerand) or atrophied cellular tissue (Larrey). It is also not always clear precisely what some of the early writers thought was the nature of the worm. The Persian-Arabic physician, Avicenna (= Abu Ali al Husain ibn Abdallah ibn Sina) is a case point. According to Hoeppli 49, Avicenna denied its animal n ature, believing it to be a vein. Amatus Lusitanius (1511-1568) was also of this view, f or he wrote in Latin (translated by Singer): A certain Ethiopian slave....was seized with pain in the leg. An ulcer developed, in which vein-like structures became prominent....The Arabian physicians especially Avicenna....describe it as the Medina vein.9

On the other hand, Singer provides the following English translation of a Latin

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rendition by Velschius of Avicenna's text: In the meanwhile a vermicular movement can be distinguished beneath the skin as though some live thing were there, and indeed as we shall see, a worm is present, for so at least some regard the thing that has arisen. 8

From the overall sense, it seems pretty certain that Avicenna was indee d referring to a worm, but the difficulty apparently lies in the accurate translation of the original Arabic (Ark, Aerk, Irk or Erk Almedini) which the Greek and Latin translators of the Middle Ages, having no opportunity of seeing th e creature, rendered as "Vena seu Nervus medinensis" (vein or nerve fro m Medina). Thus, Andry (1700) wrote: "Avicenna calls this Worm by the name of Vena by reason that it resembles a small vein" 3. According to Hoeppli again, the work Ark simply means something long, thin or filariform 49. Küchenmeister, however, quoted one autho rity in support of the suggestion that perhaps it meant "to corrode" or " to gnaw away", thus indicating that it referred to a worm which gnawed away at the flesh 59. Because of this uncertaintly , different translators have therefore used different words in their translations , depending upon their personal preferences. Examples of these various opposing views are provided by Paré and by de Veiga: "This little dragon is not a worm, nor indeed any living Thing, but only a Swelling and an Imposthum e occasioned by too hot Blood" 101 compared with "Whoever entertains such Doubts has taken a narrow view of 'em. 'Tis certain this worm moves" 132. Such confusion lasted for many cent uries for as late as 1824 superintending Surgeon Milne of Bombay, India wrote: The substance in question cannot be a worm because its situation, functions and properties are those of a lymphatic vessel and hence the idea of its being an animal is an absurdity.85

Nevertheless, the opinion that the pathology in question was due to a worm gradually gained ground. Amatus Lusitanius (1551-1568) left no doubt as to his own views when he wrote: Authors are in doubt whether this is a nerve, a vein or a worm. But I have seen the condition with my own eyes, and can bear witness that a thin, white worm in many coils was drawn forth.2

In 1674, Georg Hieronymous Velschius (Welsch) wrote a large monograph of 456 pages on the single subject of dracunculiasis. He saw drancunculi everywhere including on ancient Roman emblems, in the signs of the zodiac, among marine nemertines and polychaetes, in Arabic lettering, in many Gree k sculptures and in the emblem of the medical profession (serpents coilin g around the staff of Aesculapius which he interpreted as a Guinea worm jus t extracted by entwining it around a piece of wood) but asserted that dracunculi were definitely alive and verminous 133. Amongst those who accepted the verminous nature of disease, there wa s considerable confusion concerning the morphology of the creature. Thus , Nicholas Andry wrote in 1741: Two things have to be pointed out concerning this worm: 1. It has two heads: not

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one at the side of the other, but one situated at one end, the other one at the other end, as in some caterpillars. 2. Always one of the two heads appears dead, whereas the other one appears alive.3

Linnaeus recognized it as a worm and in 1758 in his Systema Naturae, classified the parasite in his Class Vermes, Order Intestina, naming it Gordius medinensis 71. The specific name, as already inferred, was derived from it s prevalence around the Arabian city, Medina, as was recorded by Avicenna : "The disease is commonest at Medina, whence it takes its name" 8. In the revision by Gmelin of Systema Naturae (thirteenth edition) published in 1788, the worm was transferred from the free-living species of Gordius to the genus Filaria of Müller (see chapter 23) and it became known as Filaria medinensis for some years 43. Any lingering doubts as to the animal nature, specifically the helminthi c nature, of the parasite should have been dispelled by the discovery in the early nineteenth century of the embryos (lar vae) released by the parent worm (as will be described later). The first detailed description of the worm's anatomy was published in 1868 by the Englishman, Henry Bastian, and put paid to an y lingering reservations that D. medinensis was in fact a worm. He examined six specimens which had been taken from the lower extremities of a Britis h surgeon in Bombay by a native of that Indian city. The parasites varied i n length from 18 inches to three feet and macroscopically were: of a milk-water colour....mostly quite smooth,....cylindrical, more or less flattened laterally and tapering gradually towards both extremities. About 1/20 of an inch from the posterior extremity the body becomes more abruptly narrowed, and terminates usually in a sharply curved tail or point....No vulva discoverable; and aperture doubtful....The integuments are so elastic, that the worm may be stretched to nearly twice its natural length.10

Bastian then described the appearance under the low power microscope of the small head, the lamellar nature of the chitinous integument, four powerfu l longitudinal muscles, two delicate ganglionated chords extending the whol e length of the worm, four longitudinal "circulatory vessels" and the gut. All the worms were female and viviparous. He found th at the reproductive organs were huge: The genital apparatus consists of a large, highly organized sac or uterus, distended with young Filariae and a little fine granular matter. It occupied the whole of the peritoneal cavity....except from one to two and a half inches from the anterior extremity and about a quarter of an inch or less from the tail. Both anteriorly and posteriorly, this sac terminated abruptly in a small tube twisted several times around the intestine, or forming a knotted glandular-looking mass. 10

In 1879, Fedchenko improved upon the description of the anatomy of the worm. He found a basal granular layer in the hypodermis which formed th e outer layers of the integument, discovered some transverse muscle fibres , discussed the morphology of the head, excretory system and gut, layin g particular attention upon the oesophagus and surmising that the worm ingested food, and concluded that the uterine appendages were ovaries 36.

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Bastian was intrigued by the failure to find any male worms and speculated that either the males never attained any great size and therefore failed to attract attention whereas the enormous development of the genitalia of the female s made them so large that they became palpable in superficial situations, o r possibly, that the male worms, in contrast to the females, never entered th e body. The former hypothesis was proven correct when RH Charles at las t discovered the male worm. During an autopsy in Lahore, India in 1892, h e found two nematode worms in the subperitoneal tissues which he regarded as immature D. medinensis. He went on to say On examining two....I was struck by seeing something growing from the side of each of them. This 'something' I found to be a roundworm with the characters of that to which it was attached. On drawing upon it with forceps I found, to my astonishment, that it was possible to pull it out of the body of the larger worm from a small opening near its middle....I did not completely pull it out and only withdrew it about 1 cm.18

Charles was of the opinion that the "something" was a male Dracunculus but failed to provide convincing evidence to support his case. A contemporar y commenator wrote in the British Medical Journal : Before subscribing to Dr. Charles's views, we should like to see a more detailed account of the structure of this "something"....Dr. Charles gives no account of the head, tail, testicle, alimentary canal, spicules, papillae, or any of those features characteristic of male nematodes. Until these are fully supplied we suspect that helminthologists will be inclined to regard Dr. Charles's supposed male filaria medinensis as being probably a hernia or the uterus or alimentary canal of the female....It is quite possible however, that Dr. Charles in right of his views; but in bringing them forward the least he could have done, in justice to himself and in the cause of science, was to use every means in his power to justify the position he assumes and to make it unassailable. It is not too late yet if he has the interesting specimens he so meagrely describes in his possession. 7

Subsequently, Leiper (1906) found two male worms about 22 cm long in an infected monkey 61. Surprisingly, he never provided a detailed description of their morphology yet he did not encounter the censure that Charles ha d received. The first substantial account of the morphology of the mal e Dracunculus was provided in 1937 by Moorthy 86. In his discussion of the anatomy of the Guinea worm in 1863, Bastia n remarked that he doubted the propriety of considering the worm as a species of the genus Filaria. Of the many names which had been used to designate the worm previously such as "de vena medinensis" 133, "de dracunculo Persarum" 57 and "de verme medinensis" 46, two of these "dracunculus" (derived from th e Latin word "draco" meaning "snake", "serpent" or "dragon") and "medinensis" were adopted into binary nomenclature (i.e. Dracunculus medinensis ) by Cobbold in his text book of the following year 20. In 1915 by Opinion 66, th e International Commission on Zoological Nomenclature approved this name , Dracunculus medinensis being the type of species of the genus Dracunculus 53. The first person to use the name "Dracunculus" after 1758 (the starting point for binary nomenclature following the appearance of the tenth edition o f

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Linnaeus's Systema Naturae) had been Reichard in 1759 115, and it was this name which was given official sanction. This was later disputed by Leiper , however, on the ground that Reichard only used it in a vernacular sense in his thesis. Leiper applied the same criticism to the use by Gallandat in his thesis in 177342 of the term "medinensis" to modify "dracunculus". Despite Leiper' s objections and his attempt to change the name to Füllebornius medinensis 65, the official name Dracunculus medinensis (Linnaeus 1758) Gallandat 177 3 still stands. With respect to its common name of Guinea worm, Sir James Tennent , Colonial Secretary of the British Government in Ceylon (Sri Lanka) wrote: these pests in all probability received their popular name of Guinea worm from the narrative of Bruno or Braun, a citizen or surgeon of Basle, who about the year 1611, made several voyages to that part of the African Coast, and on his return, published amongst other things, an account of local diseases. 127

EARLY THEORIES ON THE MODE OF TRANSMISSION The belief that Guinea worm was acquired from water was embedded deeply in the folk-lore of the inhabitants of many endemic areas. This was accepte d and reported by a number of European adventurers who began visiting suc h regions in the sixteenth century. The Dutch navigator, Jan van Linschoten , journeyed to the East Indies and on his return to Holland wrote a number o f books which became very popular and were translated into many Europea n languages. In 1584, he had visited Hormuz (Ormus, Ormusz) in the Gulf o f Oman (Persian Gulf) and wrote: "There is in Ormus a sickness or commo n plague of wormes, which growe in their legges, it is thought that they proceede of the water they drink"73. Van Linschoten also noted that the place was so hot that the inhabitants slept at night immersed except for their heads in troughs of water and "Thus it comes about that they are infected by worms, which grow in their legs, and are two or three feet long" 73. Thus, not only did Linschote n recognize an association with water, but he appears to have canvassed the two ideas which were to become a recurring theme over the next three centurie s concerning the acquisition of infection - ingestion of worms and penetration of worms through the skin. About the middle of the seventeenth century, Monseigneur de la Mott e Lambert, Bishop of Beirut, undertook a pastoral tour of the Middle East and a record of his experience was published. He found that in the town of Lau i n Persia (Iran): the water....is very bad and the cause of severe and mortal diseases. To this bad water supply throughout the country between Lau and Gomeron may be attributed worms of a prodigious length which engender in their thighs and legs 12

In the latter part of the same centu ry, a British traveller to the East Indies stated in the Philosophical Transactions , concerning the Guinea worm with whic h he had been afflicted: "These worms are bread by the water, between Gomroom

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and Schiraz, especially that about Laur" 74. The resemblance of Guinea worms to the free-living Gordius aquaticus or "hairworm" inhabiting ponds and rivers led some 18th century writers such as Meyer to suppose that the entozoon was really the latter worm which ha d penetrated the cellular tissues 84. Similarly, Linnaeus thought that the Guine a worm normally lived outside the human body, but when pathogenic, introduced itself through the skin of the legs 72. The Englishman James Lind (w ho introduced citrus fruits as a prophylactic against scurvy at sea) showed much more insi ght into the mode of transmission, however, when in 1768 he wrote: and thus supposing the guinea worm to be generated from animalcula or their ova contained in the waters of the country, their production in the human body may probably afterwards be prevented by drinking those waters only that have been rendered perfectly sweet by undergoing a previous putrefaction. 68

Lind achieved this purification by first sealing containers of pond water from the endemic areas in West Africa until microscopical examination indicate d that all the animals were dead, and then foll owing this with sieving of the water. At around the same period, the Frenchman, Gallandat, also favoured th e theory that infection was acquired by ingestion of water because his observ ations led him to believe that those who drank no water in Guinea escape d infection41. Likewise, the Briton, Colin Chisolm (1795) in Grenada noted with respect to Guinea worms that "the cause of this singular disease....seems to be confined to the water of some wells" 19. Chisolm found strange animalcules in such water and showed that the disease could be prevented by the filling in of the wells. Similarly, Ferg in Surinam rep orted that an outbreak of Guinea worm infection had occurred on a plantation in Surinam in 1801 and noted that both the field-hands and the household slaves, who had nothing in common except the water supply, became infected 37. On the other hand, there were several anecdote s which seemed to go against the theory that infection was acquired from ingestion of contaminated water . Küchenmeister59 quotes two such instances. While in Curaçao (Netherland s Antilles), Jacquin, who drank much water remained free from infection , whereas his companion who consumed only spirituous liquors was affected . Similarly, a Dutch general in Angola a te and drank nothing but food and beverages brought with him from Europe yet acquired the worm. Similarly, several observations by British medical offic ers in India also seemed to militate against the water ingestion theory. In 1806, Bruce claimed that watercarriers in India who carried leather bags on their backs suffered from dracunculiasis chiefly in those same parts 14. This claim was supported by Scott but rejected by a number of other observers including Smyttan, Morehead and Ewert. In 1816, Heat h reported that in an outbreak of dracunc uliasis amongst the crew of a ship which had lain for a long time in the port of Bombay, only the crew became infected whereas the officers remaine d free of the infection; both groups drank from the same water supply, but only the officers wore shoes while on shore 47.

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Consequently, these events were interpreted as indicating that infection wa s acquired from water through the skin. All this remained mere speculation, however, and no significant advances could be made until the offspring of the Guinea worm were identified. Th e embryos of D. medinensis, and the fact that female worms were viviparous , were discovered and first reported in 1819 by Rudolphi in his major work , Entoozorum Synopsis, wherein he wrote: "Filariae nostrae prole quasi farctae sunt, quod si harum longitudinem illius vero minutiem spectas, foetuum multa millium milklia singulis tribuit" 121 which may be translated roughly as saying that if the longitudinal organs of the worm are in fact observed closely, many thousands of individual embryos may be discerned. This remark lay buried among so much other data, however, that littl e notice appears to have taken of the observation and the phenomenon had to be rediscovered several times before the fact became known widely. The firs t person to do this was Jacobson in Copenhagen who examined a Guinea worm removed from a 13-14 year old b oy who had been born on the coast of Guinea; he recounted his findings in a letter send to M. Blainville in Paris in 1834 55. In the following year, Duncan in Calcutta, India also found on microscopica l examination of Guinea worms that the uteru s was packed full of embryos 27. The presence of embryos was soon verified in that country by Forbes 38 and by McLelland75. The existence of embryos was then reaffirmed in Europe by the Parisian surgeon Maisonneuve in 1844. In 1840, Maisonneuve had examined a 28 year old patient who had spent two and a half years soldiering in Senegal and had contracted dracunculiasis. During extraction of the worm, a few drops of white fluid, like whey, escaped and microscopical examination disclose d myriads of small cylindrical, amazingly active worms with pointed tails 80. Furthermore, continued observation revealed that they remained alive for one to two days. Maisonneuve commented that when the time for reproducin g arrived, the worm makes an ef fort to perforate the skin in order to discharge its young into the external environment. As already mentioned, the question which followed naturally from all o f these observations concerned the manner in which infection was transmitted to another host. Once Duncan had found embryos in the Dracunculus uterus, he was stimulated to search the envi ronment. He reported that "the soils and pools abound in the rains with a worm smaller and more slender, but otherwis e exceedingly like (Guinea worm)" 27. Likewise, Forbes in Darwar, India als o looked in water for worms and may well have found larvae liberated by female worms for he wrote: I examined several of the tanks in the neighbourhood and found the mud on their banks and in their half dry beds abundantly supplied with animalcules, some of them resembling very much those produced by the guinea worm when infecting the human limb....Two kind of these animalcules may be detected in the soft mud: one kind seven to eight times the size of the guinea worm animalcules, the other exactly resembling it.38

In the same vein, Brett (1840) claimed to have found Dracunculus in the

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flood-plains on the banks of the river near Dhun in India 13. It seemed likely, therefore, that the released embryos were carried through the medium of water, in which case t wo modes of entry seemed possible; either the worms could be ingested in contaminated water or the larvae coul d penetrate the skin when humans waded in infected water. The first person t o investigate these possibilities experimentally appears to have been Forbes in India in 1838. He obtained fr esh larvae from the leg of a sepoy (Indian soldier) then gave them to two pups. On examination of the dogs, one 4 hours and the other 24 hours later, he foun d the worms dead in the mucus of the stomach and duodenum38. This seemed to oppose the ingestion theory and gave credence to the idea that infection was acquired by worms penetrating the skin. In 1855, Carter in Bombay, India published some epidemiological observations which he also interpreted as supporting this latter concept. Over th e period of a year, 21 out of 50 boys in the School of Industry in Bombay ha d been infected with Guinea worm, although none who had been admitted to the school within the last year had b een so afflicted. The boys lived in an enclosure bounded on three sides by the sea and on the fourth side by a cliff. Within the enclosure were two wells, one three feet and the other six feet in depth; th e former was used for providing drinking water and the latter for bathing. I n addition to the boys, the wife of the sergeant who superintended the school was also infected; she bathed in the well but obtained her drinking water fro m elsewhere. Carter examined these tanks and found minute worms closel y resembling the young of guinea worms. In ano ther school, where dracunculiasis was absent, he could not find these "tankworms" and concluded that infection was acquired by bathing in, not by th e drinking of, water which contained these "tankworms" 17. The idea of skin penetration gained ground, and despite the fact that nothing had been proven, an anonymous writer in The Lancet of 1867 asserted dogmatically: The most contradictory opinions have been expressed by correspondents in the daily journals on the subject of guinea-worm disease. The real facts of the case are simply these. In certain tropical parts, minute worms abound in stagnant pools and swampy ground. These have the power of penetrating the skin, in virtue of their "boring" properties, and subsequently grow to a large size, causing, after a few months, local irritation and the formation of a quasi-abscess, which is a provision of nature to aid expulsion of the worm. The lower limb is the part most usually attacked, and the worm makes its way thither via the feet of natives, and simply because they are commonly unprotected and in contact with the bare ground. But Europeans would be equally liable to guinea-worm disease did they go about with bare feet. 4

Several years later, however, all this was to change with the epocha l discovery of Fedchenko.

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ELUCIDATION OF THE MODE OF TRANSMISSION: DISCOVERY OF THE CRUSTACEAN INTERMEDIATE HOST In the three years between 1868 and 1871, The Russian naturalist, Alekse j Fedchenko, and his wife lived in Turkestan , Samarkand and Tashkent in central Asia. It was during this period that he made his original observations on D. medinensis. Fedchenko made arrangements in 1869 with one of the loca l doctors to provide him with Guinea worms extracted recently from infecte d persons. His first attempt to study the fate of the embryos failed when he killed them by adding fresh well water which was rather cold and was rich in lim e salts. He then told how: an incident helped me in my research....On the 5th of July, in the small bottle in which (the doctor) had brought a guinea worm, I noticed a pair of small water crayfish - the Cyclops. Placing them under the microscope, I saw in each one several familiar looking embryos of the guinea worm.36

In order to convince himself that the embryos of the Guinea worm reall y entered the Cyclops, he performed an experiment. He punctured a Dracunculus and placed the embryos in a watch glass. He then added water and Cyclops which he had assured himself were free of any larvae. Although he did no t succeed in determining whether the embryos were ingested or whether the y penetrated the cuticle of the Cyclops, he discovered that "after several hours a significant number of embryos appeared in most of them, especially in males and particularly in young specimens" 36. Fedchenko found that there wer e usually five or six larvae lodged in the body cavity of each minute crustacean. He watched the evolution in the appearance of the worms over the succeeding weeks. During the first few days, the gut became more developed, then afte r two weeks the larva moulted and lost it s tail. By three weeks, the differentiation of the internal organs had become more pronounced with the rudiments of the reproductive organs appearing. Finally, Fedchenko provided an illustration of a larva after a sojourn of one month in the crustacean. He presented his findings to a meeting of the Imperial Society of Friends of Natural Sciences , Anthropology and Ethnography in Moscow on 21 January 1870, his pape r being published later that year in the Proceedings of the Society 36 Fedchenko wrote that at the beginning of his studies he had placed Dracunculus larvae in a small aquarium containing different water animals in th e hope that Guinea worm, like so many other parasites, would live first in some such animal then pass on to man. He made no mention in his paper, however, that he had been advised by others to follow any particular line of enquiry . Indeed, by recounting the incident of 5 July, he implies that his initia l observation with Cyclops was serendipitous. This does not seem to be a n accurate portrayal of the preceding events, however, for Leuckart 67 remarked that he had met Fedchenko in 1868 and had advised him to look for th e development of D. medinensis in Cyclops because of the similarity between its

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embryo and that of Cucullanus elegans, a parasite of perch, the life cycle o f which Leuckart had already work out and publis hed in 1865. Cobbold, who had met Fedchenko when the latter visited London in 1873 later wrote: It is only fair to add that the Russian traveller was led up to his discovery by the previous investigations of Leuckart concerning the young of Cucullanus. The Leipsig helminthologist had, indeed, specially instructed Fedschenko as to the probable source of Dracunculus. It is often thus that science makes its clear advances, since a master-mind is needed to set others on the right track. 21

A more important, but undoubtedly erroneous, criticism of Fedchenko' s contribution was expressed by Manson-Bahr in his textbook in 1966 when he wrote: Fedchenko (1869) is credited with the discovery of the transmission of the guinea worm, but probably Manson was the original observer (1895). Leiper believes that the stages figured by the former are those of Cucullanus (a parasite of fish), not of D. medinensis.83

In fact, Leiper had been much more circumspect than this. He had merel y observed that Fedchenko's paper, published in Russian in 1870, was ver y inaccessible and that two of the illustrations of purported Dracunculus given in Leuckart's textbook 67 were undoubtedly based upon a specimen of a Cucullanus larva66. Manson-Bahr's statement brought forth a response fro m Hughes in defence of Fedchenko. He arranged for Fedchenko's paper to b e translated and summarized it by saying that w hatever the defects in Fedchenko's drawings, his written account was convincing enough 52. Final confirmation of the validity of Fedchenko's discovery was provided shortly thereafter whe n Muller published a reproduc tion of Fedchenko's original drawings and showed that it undoubtedly represented a D. medinensis third stage larva 92. Although Fedchenko discovered that D. medinensis larvae grew and moulted in the crustacean, Cyclops, he was unable to complete the cycle o f transmission. He posed a rhetorical question, then went on to postulate, with accurate foresight, the subsequent course of events: What then happens to the embryos at a later stage? It seems to me that, taking into consideration the known facts concerning the development of other roundworms, one can state the following: Cyclops, with the embryo, enter the stomach of man through drinking water; here, under new conditions, further development occurs pertaining primarily to the genitals. The differentiation of males and females occurs, and copulation takes place. Thereafter, the males die; however, the females, to develop their offspring, take off by unknown means, toward the skin where they place themselves subcutaneously.36

In support of this hypothesis, Fedechenko drew attention to a multiplicity of diverse observations: all specimens studied so far were female; Pruner i n Egypt had discovered a worm in the liver; the head of the worm pointe d towards the skin; the fact that in Asia the infection occurred only where th e inhabitants were forced to drink stagnant water and that these people, i n contrast to the Hindus of India, did not go barefoot and rarely bathed but, i n accordance with Muslim custom, washed their face and hands five times each

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day with their hands. He concluded by saying that: Now, experimentation is needed - similar to the feeding experiments conducted in studying tapeworm or other parasitic worms - to prove whether the Cyclops, with the embryo of Filaria, swallowed by a human being, is the cause of guinea-worm disease.36

According to Cobbold 21, Fedchenko himself did later undertake some desultory experiments in this regard but without success. He fed infected crustaceans to dogs and cats, but failed to rear dracunculi in these animals. This did not put Cobbold off for he remarked: Clearly, these carnivora were unsuitable hosts. Could Fedchenko have experimented on man the results would probably have been very different. Arguing from what happens in the case of Cucullanus amongst fishes, and Trichina in man, there can be little doubt that all further and final changes undergone by the larvae are accomplished within the human host.21

Rather surprisingly, more than 20 years were to pass before anyon e repeated Fedchenko's important experiments. In 1894, Patrick Manson had a patient with Guinea worm infection in the Seaman's Hospital in London. H e collected a supply of embryos from this patient and mixed them with a number of Cyclops procured from neighbouring ponds. Twelve hours or so later, h e found that nearly every one of the copepods had 10-20 larvae coiled an d wriggling within the body cavity. He believed that infection had taken place by penetration of the joints in the integument. Over the ensuing weeks he watched the slow metamorphosis of the worms. He repeated the experiment in th e following year and found that, in contrast to Fedchenko's belief, the enclosed larvae moulted not once but twice 81. In 1905, Leiper studied dracunculiasis on the Gold Coast (Ghana) of West Africa and performed a new series of experiments in which Cyclops was infected. He thought it probable that the crustaceans were infected via their oral cavity; this view was later to be proven correct by Turkhud 129 and by Roubaud119. Furthermore, Leiper found that once metamorphosis was complete, the larvae lay quiescently within the crustacean for several weeks. Whe n hydrochloric acid was added to simulate t he acidity of gastric juice, the Cyclops were killed but the Dracunculus larvae regained their former activity an d escaped from the disintegrating intermediate hosts. He interpreted thes e observations as indicating that once the worms were set free in the stomach of the human host, they were able to proceed with further development within the human body 60. The species of Cyclops which Fedchenko in the USSR and Leiper in West Africa used are uncertain. That used by Manson in England was probabl y C. quadricornis. Other species, including C. leuckarti 119, C. hyalinus 87 , C. nigerianus 96 and C. vernalis 125 as well as other carnivorous species of Cyclops were later shown to be infected. While still in West Africa, Leiper turned his attention to attempting t o complete the life cycle of the parasite. In 1898, Plehn in the German Camer-

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oons (Cameroon) had claimed to have found a female worm, indistinguishable from the Medina worm, in a monkey eight months after feeding it banana s containing first-stage larvae 102. In the light of hindsight, however, it must b e concluded that the relationship between these two events cannot be causal. In order to prove whether or not an intermediate host was necessary, Leipe r induced a monkey to swallow thousands of newly-liberated embryos, but n o sign of infection could be found at a utopsy six months later. He must have been convinced absolutely that a vector was required for he applied living embryos to the dorsum of his own hand; no erythema or itching occurred and no patent infection developed subsequently 62. He then fed a monkey on bananas wit h Cyclops that had been infected with D. medinensis for five weeks. Six months later, he and Dr. Daniels made a careful post-mortem examination and found five worms which possessed all the characteristics of D. medinensis. Three were immature females about 30 cm long, and the other two were small male worms 22 mm in length 61,62. He concluded that: these results point strongly to the truth of the theory that infection of man takes place from the drinking of water containing infected cyclops....The finding of both male and female forms in the connective tissues relieves us of the more improbable alternatives previously open to us....The view that larvae at once make their way through the gut wall and become sexually differentiated later in the tissues of their host, brings the after-development of the parasite much more into line with that of other filariae62

In discussing the great frequency of infection in the lower limbs of humans , Leiper noted that in his experimental monkey, the female worms had made their way into the limbs, being found in the forearm, axilla and popliteal space. He remarked that "geotropism" seemed to him to provide the most likel y explanation for the distribution of the parasite. Several years later, Turkhud in the Bombay Bacteriological Laboratory in India attempted to repeat this experiment. Numbers of monkeys were infected orally with living first-stage larvae or with infected Cyclops, while others were given embryos by subcutaneous injection. Post-mortem examinations wer e made up to one and a half years later, but no dracunculi were ever found 130,131. Consequently, five "volunteers" ingested five infected Cyclops containing a total of 6-8 D. medinensis larvae on 5 April 1913. On 18 March 1914 (38 4 days later), one of the volunteers, a laboratory assistant who had remained well during the interval, developed a small blister on his right foot together wit h fever, vomiting and diarrhoea. On the 30th of that month, the blister was found to contain D. medinensis embryos. None of the other four subjects developed patent infections131. Turkhud may well have completed the life cycl e experimentally, but this report must be viewed with some circumspection as the area was endemic for dracunculiasis and the infection could have been acquired naturally. Several other unsuccessful attempts were made to repeat Leiper's exper iment with monkeys 32,119 until Brug in the Dutch East Indies in 1930 recovered

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a full-grown female worm from the calf of a gibbon 15. Four years later, Issajev in the Soviet Union reported that in a series of experiments between 1927 and 1932, he had infected 42 dogs orally and obtained female worms from 27 o f them54. In 1936, Moorthy and Sweet confirmed this result by indicating tha t they had produced patent infections in a number of dogs. Furthermore, the y recovered a large number of male and female worms 88,90. It was this latter experiment which finally provided a definitive description of the male worm, thus completing all the major links in the life-history of D. medinensis. It remained to define the route of migration of worms within the body of the definitive host. Onabamiro (1956) could find no trace of worms in dogs until 43 days of infection, when he found them par ticularly in the axillae and inguinal regions, thus suggesting that they may have migrated there via the lymphati c system97. Muller then investigated the early route of infection in dogs, cats and monkeys; he found larvae in the duodenal wall 13 hours after infection, in the abdominal mesentery for up to twelve days, then in the thoracic and abdominal muscles at two weeks. He thought it likely that a moult took place and th e worms migrated to the axillary and inguinal subcutaneous tissues. The mal e worms died between three and five months after infection and became encysted while the female worms began moving down the extremities between the eighth and tenth months 93,94

DETERMINATION OF THE INCUBATION PERIOD The time required for development of worms in these experimental infections was consistent with the period thought to be necessary for the development of patent infections in humans. It had long been known that a number of months were required for clinical expression of the infection. Kuchenmeister (1855 ) remarked that the infection was asymptomatic for a long time 59 and Moquin-Tandon (1861) wrote that the incubation period varied between two months and a year or more 91. In 1880 G Mackay, a retired Deputy Surgeon General of the Indian Army, recorded that a regiment of native infantry arrived at Madras in February 1860 when dracunculiasis was rampant. In Februar y 1861, the first cases of Guinea worm infection amongst the troops wer e admitted to the regimental hospital; during the following four months, 13 5 cases, being 25% of the strength of the regiment, occurred. Mackay wrote: Having had many opportunities of observing the origin and progress of this most troublesome and often formidable parasite, I believe that a period of from eight to twelve months is necessary for the full development of the worm in the human system79

Cases which occurred in expatriates aft er leaving endemic areas provided more certain evidence of the minimum time required. In 1879, Fox reported th e instance of a young Englishwoman in whom a Gu inea worm had appeared eight months after leaving India 40. In 1909, Manson recorded the occurrence o f

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infections in two Englishmen who had been exposed in the Sudan twelve plus or minus several months previously 82. In the following year, Powell reported an event in which 16 Indians were exposed during a three day period from 20-22 April 1902. The first worm appeared in the first patient on 3 April 1903 (h e discharged eight more over the next three months). Six more of the party were similarly afflicted between 1 May and 20 May 1903, giving incubation periods ranging between 345 and 437 days104. A somewhat shorter pre-patent period was reported by Wurtz and Sorel. In March 1911, they paid a visit of thre e hours to a village in the Ivory Coast where they noticed many cases of drac unculiasis; 260 days later, two of their se rvants were found to be infected 134. All these observations left little doubt that a period of approximately one year was required between acquisition of infection and the presentation of the adul t female worm.

RECOGNITION OF THE CLINICAL FEATURES The clinical manifestations of dracunculiasis have been apparent for all to see since time immemorial. At the beginning of the second millenium AD , Avicenna succinctly described the condition: The signs of this condition are as follows. A pustule first appears and swells up, but afterwards contracts down again to a mere bleb. Soon, however, the bleb perforates and dark red matter is continuously exuded. In the meanwhile a vermicular movement can be distinguished beneath the skin. For the most part it is the legs that are involved, but I have seen cases in which the hands and even the sides are affected.... Should the worm be ruptured, much pain and trouble ensue, and even if rupture does not take place, the condition is tiresome enough. 8

In the late seventeenth century, Lister, an English traveller recounted vividly his own experiences. He related that he had known some sufferers who had been bed-bound for up to ten months, and that there were some who had lost their legs, or even their lives. He recognized that the severity of the disease wa s increased enormously if the worms were broken during their extraction: A few days after my arrival....the fruit of my journey showed themselves; for a little below the instep of my left foot, a worm put out his head....When mine first came out, for about 40 to 50 days, it came out every day little by little, without putting me to too much pain, but that I could go up and down till it was come out about a yard and a quarter; but afterwards, one day stirring too much, I hurt the worm and enraged him, so that he broke off of himself, and going in, caused my foot and leg (up to the calf) to swell till the skin was ready to burst, which kept me sleepless and cast me into a fever. I had a chirurgeon and kept my bed for about 20 days in which time I had several fits of the said fever.74

One thing above all struck most observers, and that was the remarkabl e frequency with which the worms presented in the feet. In 1805, McGregor in India reported that in 87% of h is series of 181 patients the worms were located in such a situation78, and this observation has more or less held true in al l

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subsequent reports. For example, Forbes reported his experiences as a medical member of the Anglo-French Boundary Commissi on in the Gold Coast (Ghana) and French West Africa (Ivory Coast) colonies in 1902-1903. Forty percent of the 400 native carriers were afflicted wi th Guinea worm, the sites of emergence being the lower limb in 77% (feet in 22%), upp er limb in 9%, scrotum in 4.5%, abdominal wall in 4%, back or buttocks in 3.5%, face in 1% and penis in 1%. Nearly half of his patients had multiple infect ions, most of them having between two and ten worms39. Occasionally, massive numbers of worms are present ; Trewn reported the instance of a person who ha d 55 worms at one time 128. This, however, was not the general experience; more typical was the finding b y Fairley and Liston that the average number of worms per person in their series of 140 patients was 1.9 33 and the observation of Rao that 2,086 of 3,12 9 patients had only one worm 112. It has long been realized that most persons were quite unaware of th e presence of the worm during the prepatent period. In one large recent series, only one third of patients were a ware that anything was amiss before the blister appeared, and most of these patients only discerned a palpable worm several days earlier113. As the time for presentation of the worm approached, there was not infrequently urticaria, vomiting, fever, abdominal pain and sometime s dyspnoea, possibly produced by a toxin released by the worm 31,33. One somewhat racist commentator wrote in 1914: the patients being for the most part, in Africa at least, people of limited intelligence this testimony is unreliable. My opinion is that premonitory symptoms are not the rule; nevertheless they have been not infrequently described and are probably more common in Europeans.76

More objective investigators, however, have found that such symptom s occurred in 30-90% of their patients 16,26,33. In simple cases of Guinea worm infection, it was apparent that worm s extruded gradually over a period of four to six weeks, then the ulcer heale d leaving a scar. It was also realized from the earliest times 8 that if the worm ruptured, then severe inflammation was likely to follow. Secondary bacteria l infection often supervened; in a series of 218 cases, septic complications were present in nearly half of the patients 33. Sometimes, the worms failed to surface and became encysted and calcifie d in the tissues where they remained for many years23,114,118. Occasionally, the dracunculi were observed to enter a joint , especially the knee, where they sometimes liberated larvae into the synovia l fluid and precipitated a severe arthritis. Susceptibility to infection and resistance to reinfection is a vexed topic . Trewn, who had the experience of removing 526 guinea worms during th e space of three years, noted that some people never became infected eve n though they used the same water sources as did others who got yearly infections, thus implying that the former were immune, whether for constitutional or immunological reasons, whereas the latter had acquired no resistance t o infection128. This was confirmed by Rao who surveyed some 11,000 villagers

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in India and found almost 30% infected. Nearly two thirds of these people had had more than one attack, and 10% of them had had ten or more attacks over the years112. Similarly, Reddy and colleagues studied 10,000 villagers in th e South Indian Deccan where infection rates ranged between 11 and 53%. They found that multiple infections, reinfections, and superinfections were frequent, thus suggesting that no immunity developed 113.

DEVELOPMENT OF DIAGNOSTIC METHODS The diagnosis of Guinea worm infection is usually obvious when the wor m makes it appearance in the ulcer. If any doubt remains, some fluid exuded by the worm can be obtained and examined microscopically for the pathog nomonic larvae. Patrick Manson in 1895 described the remarkable manner in which such a collection may be obtained: Squeeze a little cold water from a sponge so that the stream should fall on the sound skin within an inch or two of the guinea-worm ulcer; at the same time watch the little hole....at the centre of the ulcer. In a few seconds a droplet of whitish fluid will be seen to well up in the little hole, or a delicate tube will be protruded from it for an inch or more, and then suddenly rupture.81

Manson believed that the worm pro lapsed a portion of its uterus an inch or two at a time through the mouth then it burst but Leiper denied this, saying that the uterus protruded through an opening just outside the circumoral ring o f papillae62. Diagnosis in the stage before rupture of the blister and presentation of the head of the worm may be made, as was done by Turkhud in his experimental infections of a human, by aspiration of fluid from the blister then examining it for the presence of larvae 131. Calcified worms may be seen on radiographs as shown by Connor 23 and by Dimier and Bergonie 25, both in 1918, but localization of living worms i s unsatisfactory as they are radiolucent. Hudellet (1919) rendered them radio opaque by injection of 10% collargol into the worm 51, then Roussel achieved a similar effect by the injection of lipiodol 120. As in other systemic helminth infections, eosinophilia is characteristic o f dracunculiasis, this first being shown by Billet in 1896 11. A variety of immunological assays have been described, with Ramsay introducing an intradermal test in 1935 110 and a complement fixation test being described i n 1940126.

THE SEARCH FOR EFFECTIVE TREATMENT The time-honoured method of treating dracunculiasis has been by winding the worm around a stick and pulling it out slowly. Amatus Lusitanius wrote in the

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sixteenth century that the Arabian physicians, especially Avicenna an d Avenzoar, had taught the following method: First the patient ties the end of the vein or nerve round a small piece of wood, and this he winds little by little till the last part of the worm is drawn out. As the structure is often three cubits long [1 cubit = approximately 50 cm], the treatment may last many days before the sufferer is altogether free of pain and inconvenience. Many adapt a cataplasm [i.e. a poultice or plaster] or cold suffusion. 9

Van Linschoten soon afterwards in 1596 provided the first known illustration of this process 73, then nearly a century later Velschius published a number of illustrations of the same procedure 133. In a review in 1880 of the treatment of Guinea worm in India, Dick re marked that the native experts practised treatment along four lines - stink the worm out, coax it out, suck it out and pull it out - then summarized his ow n investigations. Stinking the worm out with assafoetida poultices failed, while coaxing it out by prolonged immersion in running water was little mor e successful. He had no experience of sucti on with the traditional trumpet-shaped sucking tube, but determined t hat many days of slow winding could be avoided frequently by incising the skin ove r the worm and then pulling it out by traction in the space of a few minutes 24. In doing this, he merely legitimized the practice of many native barber-surgeons. In 1884, JW Reynolds, a former Britis h surgeon in Bombay described how one of them had removed a number o f worms from his own feet in 1861. (It is certain that he was the host to th e worms that Bastian used in his description, for Reynolds remarked that he later gave the worms to Harley, and Bastian in turn stated that he had received his specimens from an infected Bombay surgeon via Harley). A barber took five out of my legs very cleverly; most of them were extracted at one sitting, but two (one in each foot) held on with their hooks, and he had to leave them until the next day, when he got them out. His stock of instruments consisted of a needle and a razor; he commenced operations by finding, as near as he could guess, the centre of the worm; then he raised the skin over the centre of the worm with the point of the needle, passed the razor under it, and snipped off a tiny bit of cuticle, making an almost circular cut the size of a large pin's head. By raising almost invisible pieces of skin and tissue, and slicing them away with the razor, he deepened, but did not increase, the area of the whole, till he saw the white worm at the bottom; then passed the eye of the needle (like a tentaculum) under it, and brought up a loop. He pulled on the two sides alternatively till he got one end out, then he dealt with the other. When he found the hook had been made use of, he applied heat and friction to make it yield its hold.116

In 1883, Faulkner, a civil surgeon in Aden, claimed that electrolysis with a galvanic current was effective 35, to which Reynolds replied that galvanis m had been in use for at least 25 years 116. Most practitioners hoped that drugs would aid in the extraction of Guinea worms. Around 1895, the injection of mercuric perchloride was recommended, but this did not find lasting favour. A rather drastic method was tried in India in 1903; a number of Indian soldiers infected with Guinea worm each con sumed more than a pound of sugar a day for three days. The sugar made th e

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patient unbearably thirsty, but the dehydration made it easy to wind out th e worm unruptured 117. In 1919, Jeanselme gave three intravenous injections of novarsenobenzol to a young Senegalese soldier then a few days later a dea d worm was extracted. He was uncertain whether the arsenic had a direct action on the worm, however, as no trace of the metal could be found in the worm 56; arsenicals did not prove subsequently to be effective. Macfie (1920) though t that intravenous injections of tartar emetic (sodium antimony tartrate) recently introduced for the therapy of schistosomiasis had a beneficial effect 77, but Fairley and Liston later showed that the drugs had no action on either the adult worm or the embryos contained therein 34. In 1942, Elliot claimed that injections of phenothiazine (which had recently been recommended for the treatment of enterobiasis) each week for four weeks assisted in the removal of worms 30, but this therapy did not become generally accepted either. No significant advances were made until Raffier in 1965 showed that oral niridazole cured 70% of 71 patients on the Ivory Coast within seven days 106,107. Two years later, he also showed that thiabendazole was useful in the treatment of 234 patients in the same country 108. In 1970, Pardanani and Kothari found that metronidazole appeared useful 100. Muller then investigated the actions of these drugs and found that the worms appeared normal on histologica l examination and that the larvae developed normally in Cyclops. He concluded, therefore, that their effective ness was due to an anti-inflammatory action which facilitated the mechanical removal of the worms 95. More recently, Shafei showed that mebendazole was effective in dracunculiasis, but that its actio n differed from the other drugs because it killed the worm 123.

UNDERSTANDING THE EPIDEMIOLOGY Many of the epidemiological observations o ver the past several centuries which led to the formulation of various theories on the mode of transmission o f dracunculiasis have been discussed. These occurrences became comprehensible with the demonstration that Guinea worm infection was transmitte d through the agency of a water crustacean. Although species of Dracunculus closely related to D. medinensis have been described in various animals , humans seem to be the only important host of this worm. Dracunculiasis is now restricted to parts of Africa, the Middle East and the Indian subcontinent. In former times, however, it was prevalent in the Wes t Indies and parts of South America. Hirsch (1885) wrote concerning thes e countries: All the authorities....agree that dracontiasis was quite unknown before the importation of the negro. With the suppression of the slave trade, the disease fell to a minimum or disappeared altogether.48

The first person to draw attention to the infection in the Western Hemisphere appears to have been Don Diego Rodriguez de Valdes y de la Vanda, Spanish

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governor of Rio de la Plata in 1599 (Argentina/Uruguay) 98. In some regions, it seems that transmission occurred for a number of years as evidenced, fo r example, by the description by Ferg of an epidemic in Surinam in 1801 37. For uncertain reasons, the infection appears to have now died out in these areas. A similar situation occurred in the Dutch East Indies (Indonesia). Occasiona l exotic infections were imported into that country and Brug in 1930 from such a case, succeeded in infecting the local C. leuckarti and then producing an infection in a monkey. He attributed the free dom of the country from indigenous infection to the habit of the inhabitants of drinking running rather than stagnant water15. In many endemic areas, it has bee n found that the incidence of infection has a seasonal pattern which some times coincided with the rainy season and sometimes did not, local habits and physical factors determining the distribution of infection throughout the year. While such events have been recognized fo r many years, it is only in the last century that the reasons for the phenomenon have been understood. Thus, in Rajasthan, India, transmission occurred during the rainy season because water was then obtained from surface ponds rathe r than from deep wells 70. In contrast, in Iran where water is obtained fro m cisterns, transmission took place during the dry season because the concen tration of Cyclops was reduced by the large volume and turbidity of wate r during the rainy season 69. An ideal physical arrangement for the transmission of infection are th e stepwells so common in India. This was recognized in 1879 by Mr. Chunder Dutt, an assistant surgeon at a colliery in Chonda in the Central Provinces of India, who observed 180 cases in one village. Water for drinking and washing purposes was obtained from the only well in the vicinity of the village. Thi s well had a flight of stone stairs down which the people descended to fill their pots with water. All that could be glea ned as to the cause of the outbreak of the disease was that men from a neighbouring village where dracunculiasis was rife the year before, used to go down into the well for drawing water whils t suffering from mature Guinea worms in their feet and legs. In the curren t outbreak, he found that the field-labourers, to whom the infection was largely limited, had the habit of drinking from the well on their returning from th e fields, descending one or two steps into the water to dip their hands o r water-vessels therein28. Despite the clarity of his observations, the precis e mechanism by which infection occurred was not apparent to him, however, presumably because he had no access to recent literature reporting Fedchenko' s discovery. The importance of these wells was repeatedly recognized. Fo r example, Rao reported in in 1942 that he had examined 434 wells and found that 158, most of them step wells, contained Cyclops 112. When epidemics of dracunculiasis occurred, the infection sometimes had significant economic effects. Atten tion was drawn repeatedly to this by medical officers in charge of troops so afflicted in colonies in endemic areas. Mor e important, however, were the e ffects on rural villages where a large proportion

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of the work-force were incapacitated temporarily, thus having a deleteriou s action on agricultural production.

THE EVOLUTION OF PREVENTIVE AND CONTROL MEASURES Effective methods of avoiding Guinea worm infection were suggested by some observers even when the modes of transmission were understood only dimly. De Bourges (1666), in his narrative of the Bishop of Beirut's journey wrote : "the way to avoid this worm is to drink only wine or if water is used, only such as has been carefully filtered through linen" 12. Similarly, the method o f purifying water adopted by Lind (1768) 68 has already been referred to, as has the discovery by Chisolm (1795) 19 that the disease could be prevented by filling in of the wells (although this seems a drastic and impractical suggestion). The elucidation of the central role of Cyclops in transmission provided solid ground for the evolution of control techniques. Leiper summarized the problem by remarking: "the isolation of infective man from healthy cyclops and o f infected cyclops from man must be the object of any organized effort to stamp out dracontiasis" 62. These efforts encompassed physical, biological an d chemical approaches. Concerning physical measure s, WM Graham, a medical officer in the West African Medical Service, wrote in 1905 that Cyclops can be removed readily by straining water through a fine handkerchief. Since he did not believe that this was a practical proposition for the indigenous inhabitants, he advocate d structural alterations to existing wells to convert them into concrete trough s with conduction away of outflow water 44. In a similar vein, Leiper (1907 ) prophesied: it is evident that dracontiasis will disappear from the Coast towns when the provision of a properly-controlled water supply, obtained either from artesian wells or through pipes from some rapidly-flowing stream, permits the filling-in of the surface collections of rain water and the shallow wells upon which the natives now rely for their supplies.62

The efficacy of such measures was shown in many areas. In a part of India, for example, replacement of step wells by draw wells in a number of village s reduced greatly the incidence of infection 111. Another physical metho d suggested by Leiper was the heating of well water with steam, but this did not prove a viable technique 63 In 1912, Leiper returned to West Africa and found that in certain place s Cyclops appeared to be kept under control by the innumerable small fish living in the water sources, with a consequent absence of dracunculiasis 64. This concept was investigated in detai l by Moorthy and Sweet in India in 1936; they found that fish of the genus Barbus were a potent destroyer of Cyclops 89 A third approach has been to try chemical treatment of water. A number of chemicals have been suggested including potassium permanganate (1914) 131,

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lime (1930) 105, DDT (1953)109 , zinc dimethyldithiocarbamate (1956) 45 and chlorination (1968) 122. Such measures have had on occasion some success in certain limited areas. Currently, the best hope for controlling dracunculiasis lies in the Inter national Drinking Water Supply and Sanitation Decade due to end in December 1990. Since there is no significant animal reservoir of infection, successfu l implementation of safe water su pplies could theoretically lead to elimination of Guinea worm infection within several years, much as in the same way as has been achieved with smallpox 50. Whether or not these hopes are realized , however, only time will tell.

REFERENCES 1. AGATHARCHIDES. De mari rubra. Cited in 103 2. AMATUS LUSITANIUS. Medici physici praestantissimi: curationum medicinaliu m centuria quatuor etc., B Constantinus, Venetiis, pp 645, 1557. Partly translated in 124 3. ANDRY de BOISREGARD N. De la génération des vers dans le corps de l'homme etc., Laurent d'Houry, Paris, pp 1190, 1741. Partly translated in 49 4. ANONYMOUS. The Guinea-worm disease. Lancet ii: 314, 1867 5. ANONYMOUS. The Guinea-worm. British Medical Journal i: 488, 1880 6. ANONYMOUS. Book review of "The diseases of the Bible" by Sir Risdon Bennett . British Medical Journal ii: 1283-1284, 1887 7. ANONYMOUS. Supposed discovery of the male of Filaria medinensis . British Medical Journal ii: 1151, 1892 8. AVICENNA. Libri in re medica omnes, qui hacte nus ad nos pervenere. Id est, libri canonis quinque, De viribus cordis, De removendis nocumentis in regimine sanitas, De sirup o acetosa et cautica, translated by JP Mongio Hydruntino et J Costaeo Laudensi, V Valgrisius, Venetiis, pp 966, 1564. Original Arabic version "Al Canon fi Al Tib", c. 1000 AD. Partly translated in 124 9. AVICENNA. Ibidem. Cited in 2 10. BASTIAN HC. On the structure and nature of the Dracunculus of Guinea worm. Transactions of the Linnean Society 24: 101-134, 1863 11. BILLET A. Eosinophilie dans un cas de filariose sous cutanée de Médine. Compte s Rendus Hebdomadaires et Mémoires des Séances de la Société de Biologie 9: 18, 1896 12. de BOURGES J. Relation du voyage de Mgr. l'Evéque de Beryte, vicaire apostolique du Royaume de la Cochinchine, par la Turquie, la Perse, les Indes etc., jusqu'au Royaume de Siam et autres lieux, D Bechet, Paris, pp 245, 1666 13. BRETT FH. A practical essay on some of the principle surgical diseases of India, W Thacker and Co., Calcutta, pp 506, 1840 14. BRUCE N. Remarks on the dracunculus, or Guinea worm, as it appears in the peninsular of India. Edinburgh Medical and Surgical Journal 2: 145-150, 1806 15. BRUG SL. Dracunculus medinensis in the Dutch East Indies. Mededeelingen van de n Dienst der Volksgezondheid in Nederlandsch-Indië 19: 153-157, 1930 16. CARAYON A, CAMAIN R, GUIRAUD R, HAURET P. Aspects chirurgicaux de s helminthiasies en Afrique de l'ouest (ascaridiose, dracunculose, filariose, bilharziose). II. Pathologie de migrations habituelles aberrantes ou manquées de la filaire de Médine (À propos de 25 localisations chirurgicales). Médecine Tropicale 21: 538-549, 1961 17. CARTER HJ. Note on dracunculus in the island of Bombay. Transactions of the Medical and Physical Society of Bombay, new series, 2: 45-56, 1855 18. CHARLES RH. A contribution on the lif e-history of the male Filaria medinensis removed

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19.

20.

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

35. 36.

37. 38.

39.

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from the abdominal cavity of man. Scientific memoirs by medical officers of the Army of India 7: 51-56, 1892. Abstracted in British Medical Journal ii: 1151, 1892 CHISOLM C. An essay on the malignant pestilential Fever introduced into the Wes t Indian Islands from Boullam, on the coast of Guinea as it first appeared in 1793, 1794, 1795 and 1796, second edition, two volumes, pp 105, 1801. Also, On the Mali s Dracunculus or Guinea-worm (in Grenada). Edinburgh Medical and Surgical Journal 11: 145-164, 1815 COBBOLD TS. Entozoa: an introduction to the study of helminthology with reference, more particularly, to the internal parasites of man, Groombridge and Sons, London, p p 480, 1864 COBBOLD TS. Parasites: a treatise on the entozoa of man and animals including some account of the ectozoa, J&A Churchill, London, pp 508, 1879 COLE J. Buried treasure. British Medical Journal ii: 1412-1413, 1979 CONNOR FP. Notes on cases of surgical interest. I. Inflammatory conditions due t o calcified remains of Guinea-worms. Indian Medical Gazette 53: 297-299, 1918 DICK F. The treatment of Guinea-worm. British Medical Journal ii: 207-208, 1880 DIMIER, BERGONIE J. Recherche du filaire de Médine par la radiographie. Archives d'Électricité Médicale et de Physiotherapie 26: 337-341, 1918 DUKE J. Note on the symptoms of Filaria medinensis or Guinea worm. Indian Medical Gazette 30: 64-65, 1895 DUNCAN A. Observations on Dracunculus. Transactions of the Medical and Physica l Society of Calcutta 7: 273-281, 1835 DUTT C. Cited in British Medical Journal i: 488-489, 1880 EBBELL B. The Papyrus Ebers, the greatest Egyptian medical document, translated by B Ebbell, Levin and Munksgaard, Copenhagen, pp 135, 1937 ELLIOT M. A new treatment for dracunculiasis. Transactions of the Royal Society o f Tropical Medicine and Hygiene 35: 291-301, 1942 FAIRLEY NH, LISTON WG. Studies in the pathology of dracontiasis. Part I. India n Journal of Medical Research 11: 915-932, 1924 FAIRLEY NH, LISTON WG. Studies in the transmission of Dracunculus medinensis a negative experiment. Part II. Indian Journal of Medical Research 12: 93-104, 1924 FAIRLEY NH, LISTON WG. Studies in dracontiasis. Part IV. The clinical picture. An analysis of 140 cases. Indian Medical Gazette 12: 351-367, 1924 FAIRLEY NH, LISTON WG. Studies in dracontiasis. Part V. Observations an d reflections on intravenous medication with special reference to tartar emetic. India n Medical Gazette 12: 369-374, 1924 FAULKNER AS. Electrolysis in the treatment of Dracunculus. British Medical Journal ii: 1280-1281, 1883 FEDCHENKO AP. (Concerning the structure and reproduction of the Guinea wor m [Filaria medinensis L.].) Izvestiia Imperatorskago Obshchestva Liubitelei Estestvoznaniia Antropologii i Ethnografii - Mo skva, 8 columns 71-81, 1870. In Russian. Translated in 58 FERG. Jahrbuch der deutschen Medicin p 151, ?1801. Cited in 48 FORBES D. Extracts from the half yearly reports of the diseases prevailing at Dharwar in the 1st grenadier regiment, N.I. for the year 1836. Transactions of the Medical an d Physical Society of Bombay 1: 215-225, 1838 FORBES JG. Medical report of the Anglo-French Boundary Commission on the western frontier of the Gold Coast Colony, Janu ary 1902-May 1903. Saint Bartholomew's Hospital Reports, London 39: 171-187, 189-205, (1903) 1904 FOX T. Notes on unusual or rare forms of skin disease. I. Case of Guinea-worm disease. Lancet i: 330-331, 1879 GALLANDAT DH. Lettre sur le dragonneau, ou veine de Médine et sur l'usage d u sublime corrosif dans cette maladie. Journal de Médecine, Chirurgie, Pharmacie etc. 12: 24-28, 1760 GALLANDAT DH. Dissertio de dracunculo sive vena medinensis. Nova Act a

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43.

44. 45. 46. 47. 48.

49. 50. 51.

52. 53.

54. 55. 56.

57. 58. 59.

60. 61. 62. 63. 64.

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Physico-Medica Academiae Caesareae Leopoldino-Carolino Naturae Curiosorum , Norimb. 5: 103-116, 1773. (Manuscript dated 1771) GMELIN JF. Systema naturae per regna tria naturae secundum classes, ordines, genera, species cum characteribus, differentiis, synonymis, locis, 13th edition, G E Beer, Lipsiae, eight volumes, pp 3021-3909, 1788-1793 GRAHAM WM. Guinea-worm and its hosts. British Medical Journal ii: 1263-1265, 1905 GRETILLAT S. Le dimethyldithiocarbamate de zinc dans la prophylaxie de l a dracunculose. Médecine d'Afrique Noire, Dakar 12: 93-96, 1965 GRUNDLER. Cited in 20 HEATH GT. Observations on the generation of Guinea worm. Edinburgh Medical an d Surgical Journal 12: 120-121, 1816 HIRSCH A. Handbook of geographical and historical pathology. volume 2. Chroni c infective, toxic, parasitic, septic and constitutional diseases, translated from the secon d German edition by C Creighton, The New Sydenham Society, London, pp 681, 1886 HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, pp 526, 1959 HOPKINS DR. Guinea wo rm and the decade. World Health, November, pp 22-23, 1984 HUDELLET G. Extirpation totale du ver de Guinée après diagnostic de position par les rayons X. Bulletin de la Société Médico-Chirurgicale Française de l'Ouest-Africain 1 : 17-19, 1919 HUGHES MH. A historical note on the transmission of dracontiasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 61: 442-443, 1967 INTERNATIONAL COMMISSION ON ZOOLOGICAL NOMENCLATURE . Nematode and Gordiacea names placed in the official list of generic names (Opinion 66), Smithsonian Institution Publication 2359, Washington, DC, pp 171-176, 1915 ISSAJEV L. (Experimentelle dracunculosis beim Hunde). Meditsinskaya Parazitologiya i Parazitarn e Bolezni 3: 231-238, 1934. In Russian, with German summary JACOBSON. Extrait d'une lettre à M. Blainville, Naturelles Archives du Museum 3: 80, 1834 JEANSELME. Note sur un cas de ver de Guinée radicalement guéri par l e novarsénobenzol en injections intraveineuses. Bulletin de l'Académie de Médecine, third series, 81: 156-158, 1919 KÄMPFER. Cited in 20 KEAN B H, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, pp 677, 1978 KÜCHENMEISTER F. Die in und an dem Körper des lebenden Mensche n vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung de r thierischen und pflanzischen Pa rasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to th e group Entozoa, translated by E Lankester, The Sydenham Society, London, pp 452, 1857 LEIPER RT. The influence of acid on Guinea worm larvae encysted in Cyclops. British Medical Journal i: 19-20, 1906 LEIPER RT. Some results of the infection of monkeys with Guinea worm. Report of the British Association for the Advancement of Science 76: 200, 1906 LEIPER RT. The etiology and prophylaxis of dracontiasis. British Medical Journal i : 129-132, 1907 LEIPER RT. A method for dealing with town wells infected with Guinea worm. Journal of the London School of Tropical Medicine 1: 28-30, 1911 LEIPER RT. Report of the helminthologist, London School of Tropical Medicine, for the half-year ending April 30th, 1913. Abstracted in Tropical Diseases Bulletin 2: 195-196, 1913 LEIPER RT. Discussion on the validity of certain generic names at present in use i n medical helminthology. Archiv für Schiffs- und Tropen-Hygiene 30: 484-491, 1926

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66. LEIPER RT. Landmarks in medical helm inthology. Journal of Helminthology 7: 101-118, 1929 67. LEUCKART R. Die menschlichen Paras iten und die von ihnen herrührenden Krankheiten. Ein Hand- und Lehrbuch für Naturforscher und Aertze, CF Winter'sche Verlagshandlung, Leipzig, volume 2, pp 882, 1867-1876 68. LIND J. An essay on diseases incidental to Europeans in hot climates, with the method of preventing their fatal consequences etc., T Becket and PA de Hondt, London, pp 348 , 1768 69. LINDBERGH K. Dracunculose en Iran. Archiv für Schiffs- und Tropen-Hygiene 40 : 330-342, 1936 70. LINDBERGH K. Dracunculose dans l'état de Djodhpour (Radjpoutana), Inde. Bulletin de la Société de Pathologie Exotique 39: 318-328, 1946 71. LINNAEUS C. Systema naturae per regna triae naturae, secundum classes, ordines , genera, species, cum characteribus, differentiis, synonymis, locis, tenth edition, L Salvii, Holmiae, two volumes, pp 823, 1758 72. LINNAEUS C. Cited in 91 73. van LINSCHOTEN JH. Vera descriptio regni par s Indiae Orientalis in qua Johan. Hugonis Linstscotani navigatio in Orientem. Teucrides Annaeus Lonicer, Frankfort, 1599. Original Dutch edition, Voyage ofte Schripaert van JHLvL naer Oost ofte Portugaels Indiens etc., Amstelredam, 1596. Partly translated in 124 74. LISTER M. Part of a letter from Fort St. George, in the East Indies, giving an account of the longworm which is troublesome to the inhabitants of those parts. Philosophica l Transactions of the Royal Society of London 19: 417-418, 1697 75. McCLELLAND. Remarks on Dracunculus. Calcutta Journal of Natural History 1 : 359-371, 1840 76. McCONNELL RE. Dracontiasis or dracunculias is: a review. Journal of Tropical Medicine and Hygiene 17: 337-340, 1914 77. MacFIE JW. Intravenous injection of tartar emetic in Guinea-worm infections. Lancet i: 654-655, 1920 78. McGREGOR J. A memoir on the state of health of the 88th regiment, and of the corp s attached to it, from the 1st June 1800 to the 31st May 1801 as originally presented to the Medical Board, Bombay. Edinburgh Medical and Surgical Journal 1: 266-289, 1805 79. MACKAY G. The Guinea-worm. British Medical Journal i: 610, 1880 80. MAISONNEUVE JG. Note sur un dragonneau observé à Paris, et présenté à la Société de Chirurgie. Archives Générale de Médecine 6: 472-480, 1844. Abstracted in Lancet i: 153-153, 1845 81. MANSON P. On the Guinea-worm. British Medical Journal ii: 1350-1351, 1895 82. MANSON P. The life-span of Filaria medinensis . British Medical Journal ii: 10, 1903 83. MANSON-BAHR PH. Manson's Tropical diseases, sixteenth edition, Baillière, Tindall and Cassell, London, pp 1131, 1966 84. MEYER. Cited in 91 85. MILNE J. In, Extracts from a correspondence on the Filaria medinensis among some of the medical officers of the Honourable East India Company's service at Bombay; with a letter from Dr. Robert Grant, professor of comparative anatomy in the University o f London. Edinburgh Medical and Surgical Journal 35: 112-118, 1831 86. MOORTHY VN. A redescription of Dracunculus medinensis . Journal of Parasitology 23: 220-224, 1937 87. MOORTHY VN. Observations on the development of Dracunculus medinensis larvae in Cyclops. American Journal of Hygiene 27: 437-460, 1938 88. MOORTHY VN, SWEET WC. A note on the experimental infection of dogs wit h dracontiasis. Indian Medical Gazette 71: 437-442, 1936 89. MOORTHY VN, SWEET WC. A biological method for the control of dracontiasis. Indian Medical Gazette 71: 565-568, 1936 90. MOORTHY VN, SWEET WC. Further notes on the experimental infection of dogs with

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dracontiasis. American Journal of Hygiene 27: 301-310, 1938 91. MOQUIN-TANDON A. Elements of medical zoology, translated by R T Hulme , Baillière, London, pp 423, 1861 92. MULLER RL. A historical note on the transmission of Dracunculus. Transactions of the Royal Society of Tropical Medicine and Hygiene 61: 747-751, 1967 93. MULLER R. Studies on Dracunculus medinensis (Linnaeus). I. The early migratio n route in experimentally infected dogs. Journal of Helminthology 42: 331-338, 1968 94. MULLER R. Experimental dracontiasis in animals. Parasitology 58: 7p-8p, 1968 95. MULLER R. the possible mode of action of some chemotherapeutic agents in guine a worm disease. Transactions of the Royal Society of Tropical Medicine and Hygiene 65: 853-854, 1971 96. ONABAMIRO SD. The diurnal migration of Cyclops infected with the larvae o f Dracunculus medinensis (Linnaeus) with some observations on the development of the larval worms. West African Medical Journal 3: 189-194, 1954 97. ONABAMIRO SD. The early stages of the development of Dracunculus medinensi s (Linnaeus) in the mammalian host. Annals of Tropical Medicine and Parasitology 50 : 157-166, 1956 98. OTTSEN H. Journaal van de Reis naar Zuid-America (1598-1601). (Journaal van d e voyagie na Rio de Plata), 'S-Gravenhage, pp 253, 1918 99. PAPYROS EBERS. Das hermetische Buch über die Arzneimittel der alten Aegypter in hieratischer Schriften Herausgegeben mit Inhaltsangabe und Einleitung versehen vo n Georg Ebers, two volumes, Leipzig, 1875. The Papyrus Ebers, translated from th e German version by CP Bryan, Geoffrey Bles, London, pp 167, 1930 100. PARDANANI DS, KOTHARI ML. Metronidazole in dracunculiasis. A preliminar y report of a therapeutic trial. Indian Journal of Medical Science 24: 359-360, 1970 101. PARÉ A. Cited in 3 102. PLEHN F. Die Kamerun-Kuste. Studien zur Klimatologie, Physiologie und Pathologie in der Tropen, August Hirschwald, Berlin, pp 363, 1898 103. PLUTARCH. Oeuvres de Plutarque, traduites du Grec par J Amyot, Paris, 22 volumes, 1783-1787. Partly translated in 91 104. POWELL A. The life span of the Guinea-worm. British Medical Journal i: 73, 1904 105. PRADHAN YM. Observations on experiments designed to combat dracontiasis in a n endemic area by Col. Morison's method of "liming" wells. Indian Journal of Medica l Research 18: 443-465, 1930 106. RAFFIER G. Note préliminaire sur l'activité du CIBA 32644-Ba dans la dracunculose. Acta Tropica 22: 350, 1965 107. RAFFIER G. Preliminary note on the activity of a new antihelminthic agent i n dracunculosis. Médecine Tropicale 26: 39-46, 1966 108. RAFFIER G. Activité du thiabendazole dans la dracunculose. Médecine Tropicale 27: 673-678, 1967 109. RAMAKRISHNAN NR, RATHNASWAMY GK. Use of DDT for control of Cyclops breeding and as an anti-dracontiasis measure. Indian Medical Gazette 88: 386-390, 1953 110. RAMSAY GW. Observations o n an intradermal test for dracontiasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 28: 199-204, 1935 111. RAO CK REDDY GV. Dracontiasis in West Godavari and Kurnool districts, Andhr a Pradesh. Bulletin of the Indian Society of Malariology and Communicable Diseases 2: 275-293, 1965 112. RAO SR. Some epidemiological factors of Guinea-worm disease as noticed in a recent survey of Osmanabad district. Journal of the Indian Medical Association 11: 329-337, 1942 113. REDDY CC, NARASAIAH IL, PARVATHI G. Epidemiological studies o n guinea-worm infection. Bulletin of the World Health Organization 40: 521-529, 1969 114. REDDY CC, SIVAPRASAD MD, PARVA THI G, CHARI PS. Calcified guinea worm: clinical, radiological and pathological study. Annals of Tropical Medicine an d

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Parasitology 62: 399-406, 1968 115. REICHARD CW. Dissertatio de pediculus inguinalibus insectis et vermibus homin i molestis, Erfuti, pp 51, 1759 116. REYNOLDS JW. Electrolysis in the t reatment of dracunculiasis. British Medical Journal i: 138, 1884 117. RICHARDS WG. Note on Dracunculus medinensis (Guinea worm). Parasitology 14: 307-308, 1922 118. ROLLESTON HD. Guinea-worm embedded for 21 years under the skin of the calf of the leg. Transactions of the Pathological Society of London 43: 152, 1892 119. ROUBAUD E. Observations sur la biologie du ver de Guinée: infection intestinale des Cyclops. Bulletins de la Société de Pathologie Exotique et de ses Filiales 6: 281-288 , 1913 120. ROUSSEL B. Radiographie du ver de Guinée (filaire de Médine) après injectio n intrasomatique de lipiodol. Bulletins de la Société de Pathologie Exotique et de se s Filiales 21: 103-104, 1928 121. RUDOLPHI CA. Entozoorum synopsis cui accedunt mantissima duplex et indice s locupletissima, Sumtibus August Rücker, Berolini, pp 811, 1819 122. SABOKBAR R. Dracunculose en Iran. VIIIth International Congress of Tropica l Medicine and Malaria, Tehran, pp 938-939, 1968 123. SHAFEI AZ. Preliminary report on the therapeutic effect of mebendazole in guine a worm infection. Journal of Tropical Medicine and Hygiene 79: 197-200, 1976 124. SINGER C. On certain early referen ces to dracontiasis, the guinea-worm disease. Annals of Tropical Medicine and Parasitology 6: 386-392, 1912 125. SOUTHWELL T, KIRSHNER A. Some observations on guinea worm larvae. Annals of Tropical Medicine and Parasitology 32: 193-196, 1938 126. STEFANOPOULO GJ, DANIAUD J. Réaction de fixation du complément et intra dermo-réaction au course de la fila riose humaine à Dr. medinensis. Bulletin de la Société de Pathologie Exotique 33: 149-153, 1940 127. TENNENT JE. Sketches of the natural history of Ceylon with narratives and anecdotes illustrative of the habits and instincts of the Mammalia, birds, reptiles, fishes, insects etc., including a monograph of the elephant, and a description of the modes of capturing and training it, Longmans, London, 1868 128. TREWN HS. Guinea worm. Indian Medical Gazette 72: 606-609, 1937 129. TURKHUD DA. Proceedings of the Second All-India Sanitary Conference, 1912 , Government Central Branch Press, Simla, pp 118-120, 1913 130. TURKHUD DA. In, Report of the Bombay Bacte riological Laboratory for the year 1912, presented by Major WG Liston, Government Central Press, Bombay, pp 32-36, 1913 131. TURKHUD DA. In, Report of the Bombay Bacte riological Laboratory for the year 1913, presented by Major WG Liston, Government Central Press, Bombay, pp 14-16, 1914 . Republished as, Prophylaxis of dracontiasis. Indian Journal of Medical Research, special number, pp 217-225, 1919 132. de VEIGA T. Cited in 3 133 VELSCHIUS GH. Exercitatio de Vena Medinensi, ad mentem Ebnisinae sive d e dracunculi veterum. Specimens e xhibens novae versionis ex Arabico, cum commentarion uberiori, cui accedit altera de vermiculus capillaribus infantium, Theophili Goebelli , Augustae Vindelicorum, pp 456, 1674 134. WURTZ, SOREL. Note sur la durée de l'incubation du ver de Guinée. Revue d e Médecine et d'Hygiene Tropicale 9: 123-124, 1912

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Table 26.1. Landmarks in dracunculiasis ___________________________________________________________________ BC 1819 1834 1868 1869 1880 1892 1894 1906 1906 1914 1937 1956 1965 1967 1970 1976

Guinea worms have been known since antiquity in endemic areas but their nature was controversial. Mechanical extraction was practised Rudolphi described the larvae (embryos) of Dracunculus Jacobson rediscovered the first-stage larvae Bastian made a detailed description of the anatomy of the adult female worm Fedchenko observed that embryos developed with the body cavity of the crustacean, Cyclops Mackay described an epidemic of dracunculiasis in Indian troops and suggested that the incubation period was 8-12 months Charles claimed to find male adult worms in the retroperitoneal tissues at autopsy Manson confirmed Fedchenko's observations on development withinCyclops Leiper showed that hydrochloric acid, simulating gastric juice, stimulated the activation of larvae and their release from Cyclops Leiper fed infected Cyclops to monkeys and recovered 3 immature female and 2 small male Guinea worms at autopsy 6 months later Turkhud administered infected Cyclops to 5 volunteers; one person developed dracunculiasis one year later Moorthy provided the first detailed account of the male adult worm Onabamiro studied the route of migration of parasites in experimentally infected animals Raffier showed that niridazole assisted the extraction of worms Raffier showed that thiabendazole assisted the extraction of worms Pardanani and Kothari reported that metronidazole assisted the extraction of worms Shafei claimed that mebendazole kills Guinea worms

___________________________________________________________________

Chapter 27

NEMATODE INFECTIONS IMPORTANCE

OF

LESSE R

INFECTION WITH ANATRICHOSOMA CUTANEA This Capillaria-like parasite of the skin and nasal mucosa of monkeys in Asia and Africa was discovered by Swift, Boots and Miller in 1922 and name d Trichosoma cutaneum 327. In 1958, it was renamed Anatrichosoma cutaneum by Chitwood and Smith 67. A human case of creeping eruption of the skin due to infection with this worm was reported by Morishita and Tani in Japan i n 1960225.

INFECTION WITH ANCYLOSTOMA SPECIES A. BRAZILIENSE This parasite was first recovered from the intestine of dogs and cats b y Gomes de Faria in Brazil in 1910 who called it Ancylostomum braziliense 130. With the acceptance of Ancylostoma as the generic name for this group o f hookworms, it became known as Ancylostoma braziliense . For many years, there was controversy concerning the relationship between this worm an d A. ceylanicum, with the eventual acceptance that they were different specie s (see chapter 20). Contrary to A. duodenale, A. ceylanicum and Necator americanus, A. braziliense does not complete its development in humans, but it is the major cause of the clinical syndrome called cutaneous larva migrans. This syndrome appears to have been first described by Robert Lee in an address to the Clinical Society of London in 1874, although the worm involved in that particular case will never be precisely known: The morbid appearance consists of a fine line on the left side of the abdomen, which stretches in a convoluted manner across the side. It appears to consist of a narrow, reddish, slightly-elevated line, much resembling to the touch what would be produced by a bristle underneath the epidermis....It was said to have begun as a fine line on the right ankle, which gradually travelled up the thigh on to the abdomen, where it was at first in the right side, and during the last three weeks has travelled across to the left.172

The anonymous reporter in The Lancet who wrote the above also commented that this was: 721

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A History of Human Helminthology

a remarkable case of Skin Disease in a child, the nature of which had given rise to much diversity of opinion amongst those who had seen it, and on which there was not much light thrown by the members of the Society. 13

and concluded that a commission had been appointed to investigate the cause. In 1892, Crocker also in England, saw a similar case and, suspecting that an insect larva may be the cause, proposed the term "creeping eruption" 80. In 1895, Samson-Hammelstjerne showed that the larva of the fly, Gasterophilus, was one cause of this condition 292. The disease was particularly prevalent in the southeastern United States of America and in 1926, Kirby- Smith and his colleagues held a clinic in Jacksonville, Florida and saw 179 cases in the space of ten days. More than half o f these patients were thought to have acquired their infection at the beach. A larval nematode was seen in skin biopsies; they named it Agamonematodium migrans pending the discovery of the adult worm 162. The histological sections were submitted to Ransom at the US Bureau of Animal Industry and he gave the guarded opinion that they were third-stage larvae of the super-famil y Strongyloidea. White and Dove then implicated A. braziliense as the cause of the condition by studies in animals and by applying A. braziliense larvae to human skin experimentally 345, then this was confirmed by Shelmire wh o infected 18 volunteers experimentally 303. The distribution of infection on th e body noted many years before by Lee was typical, for Dove (1932) reviewed 301 cases in Florida and showed that the lo wer limbs were afflicted in 76%, the hand and arms in 14% and the trunk in 9% of cases. He noted that movement of the larvae was very slow, each one moving only several millimetres per day, and sometimes continuing for weeks or months 97. In 1953, Muhlesein reported that eventually the cutaneously-migrating larvae may pass to the deeper tissues and cause pneumonitis 228. Initially, the condition was treated, usually with success, by freezing o r cauterizing the skin overlying the advancing larva. In 1943, Smith claimed that antimony (Fouadin) was effective in a child with multiple infections 309 but Blank could not confirm this observation 40. Burks and Kingery believed tha t chloroquine was valuable 48 but it was supplanted by thiabendazole when th e efficacy of this drug was demonstrated by Stone and Mullins in 1965 321. A. CANINUM This hookworm parasite of dogs was first described by Ercolani in 1858 a s Sclerostoma caninum 105, then renamed Ancylostoma caninum by Hall in 1913 135 . There have been several claims, beginning with Manalang in th e Philippines199, that it has completed its development in humans. Severa l workers have shown that this worm does not usually cause cutaneous larv a migrans in humans although it might cause ground itch 149,346.

Miscellaneous Nematode Infections

723

A. MALAYANUM This hookworm was first recovered from a bear and described as Helarctos malayanus by Alessandrini in 1905 7. Infection in humans has been reporte d once357.

ANGIOSTRONGYLIASIS ANGIOSTRONGYLUS CANTONENSIS In 1935, Chen recovered thi s worm from the respiratory tract of a rat caught in Canton, China and named it Pulmonema cantonensis 64. In 1946, Dougherty transferred it to the genus Angiostrongylus of Kamensky158 naming it Angiostrongylus cantonensis 96. The generic name is derived from a combination of the Greek words (ANGEON) and (STRONGYLOS) meaning "vessel" and "round", respectively. The life cycle was first described by Mackerras and Sandars in Australia in 1955. The y reported that eggs hatched in the lungs of the rodent host then the larva e migrated up the trachea and were swallowed then expelled in the faeces. The larvae then infected a molluscan intermediate host within which they became infective larvae in about two weeks. When ingested by the definitive host, the infective larvae migrated to the brain and moulted twice. The young worm s about 2 mm long, then migrated to the lungs and began laying eggs about four weeks after infection 196. Many species of slugs and several species of lan d snails as well as a planarian, crabs, fresh-water prawns and frogs have bee n found infected with third-stage larvae, these non-molluscs serving as paratenic hosts. Most human infections are thought to have been acquired by ingestion of undercooked specimens of the giant African land snail, Achatina fulica. The first infection in a human was repo rted by Nomura and Lin (as Haemostrongylus ratti) in Taiwan in a 15 year old boy with suspected meningitis from whom six young adult worms were identif ied in the cerebrospinal fluid, but this report was buried in the Japanese literature for many years 28,238. The first well-documented fatal case in a human was reported by Rosen and hi s colleagues in 1962287 following the investigations of Rosen into the cause o f eosinophilic meningitis in Tahiti and Hawaii. The circumstances surrounding the implication of A. cantonensis in this condition have been a subject of recent controversy8,286. By 1979, 259 cases were known to have occurred in Taiwan 63. The worm is a common cause of eosinophilic meningitis, most cases having an incubation period of about three weeks and being relatively mild in severity and self-limiting in duration. Occasionally, worms have been visualized in the eye, either in the anterior chambe r or vitreous 260. Rarely, worms have been found in human lung355, but patent infections with production of eggs and excretion of larvae have not been reported thus far. The diagnosis is best made by recovery

724

A History of Human Helminthology

of the worm. Alicata and Brown were of the op inion that skin testing was useful in ruling out the diagnosis but that a positive reaction could not be relied upon because of cross-reactivity with other helminths 9. Treatment is largely symptomatic, headache often being relieved by removal of cerebrospinal fluid at lumbar puncture. Thiabendazole was reported as being active against these worms in experimental animals 82, but did not seem to be effective in humans 152. In any case, it has been suggested that killing the worms could exacerbate the inflammatory reaction with undesirable consequences in infected patients . Worms have been removed surgically from the eye. A. COSTARICENSIS In 1967, Céspedes and his colleagues published two papers describing th e clinical features and pathology of an illness which had been seen in 31 patients in Costa Rica between 1952 and 1967. The m ain features were pain in the right lower quadrant of the abdomen, often associated with a palpable mass and with an eosinophilia ranging from 8-60%. Two yo ung children died from perforative ileitis. In histological sections of these and other resected tissues, portions of a worm were found and eggs were seen in the midst of a granulomatou s inflammatory reaction and eosinophilic vasculitis. Céspedes and colleague s believed the worm to be a metastrongylid parasite of mammals which ha d infected humans by accident 52,53 In 1971, Morera and Céspedes described the causative worm which they named Angiostrongylus costaricensis 223. In the following year, Chabau d erected a new genus, Morerastrongylus, to house this worm 54, but Anderson in 1978 reduced it back to Angiostrongylus 11. Also in 1971, Morera reported the discovery of the adult worms in natural definitive hosts, the rats Sigmodon hispidus and Rattus rattus 220, and he and Ash recorded the finding of infective larvae in the tissues of the slug Baginulus plebeius 222. Since then, many other species of mammals have been found infected and human infections have been recorded from other parts of Central and northern South America. In 1973 , Morera described the life cycle of the worm; first stage larvae were passed in the faeces of an infected rat, ingested by the slug intermediate host, the n migrated to its mantle and foot and moulted twice to become infective after two to three weeks. When the infected slug was eaten by a rat, the larvae were freed from the digested mollusc and migrated into the lymphatics of the gut mucosa, moulted twice, then migrated to the ileocaecal region where they entered th e arterioles and small arteries and the adult worms, which reached 2-4 cm i n length, began to lay eggs which hatched with larvae appearing in the faece s about three weeks after infection 221. Larvae are not discharged in the faeces of humans although eggs and larvae may be seen in specimens of bowel. Th e diagnosis is therefore generally made by biopsy, although a precipitin test has been described recently by Sauerbrey 297. The mode of infection in humans i s

Miscellaneous Nematode Infections

725

uncertain since raw slugs are not generally eaten in endemic regions. They may be consumed accidentally or possibly larvae may leave the slug in the mucus and thus contaminate fruit and vegetables. Treatment with thiabendazole has been recommended by Loria-Cortes and Lobo-Sanahuja 189.

ANISAKIASIS In 1845, Dujardin erected the genus Anisakis to house certain species o f nematodes found in the stomach of marine mammals 99. It is now known that when eggs of these worms are passed in the host's faeces, they embryonate and hatch in the water and the free-swimming larvae may survive for up to thre e months 138. The freeliving larvae may be ingested by shrimp-like crustacean s (Euphausiidae) in which they develop int o infective larvae. The infective larvae may in turn be eaten by fish and squid in which they migrate into the peritoneal cavity and tissues; after death of the fish, they tend to migrate to the muscles 310. The infective larvae may then be transferred from fish to fish and are finall y eaten by whales, porpoises and dolphins and embed in the gastric mucosa of these mammals to produce tumours 330. In 1960, Rodenburg and Wielinga 284 and Kuipers and colleagues 167 in Holland described an acute abdominal illnes s in humans due to inflammation of the small intestine caused by larvae, identified at that time as Eustoma rotundatum, which had been acquired by ingestion of slightly salted herring. Later in tha t year, van Thiel and colleagues report ed 11 such cases, in most of whom worms were discovered at laparotomy for relief of intestinal obstruction; one patient developed peritonitis and two patients died 331. The identification of thes e worms was changed to Anisakis marina by van Thiel 330 then altered to A. simplex by Davey in his revision of the genus 91. The infection was first recognized in Japan in 1965 by Asami and colleagues 16. By 1979, more than 500 cases had been recorded there 358.

CAPILLARIASIS CAPILLARIA AEROPHILA This common parasite of the respiratory mucosa of cats, dogs, foxes and some other carnivores in many parts of the world was found in a fox and described as Trichosoma aerophilum by Creplin in 1839 78. It was renamed Thominx aerophila by Dujardin in 1845 99 then transferred to the genus Capillaria of Zeder359 by Travassos in 1915 to become Capillaria aerophila 333. The generic name is derived from the Latin word "capillus" meaning "hair'. The eggs ar e coughed up, swallowed and discharged in the faeces; after six week or so they become infective and infection of a new host occurs after their ingestion .

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A History of Human Helminthology

Infection in humans is rare, the first documented cases being reported in th e USSR by Skrjabin and his colleagues in 1957 308. The most common clinica l manifestation is asthma. The diagnosis is made by finding eggs in sputum or in faeces, though one patient was diagnosed after finding the worm in a lun g biopsy. This patient responded to treatment with diethylcarbamazine, thia bendazole and corticosteroids 6. C. HEPATICA This worm was discovered in the liver of a mouse in Australia in 1893 b y Thomas Bancroft who named the parasite Trichocephalus hepatica 18. In 1916, Hall erected the genus Hepaticola and transferred it to this genus naming i t Hepaticola hepatica 136. In the preceding year, however, Travassos had placed it in the genus Capillaria of Zeder359, where it is now considered to lie, so the correct name is Capillaria hepatica 333. The parasite is common in rodents , especially rats, but has also been found in many other species of mammals in all continents. Transmission occurs between carnivorous, especially canna balistic animals. Nishigori showed that after ingestion of eggs, larvae passed to the liver, mainly via the portal system a nd matured over four weeks or so; the adult worms produced eggs which were deposited in the liver parenchyma and were not normally excreted in the faeces 237. Although the adult worms soo n died, the eggs sometimes remained viable for about two years 334. When the infected liver of the host was eaten by a predatory or scavenging animal, th e eggs passed through the gut and were excreted in the faeces. When deposited on damp soil, they developed into the infective stage; these may then b e ingested in food, drink or soil 352. The first case in humans was reported by MacArthur in India in 1924. At the post-mortem examination of a 20 year old Br itish soldier who had died from pneumonia, multiple abscesses were found scattered widely in both lungs and in the liver. Masses of C. hepatica eggs were found microscopically in close proximity to the liver abscesses 194. Infection has since been diagnosed in a number of humans, either at autopsy or by finding eggs in the liver biopsies , often in patients who have presented with hepatomegaly and eosinophilia 246. Occasionally, spurious instances of infection have been reported after finding eggs in the faeces 306; presumably the ova had been ingested and passed directly through the alimentary tract 116. Effective treatment has not yet been devised; two children treated wit h antimony recovered, but this may have been coincidental 76,304. C. PHILIPPINENSIS In 1963, eggs of a Capillaria species were found in the faeces of a man who had been admitted to hospital in the Philippines with malabsorption syndrome. He died three days later and autopsy revealed worms in the small and larg e

Miscellaneous Nematode Infections

727

intestines68. In 1967, an illness causing seve re disease and sometimes death was reported in Ilocos Sur Province of the Philippines; subsequent investigations revealed Capillaria eggs in the stools of most patients 49. This led to Chitwood, Valesquez and Salazar in the following year describing the adult worms, 3-4 mm long, and naming the parasite Capillaria philippinensis 69. In 1973, a focus of infection was discovered in Thailand 256. In 1972, Cross and his colleagues indicated that monkeys had been infected experimentally by feeding the m freshwater fish and suggested that autoinfection may occur 81. It was shown that eggs passed in the faeces required almost two weeks to embryonate and tha t development to the infective larval stage in the fish intestinal mucosa took at least three weeks 35,81. In humans, the adult worms together with larvae and eggs have been found in the small intestine, especially the jejunum, and in heav y infections a severe enteropathy with malabsorption and wasting is produce d which not infrequently leads to death in a few weeks to months 50,90. Whalen and his colleagues showed that thiabendazole was partially effective in intestina l capillariasis344, then Singson and co-workers found that mebendazole wa s considerably more effective 305.

INFECTION WITH CHEILOSPIRURA SPECIES This genus was erected by Diesing in 1861 94. The worm has been recovere d once from a human; it was found in a conjunctival nodule in a Filipino farmer 4.

INFECTION WITH CONTRACAECUM OSCULATUM In 1912, Railliet and Henry raised the genus Contracaecum to house certain species of nematode parasites of reptiles and fish 275. In 1967, Schaum and Müller described larvae, identified as Contracaecum osculatum , in an eosinophilic granuloma in the intestine of a patient in Germany who ha d symptoms of peritonitis. The infection was thought to have been acquired by eating imperfectly cooked fish in the Baltic. Cure was obtained wit h thiabendazole 298.

INFECTION WITH CYCYLODONTOSTOMUM PURVISI This hookworm parasite of the large intestine of rats was described by Adams in Malaya in 1933 2. Infection in a human has been reported once 34.

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A History of Human Helminthology

INFECTION WITH DIOCTOPHYMA RENALE This parasite, commonly known as the giant kidney worm, was known t o Redi279 but was described by Goeze in 1782 and called Ascaris renalis by him126 . Goeze's specimen was recovered from a dog but the worm has sinc e been found in many carnivores. In 1802, Collet-Meygret called it in a vernacular fashion, a dioctophyme 77. Rudolphi in 1802 labelled it Strongylus gigas 289 then in 1851 Diesing renamed it Eustrongylus gigas 93. It was known by this designation for many years. In 1901, Stiles argued that it should b e called Dioctophyma renale 318, and despite some opposition, his view eventually prevailed when it was endorsed by the American Society of Parasitol ogists in 1941 (Journal of Parasitology 27: 279, 1941). Eggs are excreted in the urine and are ingested by aquatic oligochaetes in which they develop to the infective larval stage. Mammals can be infecte d directly by ingestion of infected oligochaetes, but more commonly they ar e taken up first by amphibia or fishes which are in turn ingested by the definitive host197. Only a small number of humans have been infected with this worm which measures up to a metre in length and is ab out 5 mm in diameter. In 1860, Beale in his review of parasitic infections of the urinary tract wrote: The parasite appears to have been found in the human kidney on one occasion, although Küchenmeister comes to the conclusion that it has never been met with. The specimen is preserved in the College of Surgeons. 23

Blanchard reviewed the literature in 1886 and regarded only nine human cases as authentic. One of the first presumptive cases reported in the Englis h literature was described by Cannon in 1887 51. Most proven cases have bee n diagnosed at autopsy or a worm has been expelled through the urethra. On e case has been reported in which an immature worm was identified in a nodule on the chest wall 30.

INFECTION WITH DIPETALONEMA SPECIES The genus Dipetalonema was erected by Diesing in 1861 94. Immature worms have been found in humans on several occasions including in an arm nodule 27 and in the eye26. These parasites may have been D. arbuta described by Highby in 1943143 or D. Sprenti described by Anderson in 1935. In 1932, Owen and Hennessey in Uganda reported the presence of small yellow nodules in th e bulbar conjunctiva together with proptosis and periorbital oedema in som e patients247. Poltera255 considered that these were Loa infections, but they may have been Dipetalonema or Mansonella parasites 25.

Miscellaneous Nematode Infections

729

INFECTION WITH DIPLOSCAPTER SPECIES This genus was erected by Cobb in 1913 73 to house certain species of free living worms which live in decaying organic matter. Humans are infected very rarely. Yokogawa found D. coronata in the urine of an elderly patient 356. Chandler observed this species in the stomach contents of 9 achlorhydri c patients58 who had presumably ingested them in decaying vegetable matter.

DIROFILARIASIS DIROFILARIA IMMITIS This worm was found in the heart of a dog and described as Filaria immitis by Leidy in 1856 in the United States of America 173. The microfilariae reported in dog blood by Gruby and Delafond in 1843 132 and later named by them Filaria papillosa haematica canis domestica 133 may have been D. immitis 340,341 . In 1911, Raillet and Henry 272 erected the genus Dirofilaria and transferred the parasite to it, it thus becoming known a s Dirofilaria immitis. The generic name is derived from a combination of the Latin words "dirus" and "filarium " meaning "cruel" and "ball of thread", respectively. It is transmitted b y mosquitoes including Anopheles maculipennis 131 and Culex quinquefasciatus (= fatigans)19. Occasional infections have occurred in humans with incomplete development of the worm. Faust and his colleagues first described this in 1941 following the discovery of a worm in the vena cava of a woman in Ne w Orleans111. In most cases since then, however, worms have been lodged in a branch of the pulmonary artery and many have been found by a routine chest X-ray70. They have rarely been found in the abdominal cavity 328, the eye95, and subcutaneous tissues 37. D. TENUIS This parasite of the cutaneous tissues of the raccoon in the United States o f America was described by Chandler in 1942 59. Many infections of the eye or eyelid reported from the USA as due to D. conjunctivae may have been really due to D. tenuis 241. In a number of other patients, the worms have presented as subcutaneous tumours (reviewed in 115). D. REPENS This parasite of the subcutaneous tissues of dogs was described by Railliet and Henry in 1911274. It is transmitted by mosquitoes such as Aedes aegypti33 . Human infection was first reported b y Skrjabin and his colleagues in the USSR in 1930; a worm was recovered from a subcutaneous nodule near the eye 307.

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A History of Human Helminthology

Many cases of D. conjunctivae infections reported from Europe and Asia may in fact have been D. repens infections. D. URSI This parasite of the subcutaneous tissues of bears was described by Yamaguti in 1941353 and was reviewed by Anderson in 1978 10. The vectors are simuliid blackflies. The first human infection sus pected as being due to this parasite was removed from the breast of a woman in Washington State, United States o f America342.

INFECTION WITH EUSTRONGYLIDES SPECIES Adult worms of various species of the genus Eustrongylides, which was erected by Jaegerskiöld in 1909 151, are parasites of the anterior gut o f fish-eating birds. The infective larvae develop in small fish and amphibia i n which they may reach up to 10 cm in length. Unencapsulated, migrating larvae may be found in the tissues of mammals that have eaten infected fish. Thre e fishermen in the United States of A merica swallowed live bait minnows and all developed severe abdominal pain; two required operative intervention t o remove worms migrating into the peritoneal cavity 134.

GNATHOSTOMIASIS GNATHOSTOMA SPINIGERUM This parasite was discovered by Richard Owen in 1836 in the stomach wall of a tiger which had died in the London Zoological Gardens. He erected a ne w genus, Gnathostoma, derived from a combination of the Greek words (GNATHOS) and µ (STOMA) meaning "jaw and "mouth", respectively, to house this species which he named Gnathostoma spinigerum ; the specific epithet reflects the rings of spines on the parasite's head 248. Almost 100 years were to pass before inroads were made into an under standing of the life cycle of this worm. In 1912, Mitter found the parasite in a cat, dog and leopard 212, then Chandler in 1925 reported finding the worm i n 10-30% of cats examined post-mortem in India 56. He also noted finding encysted larvae in the mesentery of Indian snakes (rock python and cobra) 57. Several years later, Heydon described the development in water of G. spinigerum eggs obtained from an infected cat and observed spontaneous hatching of larvae142. In 1933, Prommas and Daengsvang in Thailand reported that they had shown experimentally that Cyclops was the first intermediate host; th e larvae forced their way into the body cavity of the copepod and moulted after

Miscellaneous Nematode Infections

731

10-14 days to become second-stage larvae 257. They were unable to infect cats with infected Cyclops but showed that a second intermediate host was required. When the freshwater fish, Clarias batrachus, ingested infected Cyclops, the second-stage larvae escaped and migrated to the tissues where they moulte d again to become infective third-stage larvae 258. They then completed the lif e cycle experimentally by infecting cats with infected fish 259. Africa and his colleagues in the Philippines then re ported (in a paper dated October 1936, but which seems to have been published somewhat later since it did not arrive at the Bureau of Hygiene and Tropical Diseases in London until 17 March 1938) that they had found encysted gnathostome larvae in the flesh of three species of naturally-infected freshwater fi sh, then recovered adult G. spinigerum from the stomach nodule of a presumably "clean" cat which had been fed larvae obtained from an infected fish, Glossobius giurus 5. Daengsvang and Tansurat i n Thailand then showed that natural inf ections occurred in over 90% of the frogs, Rana rugulosa, 80% of the eel, Monopterus albus, and 30-40% of the freshwater fishes, Ophiocephalus striatus and Clarias batrachus, that they examined86. Miyakazi indicated in 1954 that he had found infective larvae i n crayfish, crabs, amphibia, reptiles, fish and many mammals that had eaten fish flesh, but that the larvae only matured to the adult stage in the stomach of dogs and felines after a migration through the tissues 213. The various hosts of infective third-stage larvae, probably including man, may become infecte d either by ingestion of infected Cyclops or by the consumption of anothe r infected vertebrate (i.e. a paratenic host) 84. Humans are thought to be usually infected by eating poorly-cooked infected fish or domestic birds (ducks an d chickens). In Thailand, many living infective larvae are found in a kind o f fermented food made from the raw flesh of freshwater fish which is a favourite dish of Thai women 83, while in Japan, "sashimi", the sliced raw flesh of animals or fish, is enjoyed frequently 214. The first human infection with this parasite was described by Levinson in 1889. The worm was remove d from an abdominal tumour in a Thai woman by Dr Deunzer in Bangkok and forwarded to Levinson who named it Cheiracanthus siamensis 183. It was transferred to the genus Gnathostoma, becoming G. siamense, by Railliet in 1893 263, and was then shown to be synonymous with G. spinigerum by Leiper180. The larvae may migrate throughout the huma n body. Their presence may become manifest when they appear superficially , either causing an abscess 204,293, or migrating through the subcutaneous tissues producing a form of cutaneous larva migrans 142,329 or migratory oedema 283. The worm often attempts to extrude itself, often through the skin, but also via the mucous membrane of the oral cavity 283, respiratory tract and urinary tract. I n one patient who had transient swellings for seven years and then had a worm removed from an abscess in his right hand, swellings continued intermittently for another ten years until a second worm was extracted; Maplestone and Rao thought it likely that the worm had lived for 17 years 205. In 1945, Mukerji and Bhaduri reported the extraction of a worm from the anterior chamber of a n

732

A History of Human Helminthology

eye229, then the same patient seems to have b een described by Sen and Ghose 302. When the parasites migrate through the deeper tissues, they may produc e visceral larva migrans. The first fatal case recorded was described b y Chitanondh and Rosen in 1967; a Thai woman developed a progressiv e ascending paralysis and a worm was found in the spinal cord at autopsy 65. Larvae may also migrate through the brain to produce an eosinophili c meningoencephalitis 47,261. The diagnosis is made by recovery of the worm but immunoassays, particularly skin tests, may be valuable 214. Treatment is by surgical removal. Effective chemotherapy has not yet been demonst rated although ancylol, a compound not available for human use, has been shown to be effective against migratin g larvae in cats 85. G. HISPIDUM This parasite found in the stomach of pigs was described by Fedchenko i n 1872112. It rarely infects humans 224.

INFECTION WITH GONGYLONEMA PULCHRUM This consmopolitan parasite of ruminants was first described by Molin i n 1857 215. The name is derived from a combination of the Greek word s (GONGYLOS) and µ (NEMA) meaning "round" and "thread", respectively. The adult worm, up to 6 cm in length, lives in the mucosa an d submucosa of the oral cavity and oesophagus of animals. Eggs are passed in the faeces and ingested by dung beetles or cockroaches; they hatch in the intestine and the larvae burrow into the body cavity and encapsulate. The definitive host becomes infected by swallowing an infected insect 22. The first human infection was recorded in Italy in 1864 by Pane who called the worm Filaria labialis 249. In 1916, Ward described the extraction of a worm from beneath the mucosa of the lower lip of a 16 year old girl; the patient had stated that she had seen the worm on three occasions during its migratio n between the lips and the fauces 339. About 30 human cases have now bee n reported. Most worms have be en found in the buccal cavity or its environs, but Feng and colleagues have recorded one patient w ith oesophageal localization 114. The worms have been removed surgically; anthelmintic therapy is uncertain.

INFECTION WITH HAEMONCHUS CONTORTUS In 1803, Rudolphi described Strongylus contortus as a parasite of sheep 290. In 1898, Cobb erected the genus Haemonchus and transferred this parasite into it, the worm thus becoming known as Haemonchus contortus 72. The generic

Miscellaneous Nematode Infections

733

name is derived from a combination of the Greek words µ (HAIMA) and (ONCHOS) meaning "blood" and "spear", respectively. Infection i s rare in humans. de Magalhaes recorded the infection once in Brazil 198 and Sweet described the infection in three aborigines in Western Australia 326.

INFECTION WITH LAGOCHILASCARIS MINOR This species was first described by Leiper in 1909 who received the specimen obtained from a human infected in Trinidad 177. The name is derived from a combination of the Greek words (LAGOS), (CHEILOS), and (ASKARIS, ASCARIS) meaning "hare-lipped" and "worm" , respectively; this reflects the deep median depression in each lip which gives the parasite the form of a harelip. This worm has not yet been identified i n animals and the life cycle is uncertain. The infection has been reported i n humans a number of times. In most instances it has been recovered from th e tissues of the head and neck with colonies of adult worms, eggs and larvae in various stages of development being found in abscesses or nodules whic h develop over months or years 42. Recently, a fatal case of encephalitis has been described285. Variable success has been achieved with diethylcarbamazine 98,171, thiabendazole 217,239 and levamisole 42.

INFECTION WITH MAMMOMONOGAMUS LARYNGEUS This parasite of the upper respiratory tract of cattle and felines, commonl y known as "gapes" was recovered from an ox and described by Railliet in 1899 who named it Syngamus laryngeus, the specific epithet reflecting its location in the host265. In 1948, Rizhikov transferred the worm to the genu s Mammomonogamus 282. The life cycle of this worm is uncertain. In 1913 , Leiper recorded the discovery by King in St. Lucia, West Indies of a male and female worm which were coughed up by a woman, with a chronic cough . Leiper named the parasite Syngamus Kingi 179,180. It was later considered to be synonymous with M. laryngeus, although Buckley believed S. Kingi to be synonomous with S. nasicola von Linstow, 1899 45. Hoffman in 1931 recounted removing a red object from the posterior wall of the pharynx of a patient who had had a continuous cough since visiting a farm several weeks previously; it proved to be a pair of M. laryngeus in copula 144. Mornex and colleagues have recently reviewed human Mammomonogamus infections and indicated that 78 cases have been reported, mostly from Central America and the Caribbean 226.

734

A History of Human Helminthology

MANSONELLIASIS MANSONELLA OZZARDI For a number of years, Patrick Manson in London corresponded with friends and acquaintances all over the w orld in an endeavour to collect statistics on the various species of filariae. Filaria sanguinis hominis (= F. nocturna = Wuchereria bancrofti) was well-known and Manson himself had described two new species, microfilaria diurna (= Loa loa) and microfilaria perstans (= Mansonella perstans) in 1891. In 1897, he presented his findings to the annual meeting of the British Medica l Association held in Montreal, Canada, in which he concluded that there were another two species of human filariae 202. In 1893 and again in 1895, Dr Newsham of St. Vincent, West Indies, had sent him a large number of blood films prepared from residents of that island. In six o f them, Manson found microfilaria bancrofti, but in ten of them he discovered: an entirely new filaria which at Blanchard's suggestion, I have named filaria Demarquayi. This new filaria is shaped exactly like filaria nocturna and filaria diurna but is very much smaller. I do not feel justified in giving the measurements of the dried organisms, the only specimens available, as in consequence of the shrivelling the parasites have undergone, the dimensions may be materially altered; suffice it to say that filaria Demarquayi is less then half the size of filaria nocturna. Filaria Demarquayi has no sheath, but, like filaria perstans, is naked in the blood . . it exhibits no diurnal periodicity whatever, being present in the peripheral blood both during the day and during the night.202

In early 1897, Dr Ozzard in British Guiana (Guyana) had sent Manson 6 3 slides prepared from people living in the interior of that country. Manson found no evidence of W. bancrofti infection, but in 27 of them he discovered tw o different microfilariae: One of these minute filariae closely resembled filaria Demarquayi of St. Vincent, being minute and sharp-tailed and without a sheath; the other closely resembled, if it was not identical with, filaria perstans a parasite which hitherto I had found only in West African blood.202

Manson decided that of these two microfilariae (which he referred to a s "Demerara filaria" - Demerara bein g a town in British Guiana), the blunt-tailed form was indeed F. perstans, but from reasoning that is difficult to follow , wrote: I do think the sharp-tailed Demerara filaria is a new species and not identical with filaria Demarquayi....this new filaria of Demerara....I propose to call provisionally filaria Ozzardi.202

CW Daniels in British Guiana, however, was less certain, for one year later he reported to the British Medical Association: "If the sharp-tailed embryo s represent another species, it has yet to be decided whether it is a new one or the f. demarquayi" 88. Otto Galgey, colonial assistant surgeon in St. Lucia, West Indies, was even more forthright. He noted considerable variability in size of the F. demarquayi he had found in St. Lucia, and after comparing them with specimens o f

Miscellaneous Nematode Infections

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F. ozzardi concluded that they were one and the the same worm: I am inclined to believe that all are filaria Demarquayii; that is to say, that the filaria Demarquayii of St. Vincent, and that discovered by me in St. Lucia, and the sharp-tailed form of filaria Ozzardi (British Guiana) are identical. 120

In 1899, Daniels reported finding an adult female worm and a portion of a n adult male worm which differed from the adult F. perstans (which he had described the previous year) at the autopsy of patient who had had microfilaria perstans and microfilaria ozzardi in his peripheral blood. They were foun d lying free in the subperitoneal connective tissues of the anterior abdomina l wall. He described the parasites, comparing them with F. bancrofti and F. perstans and concluded: The differences observed both in the male and female are sufficient, I consider, to differentiate this from the other described adult filariae. The name 'Filaria Ozzardi' might be retained for the new species.89

Later that year Galgey found two parental forms of F. demarquayi in the mesentery of an infected patient in St Lucia 121. He sent them to Ozzard i n British Guiana for identification, but owing to imperfections in the specimens, Ozzard was not able to come to any definite conlusion. In 1902, Low reported that he had compared microfilaria demarquayi from St. Lucia, Dominica and St. Vincent and microfilaria ozzardi from British Guiana, and had concluded that they were identical 190. With the recognition that F. demarquayi and F. ozzardi were synonymous, the correct name appeared to be Filaria demarquayi since Manson had described this parasite first in his original 1897 paper. Since this name had already been used for W. bancrofti by Zune361, however, Railliet proposed the designation F. juncea 266. Leiper pointed out, however, that the second name given by Manson, F. ozzardi, had priority 180. In 1914, Biglieri and Araoz found a microfilaria in persons living in the province of Tucumán in northern Argentina, and named it microfilaria tucumani 36; this parasite was also later shown to be synonymous with microfilaria ozzardi 337. In 1929, Faust erected the genus Mansonella in honour of Manson, with this parasite as the type and only species 108. When Chabaud and Bain reclassified the Dipetalonema group in 1976, they omitted M. ozzardi as they considered it insufficiently known for taxonomic consideration 55. In 1982, Orihel and Eberhard redescribed the species and redefined the genus using materia l obtained by infection of experimental monkeys ( Erythrocebus patas)242. Low in 1901 attempted to determine the vector of the parasite by exposing infected patients to Culex fatigans (= quinquefasciatus), Stegomyia fasciata (= Aedes aegypti), C. taeniatus and Anopheles albipes, but found that they were refractory to infection. Subsequently, he caught and dissected a variety of blood-sucking insects feeding on inhabitants in a heavily endemic area o f British Guiana, but with negative results 190. In 1933, Buckley in St. Vincen t indicated that microfilaria ozzardi was taken up by and developed in gnats of the genus Culicoides 45, especially C. furens 46. Many years later, Nelson and Davies showed that C. phlebotomus was a vector in Trinidad 231, while the

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blackflies, Simulium species, were implicated in transmission in parts of South America332,335. Manson had written in 1897 that although he did not known what the y were, he had no doubt that the pa rasite had some pathological consequences 202. In the following year, however, Daniels declared that there was as yet n o evidence of a pathological role for these worms as most infected person s seemed to be in good health, even when the worms were numerous 88. This view was echoed by Low in 1902: The presence of the parental and embryonic forms of filaria Demarquayii seems to give rise to no pathological effects or clinical symptoms. As the habitat of the parent is in the loose connective tissue of the peritoneum, with perhaps the exception of setting up some slight local inflammation on its death, it cannot do much harm, as it does not implicate important structures.190

This latter concept has since stood the test of time. Diagnosis depends upo n recovery of microfilaria from the blood, or less frequently, in skin samples 184. Treatment is unnecessary; in any case, none in available. M. PERSTANS The blunt-tailed microfilaria of M. perstans was found by Mackenzie an d Manson in 1890 in the same patient (who later died from sleeping sickness) in whom they discovered what turned out to be microfilaria loa. These events and the naming by Manson of the parasite first Filaria sanguinis hominis mino r (because of the smaller size of the microfilaria when c.f. microfilaria loa)200, then its designation as Filaria sanguinis hominis perstans (later F. perstans to meet the needs of binomial nomenclature) because it had no periodicity in contrast to the nocturnal periodicity of microfilaria bancrofti and the diurnal periodicity of microfilaria loa 201 have been described in chapter 23. Th e finding by Manson in 1897 of a similar microfilaria in blood sent to him from Central America 202 is recorded in the section on M. ozzardi. This observation stimulated C W Daniels in British Guiana to search for the parent worm. I n December 1897, he was rewarded with success in finding male and femal e worms in the mesentery and in subpericardial fat in two individuals who had had both microfilaria perstans and microfilaria ozzardi in their blood during life. He described the morphology of the worms, and since all the female worms had blunt-tailed larvae, it seemed likely that they were the parental form o f microfilaria perstans. Daniels wrote: Although this is undoubtedly a new species of filaria I do not propose at present to give it a name, seeing that it may turn out to be the parental form of one of the already known and named species of nematode embryos described by Manson. Very probably it may be the parental form of filaria perstans. 87

In 1898, Manson described two Congoles e patients with sleeping sickness who were also infected with F. perstans 203. One of them soon died, and Mr O'Neill of the Charing Cross Hospital found a mature filaria in the connective tissu e

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behind the abdominal aorta. Manson comp ared this with the nematode from the Americas described by Daniels and determined that they were the one and the same, thus proving that Daniels had indeed discovered the adult form of F. perstans 14. This opinion was supported soon afterwards by Low 191. Thereafter, changes in the nomenclature of this parasite became rather like a game of musical chairs. In 1912, Railliet, Henry and Langeron 276 transferred it to the genus Acanthocheilonema which had been raised in 1870 b y Cobbold75, thus becoming Acanthocheilonema perstans . However, Yorke and Maplestone357 considered that Acanthocheilonema was a synonym of Dipetalonema erected by Diesing in 1861 94, so it became known as Dipetalonema perstans. In 1935, Faust 109 described the genus Tetrapetalonema and Yeh354 then Chabaud and Bain in 1976 55 placed it in this genus, the worm thus being described as Tetrapetalonema perstans . This fashion was evanescent , however, for in 1982, Orihel and Eberhard redefined the genus Mansonella and transferred this worm into that genus 242; it is therefore known currently as Mansonella perstans. Analogy with other filarial parasit es suggested that this worm was probably transmitted by insect intermediate hosts but a number of years were to pas s before this was proven. An interesting but odd exchange over the transmission of infection took place at the beginning of the present century. The unorthodox Charlton Bastian postulated that F. perstans was really a member of the genus Tylenchus which contained nematode parasites of plants, and suggested tha t infection was acquired by eating bananas 20. This brought a fulsome response from Low who may have thought that Bastian himself was bananas: "filari a perstans has nothing to do with the genus Tylenchus nor do bananas play any part in the distribution or spread of this filaria" 192. Not to be outdone, Bastian returned to the fray adducing various arguments 21 which were once more refuted by Low 193. In 1908, Fülleborn succeeded in achieving some development of microfilariae in Anopheles maculipennis 118. In 1921, Sergent and Gouillon reported unsuccessful attempts to infect Culex pipiens 301, but in 1927 Dyce Sharp in a preliminary note announced the development of F. perstans in Culicoides grahami 103. In the following year, he provided a more formal and detaile d description of the events, with the product ion of infective larvae eight days after experimental infection of C. austeni 104. In 1952, Hopkins and Nicholas showed that C. grahami was a possible but poor vector when compared with C. austeni 146. Initially, Manson ascribed no pathological consequences to M. perstans infection, but then transiently entertained the idea that it might be the cause of sleeping sickness200,201. This possibility was banished, however, when th e different geographical distributions of the two conditions were established and the trypanosomal aetiology of the illness was ascertained. In 1903, Low wrote: Filaria perstans, like filaria Demarquayii, gives rise to no pathological symptoms, the position of the worms in the connective tissues of the mesentery apparently causing

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no harm.191

Although there have been occasional claims to the contrary 71,219,227,323, most commentators have upheld this view. The diagnosis is made by finding th e microfilariae in the blood. Diethylcarbamazine has little action on the worm 139 but mebendazole may be active 338. M. STREPTOCERCA In 1922, JW Macfie and TF Corson on the Gold Coast (Ghana) found microfilariae in the skin of 22 out of 50 healthy adults which could be distinguished from those of Onchocerca volvulus by having a slender body, crook-shape d posterior end, and a blunt tail. Sections of the skin showed that they were lying in the dermis and were surrounded by a slight degree of cellular infiltration . MacFie and Corson placed these worms in the genus Agamofilaria of Stiles320 and named them Agamofilaria streptocerca 195. The same parasites were found later by Dyce Sharp in 1927 in the British Cameroons (Cameroon) 102 then by other observers in West and Central Africa. Like M. perstans, this parasite has had a complex nomenclatural history. In 1949, Faust 110 transferred it to the genus Acanthocheilonema of Cobbold 75 thus naming the worm Acanthocheilonema streptocerca. Meanwhile, Peel and Chardome 251 in 1946 had reported the discovery of two female worms and a fragment of a mal e worm in a chimpanzee (Pan paniscus) in the Belgian Congo (Zaire) and had placed the parasite in the genus Dipetalonema of Diesing94, naming it Dipetalonema streptocerca. In 1976, Chabaud and Bain 55 transferred it to the genus Tetrapetalonema of Faust109 to become Tetrapetalonema streptocerca . Finally, Orihel and Eberhard 242 in 1982 considered that Tetrapetalonema was synonymous with Mansonella and renamed the parasite Mansonella streptocerca. The adult female worm was first di scovered in human tissue by Meyers and his colleagues in 1972 209, then they found the adult male in 1977 211. Chardome and Peel showed in 1949 that this parasite was transmitted by Culicoides grahami 60, then Duke100 proved that C. milnei was also a vector. The infection may be asympyomatic but some dark skinned persons presen t with itching and hypopigmented macules. Meyers and colleagues reported that diethylcarbamazine kills microfilariae in the tissues and produces degenerative changes in adult worms 210. INFECTION WITH MENINGONEMA PERUZZII In 1973 Orihel and Esslinger described Meningonema peruzzii which had been collected from three monkeys (Cercopithecus talaporn )243. The generic name is derived from a combination of the Greek words µ (MENINX) and µ (NEMA) meaning "membrane" and "thread", respectively. The sam e

Miscellaneous Nematode Infections

739

worms had been reported by Peruzzi in 1928 in Uganda 253. Orihel240 then suggested that these worms were the true cause of the meningoencephaliti s attributed by Dukes and his colleagues to Dipetalonema (= Mansonella) perstans 101. INFECTION WITH METASTRONGYLUS ELONGATUS In 1845, Dujardin described Strongylus elongatus, a parasite of the respiratory tract of pigs99. In 1911, Railliet and Henry 273 transferred this worm to the genus Metastrongylus which had been erected by M olin in 1861 216. The generic name is derived from a combination of the Greek words µ (META) and (STRONGYLOS) meaning "with" and "round", respectively . Infections in humans are very rare, the first being described by Dujardin in the respiratory tract of a six year ol d boy99. Chatin in 1888 reported infection in the gastrointestinal tract of a pork vendor 61. INFECTION WITH MICROFILARIA SPECIES (Adult worm undescribed) M. BOLIVARENSIS This unsheathed microfilaria was found i n the blood of American Indians living in a remote part of Venezuela and reported by Godoy and colleagues in 1980 125. M. RODHAINI This infection was first described from the chimpanzees Pan paniscus and Pan satyrus by Peel and Chardome in Zaire in 1946 251. Microfilaria indistinguishable from this parasite were seen in skin biopsies of people in Gabon b y Richard-Lenoble and colleagues in 1982 281. M. SEMICLARUM In 1974, Fain reported the finding of a dis tinctive unsheathed microfilaria in the blood of 52 inhabitants in three villages in Zaire. He named this parasit e microfilaria semiclarum because it had a long, clear region on the posterior half of the body106. The adult worms, reservoir host, and life cycle are unknown. INFECTION WITH MICRONEMA DELETRIX This species was described by Anderson and Bemrick in 1965 from thousands of worms found in bilateral tu mours in the nares of a horse in the United States of America 12. The generic name is derived from a combination of the Gree k words µ (MIKROS, MICROS) and µ (NEMA) meaning "small" and

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A History of Human Helminthology

"thread", respectively. Three fatal cases with this parasite or a M. deletrix-like worm have been recorded, the first being reported by Hoogstraten and Young in 1975; a 5 year old boy in Canada died from meningoencephalitis caused by the worm after he passed through a manure spreader and sustained multipl e lacerations 145.

INFECTION WITH NECATOR SUILLIS This hookworm parasite of pigs was designated Necator suillis by Ackert and Payne in 19231. Buckley in 1932 infected himself on 11 separate occasion s with infective larvae (about 80 worms each time) prepared from eggs obtained from N. suillis recovered from pigs at an abbatoir in Trinidad. Eggs were first seen 54 days after the first application to his skin and continued to be passed over the next four months. Only three adult worms were recovered afte r treatment with oil of chenopodium 44.

INFECTION WITH OESOPHAGOSTOMUM SPECIES A number of species of the genus Oesophagostomum, raised by Molin in 1861216, are parasites of subhuman primates, swine and sheep. The generi c name is derived from a combination of the Greek words (OESOPHAGOS) and µ (STOMA) meaning "gullet" and "mouth" , respectively. These parasites are often called "nodular worms" since the y produce large nodules in the wall of intestine, especially in the caecum an d colon. Included amongst those which may occa sionally infect humans are O. bifurcum described by Creplin in 1849 79, O. aculateum by von Linstow in 348 1879 185, O. apiostomum by Willach in 1891 , O. bifurcum by Creplin in 79 1849 , O. brumpti by Raillet and Henry in 1905 268 and O. stephanosum described by Stossich in 1905 322; some of these may be synonyms of each other. The first human infection was found in a person from the Omo River in East Africa 268, then Leiper reported O. apiostomum infection in man after the parasite was collected by Foy in Nigeria 178. More recently, Anthony an d McAdam reviewed 34 cases seen in Uganda. The most common presentation was as a mass in the ileocaecal re gion although nodes or abscesses, usually 1-2 cm in diameter, may be seen in other parts of the small and large bowel 15. Operative intervention may be necessary to effect the diagnosis or to reliev e intestinal obstruction. No anthelmintics have yet been shown to be effective.

Miscellaneous Nematode Infections

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INFECTION WITH OSTERTAGIA SPECIES In 1890, von Ostertag described a parasite recovered from cattle which h e named Strongylus convolutus 244. Two years later, Stiles renamed it Strongylus ostertagi 317. In 1894, Stadelmann described a similar parasite in sheep which he named Strongylus circumcincta 315. In 1907, Ransom erected the genu s Ostertagia and transferred these worms into it, the parasites thus becomin g known as Ostertagia ostertagi and Ostertagia circumcincta 277. In 1941, Kasimov recorded finding two male sp ecimens of O. circumcincta in the stools of a patient after administration of anthelmintics 159 then reported the discovery of a single O. ostertagi in the small intestine of a man at autopsy 160. Lapage noted in a comment on these papers that it was possible that these worms might have been ingested in uncooked or partly cooked abomasum of cattle, sheep or goats169.

INFECTION WITH PELODERA SPECIES Pelodera strongyloides, described in 1866 by Schneider 299, is a parasite of the orbit of wild rodents, and the skin of dogs, horses, cattle and sheep. Huma n infection has been reported once when it was found infecting the skin of an 11 year old Polish girl 250.

INFECTION WITH PHYSALOPTERA CAUCASICA This worm was found in the ileum of a patient in the Caucasus and name d Physaloptera caucasica by von Linstow in 1902 186. The generic name is derived from a combination of the Greek words (PHYSALIS) and (PTEROO) meaning "bubble" and "wing", respectively. In 1907 , Leiper also described a worm that had been removed from the stomach of a person in Uganda and named it P. mordens 176. He later suggested that monkeys may be the reservoir of infection180. The worms, 2-10 cms long, live with their head embedded in the mucosa of the alimentary tract anywhere between th e oesophagus and the ileum, but they may also be found in the liver. The infection is rare in humans although Vandepitte and colleagues in 1964 reported finding five cases in Zaire in one year. These patients complained of vomiting an d epigastric pain and eggs were found in their faeces336. Another patient has been described recently in whom worms that were probably Physaloptera caused gangrene of the distal small bowel 235. The life cycle of this worm is unknown and the treatment of the infection is uncertain.

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A History of Human Helminthology

INFECTION WITH RHABDITIS SPECIES The genus Rhabditis was erected in 1845 by Dujardin 99 to house a number of species of free-living nematodes which live typically in decaying organic matter but which may occasionally be found temporarily on damaged human tissue or in the lumen of various organs. Rhabditis species found in faeces have usually been ingested in contaminated food or water and have passed through th e alimentary tract or have contaminated faecal droppings deposited on the soil. Kobayashi reported finding a Rhabditis which he called R. hominis in 17 students in Japan and noted that there were no ill-effects; the worms wer e expelled spontaneously in 2-3 months 163. Rhabditis species have also been found in urine 113 and in skin 236.

INFECTION WITH RICTULARIA SPECIES This genus was erected by von Frölich in 1802 117. The worms are normall y parasites of rodents and bats but an adult female worm has been seen in New York in a human appendix 161.

INFECTION WITH SPIROCERCA LUPI This parasite of wolves and dogs was named Strongylus lupi by Rudolphi 291 in 1809 then transferred to the genus Spirocerca of Raillet and Henry 273.In 1959, Biocca reported the case of an infection of a baby who had been born on e month prematurely and had developed intestinal obstruction and peritonitis as a consequence of worms embedded in her terminal ileum 38. It is believed that the mother must have ingested an infected beetle while pregnant.

INFECTION WITH TERNIDENS DEMINUTUS This parasite of the large intestine of several simian species was described as Triodontophorus deminutus by Raillet and Henry 267 in 1905 then renamed Ternidens deminutus by them in 1909 270. The generic name Ternidens is derived from a combination of the Latin words "ter" and "dens" meanin g "thrice" and "tooth", respectively, and indicates the presence of three complex teeth in the buccal cavity. Infection of a woman with this parasite was reported by Leiper in 1908 175. In 1929 Sandground recovered T. deminutus-like eggs from the faeces of a medical missionary who had spent 25 years in Africa, cultured larvae, an d produced an experimental infection in a vo lunteer, although he failed to recover adult worms after carbon tetrachloride treatment 294. In a subsequent survey in

Miscellaneous Nematode Infections

743

Southern Rhodesia (Zimbabwe), he found that in some regions more than 50% of the population were infected 295. He attempted to transfer infection to more humans and to subhuman primates but failed, as did Goldsmid many year s later 127. Sandground used carbon tetrachloride and tetrachlorethylene i n treatment. More recently, thiab endazole128 and pyrantel embonate 129 have been shown to be effective.

INFECTION WITH TERRANOVA SPECIES This genus was erected by Leiper and Atkinso n in 1914 to house certain worms collected by Atkinson during the ill-fated British Antarctic Expedition o f 1910-1913 led by Captain Scott 182. The genus was named after the ship (itself named "Terra Nova" meaning "new land") which took the party to th e Antarctic. The life cycle is probably similar to that of Anisakis. The first human infections were reported in Japan in 1972 by Suzuki and his colleagues who described 5 patients in whom a larva was seen penetrating the gastric mucosa 325. Koyama and colleagues then described the morphology of the larvae removed from these patients 166. The infections were thought t o have been acquired by eating raw fish. A number of similar cases have bee n reported since. Some of these may b e due to infection with Phocanema species since the larvae of this genus, erected by Myers 230 in 1959, are indistinguishable from those of Terranova.

INFECTION WITH THELAZIA T. CALLIPAEDA This worm, 5-17 mm in length, which was found in a dog, was described b y Railliet and Henry271 in 1910. The generic name is derived from the Gree k word (THELAZO) meaning "to suck". In 1917, Stuckey 324 and 147 Houghton in China described infections of the human eye with a worm they identified as Filaria palpebralis. Leiper, however, considered that the parasite was almost certainly T. callipaeda 181, an opinion which was shared by Faust 107, the latter describing the male worm for the first time and showing that rabbits were a host. The life cycle is uncertain but other species of Thelazia use flies (Musca, Fannia) as intermediate hosts. According to Kagei and colleagues, 30 cases have now been reported from Japan 155. The worm usually causes littl e conjunctivitis but often stimulates marked tear production. Movement over the corneal surface can cause corneal opacities. The worm may be removed with forceps after anaesthesia of the eye.

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A History of Human Helminthology

T. CALIFORNIENSIS This species has been recovered from a number of animal and bird hosts i n California. It was first described by Kofoid and Williams 164 in 1935 after two worms, 10-13 mm long, were removed from the eye of a doctor wh o complained of an irritation in his eye; he remembered that some flying insect had hit his eye ten days previously. Several cases have been reported since.

TOXOCARIASIS TOXOCARA CANIS This ascarid parasite of dogs was described by Werner in 1782 as Ascaris canis 343. In 1907, Leiper erected the genus Belascaris and, holding that Ascaris canis was synonymous with Fusaria mystax of the cat described by Zeder359, called it Belascaris mystax 174. In 1916, however, Johnston transferred the worm to the genus Toxocara, which had been erected by Stiles in 1905 319, and named it Toxocara canis 154. The name Toxocara is derived from a combination of the Greek words (TOXON) and (KARA, CARA) meaning "bow" and "head", respectively. There are rare records of the infection in humans by the adult form of this parasite, but they are questionable, probably being in reality immature Ascaris lumbricoides 39,350. In dogs, infection is usually acquired across the placenta or via the mother's milk, although infective egg s in soil or larvae in paratenic hosts may be ingested 314. When paratenic hosts are infected, larvae migrate into the tissues, fail to mature and become encapsulated. This fate also befalls T. canis larvae in humans. In monkeys, such lar vae have been shown to remain alive for at least nine years 24. In 1947, Josephine Perlingiero and Paul György of the Philadelphia General Hospital reported the case of a two year old black boy admitted to hospital in 1944 with fever, weight loss, cough, vomiting, transient diarrhoea , hepatomegaly and marked eosinophilia. Because the vomiting continued and abdominal distension developed, he was subjected to laparotomy and the liver was found "to have small, gray-white lesions scattered over the smooth surface of all lobes"252. Biopsy revealed focal necrotic lesions with numerou s polymorphonuclear and eosinophilic granulocytes and giant cells. In view of the fact that he "improved remarkably" after he vomited a single male A. lumbricoides, the illness was ascribed to infection with this parasite 252. A similar case was described by Zuelzer and Apt two years later 360, then in 1950 Mercer and colleagues found nematode larvae which they indentified as A. lumbricoides in lesions in the liver of a patient with a similar condition 208, as did Behrer in the following year 31. Meanwhile, in 1950, Helenor Wilder of the United States Armed Force s

Miscellaneous Nematode Infections

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Institute of Pathology had described an ocular disease which she called nematode ophthalmitis. She discussed a large series of cases, mostly of children , from whom an eye had been enucleated because of a suspected diagnosis o f retinoblastoma. Histological examination, however, revealed eosinophili c granulomas, and in 24 of 46 such specimens, nematode larvae were found in serial sections. A number of the m were examined by BG Chitwood who wrote: "So far as can be determined on the basi s of the material at hand, the specimens are third stage hookworm larvae" 66. Wilder remarked sagaciously, however , that the fact that the larvae in these cases had been identified as being probably those of hookworms did not rule out other nematodes such as Strongyloides and Ascaris as possible causes of this endophthalmitis. Most of the childre n came from the southeastern USA and Wilder concluded: The findings of intraocular larvae by serial sectioning and the identification of the specific pathologic reaction that they evoke has led to the conclusion that nematodes play an important and hitherto unrecognized role in blindness in children 347

In 1952, Beaver and his colleagues, Snyder, Carrera, Dent and Lafferty, in New Orleans described three patients with hepatomegaly, anaemia and eosinophilia, in one of whom a larva was seen in a liver biopsy. Consequently, they coined the term "visceral larva migrans" to distinguish it from cutaneous larva migrans caused by larvae of Ancylostoma braziliense and other parasites in the skin. By utilizing serial sections, it was pos sible to reconstruct almost the whole of the worm and it was concluded that it "resembled the infective stage o f Toxocara canis or T. cati" 29. Mice were thereupon infected with T. canis and T. cati eggs and worms similar to that found in the human case wer e demonstrated subsequently in histological sections 29. In the following year, "by means of an experiment which cannot be commended" 349, Smith and Beaver produced the disease experimentally in humans. They administered orally 200 embryonated eggs of T. canis to two mentally defective children aged two and three years, respectively; both developed eosinophilia and some degree o f hepatomegaly311. This result was confirmed in a human volunteer by Chaudhuri and Saha in 1959 62. In 1956, Nichols re-examined five of Wilder's cases and identified the larvae in the eyes as those of Toxocara 233,234, then in 1959, Irvine and Irvine reported finding T. canis larvae in the eye of a child in California 150. By 1981, over 1900 cases of toxocariasis had been reported from many parts of the world and most of these have been due to T. canis but a few have been caused by T. cati 124. Infection in humans is usually acquired by ingestion of eggs in the soil . Toxocara ova were found in soil samples of 45% of dooryards in New Orl eans140 and in 24% of public parks in Britain 41. Infection is therefore common in children who ingest soil (pica). The diagnosis may be established by finding larvae in biopsy specimens but this is often difficult. Immunodiagnostic assays are therefore valuable. A precipitin test was described in 1956 by Heiner and Kevy141 and a skin test a few years later 351. More recently, Matthes and Buchwalder considered a microprecip itation test using live larvae as the most useful

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A History of Human Helminthology

immunodiagnostic procedure 207. There have been scattered reports that th e infection responds to treatment with thiabendazole 232, but this has not always been the experience 17. Similar contradictory results have followed treatmen t with diethylcarbamazine 312. Photocoagulation of the eye lesions is sometimes possible148. T. CATI This ascarid parasite of cats was described as Ascaris cati by Schrank in 1788300. Zeder in 1800 named it Fusaria mystax359 , then Rudolphi renamed it Ascaris mystax 288 and Leiper in 1907 used it as the type species of his new genus, Belascaris, calling it Belascaris mystax 174. Railliet and Henry in 1911 reverted to the specific description of Schrank, naming it Belascaris cati 274. In 1927 Brumpt transferred it to the genus Toxocara of Stiles319, it thus being designated Toxocara cati 43. Cats acquire the infection by ingesting embryo nated eggs or larvae in paratenic hosts. In contrast to T. canis, transplacental transmission does not occur but t ransmammary transmission is common. Some larvae complete their development to for m adult worms in the gut of young cats but most larvae migrate to the muscles in older cats 313. Complete development in humans is rare. The first such patient was possibly reported by Pickells in Ireland in 1824254 then more probably by Bellingham O'Brien32 in the same country a few years later then by Cobbold in England in 1863 74. According to von Reyn and colleagues, there have been 20 reports of infection in humans 280, but many of these may be spurious o r follow the ingestion by a child of a young adult worm. More commonly, T. cati may cause visceral larva migrans.

TRICHOSTRONGYLIASIS In 1892, Giles in India recov ered a worm which he named Strongylus colubriformis from nodules in the intestine of a sheep 123. In the following year, Railliet described S. instabilis 263 then in 1896 he also described S. probulurus 264. In 1905, Looss erected the genus Trichostrongylus, transferred S. instabilis and S. probulurus into it, and described a new species, T. vitrinus 188. The generic name is derived from a combination of the Greek words (THRIX) [combining form - (TRICHO-)] and (STRONGYLOS) meaning "hair" or "thread" and "round", respectively. In 1911 Ranso m transferred S. colubriformis into the genus Trichostrongylus 278. Other species described were T. axei 269, T. orientalis 153, T. skrjabini 157 and T. brevis 245. All of the above species are now known to infect humans. In 1925, Koino reported that T. orientalis infections in mice seemed t o follow the same route through the lungs as do hookworms. Although infection could be established percutaneously, he believed that oral infection was th e usual and more efficient mode of infection 165. Monnig218 then Hasegawa137

Miscellaneous Nematode Infections

747

showed, however, that after oral infection, s ystemic migration did not occur; the larvae migrated into the mucosa and matured in about three to four weeks. The first human infection with a Trichostrongylus species was reported by Looss in 1895 who described infection with the worm he named Strongylus subtilis 187. Later Lane168 showed that S. subtilis was synonymous with S. colubriformis described by Giles in 1892 123 so Looss's name lapsed in favour of T. colubriformis. Initially, such infections were regarded as accidental i n those who kept close proximity with animals. Eventually, however, it wa s realized that human infection was much more frequent in many parts of th e world than had hitherto been suspect ed. For example, Kalantarian found a 15% prevalence in Armenia 156, Stewart showed that 70% of the population in one part of Iran was infected 316, Lawless and colleagues reported a 70% infection rate in an Egyptian village 170, and Otsuru observed a frequency of 40% in parts of Japan245. Infection may persist for years; Sandground described one patient in whom the infection had laste d for at least 8.5 years 296. These various surveys revealed that in the vast majority of patients, infection produced no ill-effects. The diagnosis of trichostrongyliasis is made by finding eggs in the faeces, although specific identification depends upon recovery of the adult worms . Otsuru showed in 1962 that bephenium hydroxynaphthoate was effective 245, then thiabendazole 206 and pyrantel pamoate 122 were also found to be useful.

INFECTION WITH UNCINARIA STENOCEPHALA This hookworm parasite of dogs was described by Railliet in 1885 262. Patent infections do not develop in humans but Fülleborn in 1927 showed by experimental infection of his own skin that it may cause cutaneous larva migrans 119.

REFERENCES 1. ACKERT JE, PAYNE FK. Investigations on the control of hookworm disease. XII . Studies on the occurrence, distribution and morphology of Necator suillis including descriptions of the other species of Necator. American Journal of Hygiene 3: 1-25, 1923 2. ADAMS AR. Report on a collection of nematodes from the Federated Malay States . Annals of Tropical Medicine and Parasitology 27: 1-13, 1933 3. ADDARIO C. Su di un nem atode dell'occhio umano. Annali di Ottalmologia, Milano 14: 135-148, 1885 4. AFRICA CM, GARCIA EY. A new nematode parasite ( Cheilospirura sp.) of the eye of man in the Philippines. Journal o f the Philippine Islands Medical Association 16: 603-607, 1936 5. AFRICA CM, REFUERZO PG, GARCIA EY. Further observations on the life cycle of Gnathostoma spinigerum. Philippine Journal of Science 61: 221-225, 1936 6. AFTANDELIANS R, RAFAAT T, TAFFAZOLI M, BEAVER PC. Pulmonary capillariasis in a child in Iran. American Journal of Tropical Medicine and Hygiene 26: 64-71, 1977 7. ALESSANDRINI GC. Su di alcune uncinariae parasite dell'uomo e di altri vertebrati. Bolletino della Società dei Naturalisti in Napoli, second series, 6: 23-48, 1905

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8. ALICATA JE. Priority in determining the cause and method of human infection in cases of eosinophilic meningitis in Tahiti. Tropical Medicine and Hygiene News 35: 111-114, 1986 9. ALICATA JE, BROWN RW. Preliminary observations on the use of an intradermal test for the diagnosis of eosinophilic meningoencephalitis in man caused by Angiostrongylus cantonensis. Canadian Journal of Zoology 40: 119-124, 1962 10. ANDERSON RC. Description and relationships of Dirofilaria ursi Yamaguti, 1941 and a review of the genus Dirofilaria Railliet and Henry, 1911. Transactions of the Roya l Canadian Institute 29: 25-64, 1952 11. ANDERSON RC. Keys to genera of the superfamily Metastrongyloidea. CIH keys to the nematode parasites of vertebrates, No. 5, Commonwealth Agricultural Bureaux, Farnham Royal, Slough, U.K., 1978 12. ANDERSON RV, BEMRICK WJ. Micronema deletrix, n. sp., a saprophagous nematode inhabiting a nasal tumour of a horse. Proceedings of the Helminthological Society o f Washington 32: 74-75, 1965 13. ANONYMOUS. Lancet ii: 803, 1874 14. ANONYMOUS. The parental form of Filaria perstans. British Medical Journal i: 429, 1899 15. ANTHONY PP, McADAM IW. Helminthic pseudotumou rs of the bowel: thirty four cases of helminthoma. Gut 13: 8-16, 1972 16. ASAMI K, WATANUKI T, SAKAI H, IMANO H, OKAMOTO R. Two cases o f stomach granuloma caused by Anisakis-like larval nematodes in Japan. American Journal of Tropical Medicine and Hygiene 14: 119-123, 1965 17. AUR RJ, PRATT CB, JOHNSTON WW. Thiabendazole in visceral larva migrans . American Journal of Diseases of Children 121: 226-229, 1971 18. BANCROFT TL. On the whipworm of the rat's liver. Journal and Proceedings of th e Royal Society of New South Wales 27: 86-90, 1893 19. BANCROFT TL. On some further observations on the life-history of Filaria immitis, Leidy. Journal and Proceedings of the Royal Society of New South Wales 37: 254-257, 1903. Reprinted in British Medical Journal i: 822-823, 1904 20. BASTIAN HC. Note on the probable mode of infection by the so-called Filaria perstans, and on the probability that this organism really belongs to the genus Tylenchus (Bastian). Lancet i: 286-287, 1904 21. BASTIAN HC. The anatomical characters of the so-called Filaria perstans and on the mode of infection thereby. Lancet i: 643-644, 1904 22. BAYLIS HA, PAN TC, SAMBON JE. Some observations and experiments in northern Italy. A preliminary note. Journal of Tropical Medicine and Hygiene 28: 413-419, 1925 23. BEALE L. A course of lectures on urine, urinary deposits and calculi. IV. Third class of urinary deposits: entozoa. British Medical Journal ii: 1007-1008, 1860 24. BEAVER PC. Zoonoses, with particular reference to parasites of veterinary importance. In, Biology of parasites, E.J. Soulsby (Editor), Academic Press, New York, pp 215-227, 1966 25. BEAVER PC, JUNG RC, CUPP EW. Clinical parasitology, ninth edition, Lea an d Febiger, Philadelphia, pp 825, 1984 26. BEAVER PC, MEYER EA, JARROLL EL, ROSENQUIST RC. Dipetalonema from the eye of a man in Oregon, U.S.A. American Journal of Tropical Medicine and Hygiene 29: 369-372, 1980 27. BEAVER PC, ORIHEL TC. Human infection with filariae of animals in the United States. American Journal of Tropical Medicine and Hygiene 14: 1010-1029, 1965 28. BEAVER PC, ROSEN L. Memorandum o n the first report of Angiostrongylus in man, by Nomura and Lin, 1945. American Journal o f Tropical Medicine and Hygiene 13: 589-590, 1964 29. BEAVER PC, SNYDER CH, CARRERA GM, DENT JH, LAFFERTY JW. Chroni c eosinophilia due to visceral larva migrans. Pediatrics 9: 7-19, 1952 30. BEAVER PC, THEIS JH. Dioctophymatid larval ne matode in a subcutaneous nodule from

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76. COCHRANE JC, SKINSTEAD E E. Capillaria hepatica in man - followup of a case. South African Medical Journal 34: 21-22, 1960 77. COLLET-MEYGRET GF. Mémoire sur un ver trouvé dans le rein d'un chien. Journal de Physiologie, Paris 55: 458-464, 1802 78. CREPLIN FHC. Eingeweidewürmer, Binnenwürmer, Thierwürmer. In, Allgemein e Encyclopädie der Wissenschaften und Künste etc., J S Ersch und J G Gruber, (Editors), Leipzig, 32: 277-302, 1839 79. CREPLIN FHC. Nachträge von Creplin zu Gurlt's Verzeichnisse der Thiere, in welchen Endozoen gefunden worden sind. Archiv fü r Naturgeschichte, Berlin, 15J, 1: 52-80, 1849 80. CROCKER HR. Creeping eruption. Annals of Dermatology 3: 1184, 1892 81. CROSS JH, BANZON T, CLARKE MD, BASCA-SERVILLA V, WATTEN RH , DIZON JJ. Studies on the experimental transmission of Capillaria philippinensis in monkeys. Transactions of the Royal Society of Tropical Medicine and Hygiene 66 : 819-834, 1972 82. CUCKLER AC, EGERTON JR, ALICATA JE. Therapeutic effect of thiabendazole on Angiostrongylus cantonensis infections in rats. Journal of Parasitology 51: 392-396, 1965 83. DAENGSVANG S. Human gnathostomiasis in Siam with reference to the method o f prevention. Journal of Parasitology 35: 116-121, 1949 84. DAENGSVANG S. A monograph on the genus Gnathostoma and gnathostomiasis in Thailand, Southeast Asian Medical Information Centre, Tokyo, 1980 85. DAENGSVANG S. Chemotherapy of feline Gnathostoma spinigerum migration stage with multiple subcutaneous doses of ancylol. Southeast Asian Journal of Tropica l Medicine and Public Health 11: 359-362, 1980 86. DAENGSVANG S, TANSURAT P. A contribution to the knowledge of the secon d intermediate host of Gnathostoma spinigerum Owen 1836. Annals of Tropical Medicine and Parasitology 32: 137-140, 1938 87. DANIELS CW. Discovery of the parental form of British Guiana blood worm. British Medical Journal i: 1011-1012, 1898 88. DANIELS CW. Filariae and filarial disease in British Guiana. British Medical Journal ii: 878-880, 1898 89. DANIELS CW. The probabl e parental form of the sharp-tailed filaria found in the blood of aboriginals of British Guiana. British Medical Journal i: 1459-1460, 1899 90. DAUZ U, CABRERA BD, CANLAS B. Human intestinal capillariasis. I. Clinica l features. Acta Medica Philippina, series 2, 4: 72-83, 1967 91. DAVEY JT. A revision of the genus Anisakis Dujardin, 1845 (Nematoda: Ascaridata). Journal of Helminthology 45: 51-72, 1971 92. DESPORTES C. Filaria conjunctivae Addario 1885, parasite accidental de l'homme, est un Dirofilaria. Annales de Parasitologie Humaine et Comparée 17: 380-404, 515-532, 1940 93. DIESING CM. Systema helminthum, Wilhelmum Braumüller, Vindobonae, tw o volumes, pp 1267, 1849-1851 94. DIESING CM. Revision der Nematoden. Sitzungsberichte der Akademie de r Wissenschaften in Wien. Mathematisch-naturwissenschaftliche Klasse 31: 42: 595-736, 1861 95. DISSANAIKE AS. Zoonotic aspects of filarial infection in man. Bulletin of the World Health Organization 57: 349-357, 1979 96. DOUGHERTY EC. The genus Aelurostrongylus Cameron, 1927 (Nematoda : Metastrongylidae) and its relatives; with descriptions of Parafilaroides, gen. nov., and Angiostrongylus gubernaculatus , sp. nov. Proceedings of the Helminthological Society of Washington 13: 16-25, 1946 97. DOVE WE. Further studies on Anchylostoma braziliense and the etiology of creeping eruption. American Journal of Hygiene 15: 664-711, 1932 98. DRAPER JW. Infection with Lagochilascaris minor. British Medical Journal i: 931-932, 1963

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Société de Pathologie Exotique et de ses Filiales 5: 251-259, 1912 276. RAILLIET A, HENRY AC, LANGERON. Le genre Acanthocheilonema Cobbold, et les filaires péritonéales des carnivores. Bulletins de la Société de Pathologie Exotique et de ses Filiales 5: 392-395, 1912 277. RANSOM BH. Notes on parasitic nematodes, including descriptions of new genera and species, and observations on life histories. Circular (116), Bureau of Animal Industry , United States Department of Agriculture, pp 7, 1907 278. RANSOM BH. The nematodes parasitic i n the alimentary tract of cattle, sheep, and other ruminants. Bulletin (127), Bureau of Animal Industry, United States Department o f Agriculture, pp 132, 1911 279. REDI F. Opusculorum pars secunda, sive experimenta circa varias res naturales , speciatim illas quae ex indiis afferuntur etc., pp 312; opusculorum pars tertia, sive d e animalculis vivis, quae in corporibus animalium vivorum reperiuntur observationes. In, Opuscula varia physiologica, T Haak et S Luchtmans, Lugduni Batavorum, thre e volumes, pp 342, 1729 280. von REYN CF, ROBERTS TM, OWEN R, BEAVER PC. Infection of an infant with an adult Toxocara cati (Nematoda). Journal of Pediatrics 93: 247-249, 1978 281. RICHARD-LENOBLE D, KOMBILA M, BAIN O. Foyer de filariose humaine a u Gabon à microfilaire dermique indifférenciable de microfilaria rodhaini. Annales d e Parasitologie Humaine et Comparée 57: 506, 1982 282. RIZHIKOV KM. (Phylogenetic relationships within the nematode family Syngamidae, with revision and systematic fin dings.) Dokladi Akademii Nauk SSR 62: 733-736, 1948. In Russian, with English summary 283. ROBERT L. La gnathostomose humaine, oedème ambulant siamois dû à Gnathostoma spinigerum (R. Owen, 1835). Bulletins de la Société de Pathologie Exotique et de ses Filiales 15: 854-860, 1922 284. RODENBURG W, WIELINGA WJ. Eosinfiele flegmone van de dunne darme , veroorzakt door een worm. Nederlandsch Tidjscrift voor Geneeskunde 104: 417-421 , 1960 285. ROSEMBERG S, LOPES MB, MASUDA Z, CAMPOS R, VIEIRA BRESSAN MC. Fatal encephalopathy due to Lagochilascaris minor infection. American Journal o f Tropical Medicine and Hygiene 35: 575-578, 1986 286. ROSEN L. Reply to 8. Tropical Medicine and Hygiene News 35: 114-117, 1986 287. ROSEN L, CHAPPELL R, LAQUEUR GL, WALLACE GD, WEINSTEIN PP . Eosinophilic meningoencephalitis caused by a metastrongylid lungworm of the rat . Journal of the American Medical Association 179: 620-624, 1962 288. RUDOLPHI CA. Fortsetzung der Beobachtungen über die Eingeweidewürmer. Archiv für Zoologie und Zootomie 2: 1-67, 1802 289. RUDOLPHI CA. Beschreibung von Strongylus gigas. In, Beyträge zur Anatomie und Physiologie der Thiere, JA Albert, (Editor), Bremen, Heft 1, pp 115-116, 1802 290 RUDOLPHI CA. Neue Beobachtungen über die Eing eweidewürmer. Archiv für Zoologie und Zootomie 3: 1-32, 1803 291. RUDOLPHI CA Entozoorum, sive vermium intestinalium historia naturalis, Treuttel & Würtz, Paris, three volumes, pp 1370, 1808-1810 292. SAMSON-HIMMELSTJERNE CV. (Concerning a new disease of the skin.) Vratsch 16: 1364, 1895. In Russian 293. SAMY PC. Gnathostoma siamense or Gnathostoma spinigerum . Indian Medical Gazette 53: 436, 1918 294. SANDGROUND JH. Ternidens deminutus (Railliet and Henry) as a parasite of man in Southern Rhodesia, together with observations and experimental infection studies on an unidentified nematode parasite of m an from this region. Annals of Tropical Medicine and Parasitology 23: 23-32, 1929 295. SANDGROUND JH. Studies on the life-history of Ternidens deminutus , a nematode parasite of man, with observations on its incidence in certain regions of southern Africa.

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Annals of Tropical Medicine and Parasitology 25: 147-184, 1931 296. SANDGROUND JH. On the potential longevity of various helminths with a record of a species of Trichostrongylus in man. Journal of Parasitology 22: 464-470, 1936 297. SAUERBREY M. A precipitin test for the diagnosis of human abdomina l angiostrongyliasis. American Journal of Tropical Medicine and Hygiene 26: 1156-1158, 1977 298. SCHAUM E, MÜLLER W. Die Heterocheilidiasis. Eine Infektion des Menschen mi t Larven von Fisch-Ascariden. Deutsche medizinische Wochenschrift 92: 2230-2233, 1967 299. SCHNEIDER AF. Monographie der Nematoden, pp 357, Berlin 1866 300. SCHRANK FP. Verzeichnisse der b isher hinlängich bekannten Eingeweidewürmer nebst einer Abhandlung über ihre Anverwandtschaften, München, pp 116, 1788 301. SERGENT E, GOUILLON P. Essais d'inocul ation à un singe d'une filariose humaine par des piqûres de Culex pipiens. Archives des Instituts Pasteur de l'Afrique du Nord 1: 85, 1921 302. SEN K, GHOSE N. Ocular gnathostomiasis. British Journal of Ophthalmology 29 : 618-626, 1945 303. SHELMIRE B. Experimental creeping eruption from a cat and dog hookworm ( A. braziliense). Journal of the American Medical Association 91: 938-943, 1928 304. SILVERMAN NH, KATZ JS, LEVIN SE. Capillaria hepatica infestation in a child. South African Medical Journal 47: 219-221, 1973 305. SINGSON CN, BANZON TC, CROSS JH. Mebendazole in the treatment of intestinal capillariasis. American Journal of Tropical Medicine and Hygiene 24: 932-934, 1975 306. SKRJABIN KI, POJDAPOLSKAYA WP, SCHICHOBALOWA NP. (Neue Fälle der Hepaticolosis beim Menschen.) "Russian Journal of Tropical Medicine" 7: 449-450 , 1929. In Russian, with German summary 307. SKRJABION KI, ALGANSES AJ, SCHOULMANN ES. (Premier cas de Dirofilaria repens chez l'homme.) Tropickeskaya Meditsina i Veterinariya, Moscow 2: 9, 1930. In Russian, with French summary 308. SKRJABIN KI, SHIKHOVALOVA NP, ORLOV IV. (Essentials of nematodology. VI. Trichocephalidae and Capillariidae of animals and man and diseases caused by them , Academy of Sciences of USSR, Moscow, pp 420-423, 1957.) In Russian. Englis h translation, Israel Progam for Scientific Translation, Jerusalem, pp 416-419, 513-515 , 1970 309. SMITH DC. the treatment of creeping eruption with sodium antimony biscatecho l (Fuadin). Journal of the American Medical Association 123: 694-695, 1943 310. SMITH JW, WOOTTEN R. Experimental studie s on the migration of Anisakis sp. larvae (Nematoda: Ascaridida) into the flesh of herring, Clupea harengus L. International Journal for Parasitology 5: 133-136, 1975 311. SMITH MH, BEAVER PC. Persistence and dis tribution of Toxocara larvae in the tissues of children and mice. Pediatrics 12: 491-496, 1953 312. SNYDER CH. Visceral larva migran s - ten years' experience. Pediatrics 28: 85-91, 1961 313. SPRENT JF. The life history and development of Toxocara cati (Schrank) 1788) in the domestic cat. Parasitology 46: 54-78, 1956 314. SPRENT JF. Observations on the development of Toxoocara canis (Werner 1782) in the dog. Parasitology 48: 185-198, 1958 315. STADELMAN H. Ueber Strongylus circumcinctus , einem neuen Parasiten aus de m Labmagen des Schafes. Sitzungsberichte der Gesellschaft Naturforschender Freunde zu Berlin, pp 142-146, 1894 316. STEWART IS. Human infestation with Trichostrongylus in South Persia. British Medical Journal ii: 737-739, 1949 317. STILES CW. A word in regard to the Filaridae found in the body cavity of horses and cattle. Journal of Comparative Medicine and Veterinary Archives 13: 143-147, 1892 318. STILES CW. A discussion of certain questions of nomenclature as applied to parasites. Zoologische Jahrbücher, Abteilun g für Systematik, Oekologie und Geographie der Tiere,

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Jena 15: 157-208, 1901 319. STILES CW. The determination of generic types, and a list of roundworm genera with their original and type species, CW St iles and A Hassall, Bulletin (79), Bureau of Animal Industry, United States Department of Agriculture, pp 1-150, 1905 320. STILES CW. Agamofilaria georgiana n. sp., an apparently new roundworm parasite , from the ankle of a negress. Hygiene La boratory, United States Public Health and Marine Hospital Service, Bulletin 34, pp 9-30, 1907 321. STONE OJ, MULLINS JF. Thiabendazole effectiveness in creeping eruption. Archives of Dermatology 91: 427-429, 1965 322. STOSSICH M. Sopra alcuni nematodi. Annuario del Museo Zoologico della Real e Universita di Napoli, new series, 1: 1-4, 1904 323. STOTT G. Pathogenicity of Acanthocheilonema perstans . Journal of Tropical Medicine and Hygiene 65: 230-232, 1962 324. STUCKEY EJ. Circumocular filariasis. China Medical Journal 31: 24-25, 1917 325. SUZUKI H, OHNUMA H, KARASAWA Y, OHBAYASHI M, KOYAMA T , KUMADA M, YOKOGAWA M. Terranova (Nematoda: Anisakidae) infection in man. I. Clinical features of five cases of Terranova larva infection. Japanese Journal o f Parasitology 21: 252-256, 1972 326. SWEET WC. The intestinal parasites of man in Australia and its dependencies as found by the Australian Hookworm Campaign. Medical Journal of Australia i: 405-407, 1924 327. SWIFT HF, BOOTS RH, MILLER CP. A cutaneous nematode infection in monkeys. Journal of Experimental Medicine 35: 599-620, 1922 328. TADA I, SAKAGUCHI Y, ETO K. Dirofilaria in the abdominal cavity of a man i n Japan. American Journal of Tropical Medicine and Hygiene 28: 988-990, 1979 329. TAMURA H. (On creeping disease.) Hifu-Ka Oyobi Hinyoôki-Ka Zasshi pp 827-834, 891-910, 1919. In Japanese . Abstracted in Tropical Diseases Bulletin 18: 116-117, 1921 330. van THIEL PH. the final hosts of the herringworm Anisakis marina. Tropical and Geographical Medicine 18: 310-328, 1966 331. van THIEL PH, KUIPERS FC, ROSKAM TH. A nematode parasitic to herring, causing acute abdominal syndromes in man. Tropical and Geographical Medicine 12: 97-113 , 1960 332. TIDWELL MA, TIDWELL M, MUÑOZ de HOYOS P. Development of Mansonella ozzardi in a black fly species of the Simulium sanguineum groups from eastern Vaupes, Colombia. American Journal of Tropical Medicine and Hygiene 29: 1209-1214, 1980 333. TRAVASSOS LP. Contribui ções par o conhecimento da fauna helmintolojica brasileira. V. Sobre as especies brasileiras do genero Capillaria, Zeder, 1800. Memorias d o Instituto Oswaldo Cruz 7: 146-172, 1915 334. TROISIER J, DESCHIENS R. L'hépatic oliase. Annales de Médecine 27: 414-425, 1930 335. UNDIANO C. Importancia y actualización del nuevo concepta da la patogenicidad de la mansoneliasis. Revista de la Faculdad de Ciencias Médicas de la Universidad Nacional de Cordoba 24: 183-189, 1966 336. VANDEPITTE J, MICHAUX JL, FAIN A, GATTI F. Premières observation s congolaises de physaloptérose humaine. Annales de la Société Belge de Médecin e Tropicale 44: 1067-1076, 1964 337. VOGEL H. Ueber Mikrofilaria demarquayi und die Mikrofilaria aus Tucuman i n Argentinien. Abhandlungen aus dem Gebiet der Auslandkunde, Hamburg Universität 26: 573-578, 1927 338. WAHLGREN M. The successful treatment of Dipetalonema perstans filariasis with mebendazole. Annals of Tropical Medicine and Parasitology 76: 557-559, 1982 339. WARD HB. Gongylonema in the role of a human parasite. Journal of Parasitology 2 : 119-125, 1916 340. WELCH FH. On a species of filaria fo und in the interior of the vascular system of a dog: relative to the filaria in the blood, and the ova and larvae of a nematode worm in th e urine, of man. Lancet i: 336-338, 1873

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341. WELCH FH. Haematozoa. Lancet i: 508, 1873 342. WELTY RF, LUDDEN TE, BEAVER PC. Dirofilariasis in man: report of a case from the state of Washington. American Journal of Tropical Medicine and Hygiene 12 : 888-891, 1963 343. WERNER PC. Vermium intestinalium praesertim taeniae humano, brevis expositionis continuatio, SL Crusium, Lipsiae, volume 1, part 2, pp 28, 1782 344. WHALEN GE, ROSENBERG EG, STRICKLAND GT, GUTMAN RA, CROSS JH, WATTEN RH, UYLANGCO C, DIZON JJ. Intestinal capillariasis. A new disease of man. Lancet i: 13-16, 1969 345. WHITE GF, DOVE WE. The causation of creeping eruption. Journal of the American Medical Association 90: 1701-1704, 1928 346. WHITE GF, DOVE WE. A dermatitis caused by larvae of the Ancylostoma caninum . Archives of Dermatology and Syphilology 20: 191-200, 1929 347. WILDER HC. Nematode ophthalmitis. Transactions of the American Academy o f Ophthalmology and Otorhinolaryngology 55: 99-109, 1950 348. WILLACH P. Sclerostoma apiostomum nov. sp. Ein neuer und gefährlicher Parasit der Affen. Archiv für Wissenschaftliche und practische Tierheilkunde 17: 340-346, 1891 349. WOODRUFF AW. Toxocariasis. British Medical Journal ii: 663-669, 1970 350. WOODRUFF AW. Not an i nfection with adult Toxocara canis. British Medical Journal 283: 1124, 1981 351. WOODRUFF AW, THACKER CK, SHAH A I. Infection with animal helminths. British Medical Journal i: 1001-1005, 1964 352. WRIGHT KA. Observations on the life cycle of Capillaria hepatica (Bancroft, 1893) with a description of the adult. Canadian Journal of Zoology 38: 167-182, 1961 353. YAMAGUTI S. Studies on the h elminth fauna of Japan. Part 35. Mammalian nematodes II. Japanese Journal of Parasitology 9: 409-439, 1941 354. YEH LS. On a filarial parasite, Deraiophoronema freitastenti n. sp., from the giant anteater Myrmecophaga tridactyla from British Guiana, and a proposed reclassification of Dipetalonema and related genera. Parasitology 47: 196-205, 1957 355. YII CY, CHEN CY, FRESH JW, CHEN T, CROSS JH. Human angiostrongyliasi s involving the lungs. Chinese Journal of Microbiology 1: 148-150, 1968 356. YOKOGAWA S. A human case of accidental parasitism of Diploscapter coronat a (Cobb, 1893) Cobb, 1913. Zoological Magazine, Tokyo 48: 507-512, 1936 357. YORKE W, MAPLESTONE RA. The nematode parasi tes of vertebrates, J&A Churchill, London, pp 536, 1926 358. YOSHIMURA H, AKAO N, KONDO K, ONISHI Y. Clinicopathological studies on larval anisakiasis, with special r eference to the report of extra-gastrointestinal anisakiasis. Japanese Journal of Parasitology 28: 347-354, 1979 359. ZEDER JG. Erster Nachtrag zur Naturgeschichte der Eingeweidewürmer von J A E Goeze mit Zusätzen und Anmerkungen herausgegeben von Zeder, Siegfried Lebrech t Crusius, Leipzig, pp 320, 1800 360. ZUELZER W, APT L. Disseminated visceral lesions associated with extrem e eosinophilia. American Journal of Diseases of Children 78: 153-181, 1949 361. ZUNE A. Urine chyleuses et hématochyleuses, Paris, pp 82, 1891

Chapter 28

MISCELLANEA

IMAGINARY WORMS AND PSEUDOPARASITES Imaginary parasites, usually worms, have been dreamt up and claimed as the cause of disease in many societies until, and including, recent times. Worm s were frequently found in the viscera and tissues of animals killed for culinary purposes so it was a logical step to assume that similar worms must occur in humans and were likely to produce illness. It was not until autopsies of humans became commonplace that erroneous ideas of fantastic parasites wer e expunged. In addition to these imaginary parasites, which were purely an d simply figments of the imagination, pseudop arasites were also described. These arose from misguided interpretations of pathological changes such a s coagulated blood or necrotic tissue or secondary infestation of human tissues and excretions by non-parasitic organisms. IMAGINARY PARASITES Imaginary parasites are well-described in the ancient literature. Thus, Ra, the sun-god of Egypt, was supposed to have fallen sick when a worm arose from his sputum and bit on the heel (cited in 24). The Indian medical work, th e Sushruta Samhita, written around the first century AD, alleged that there were three types of worms living in humans. Th e first arose in the faeces and of these there were said to be seven varieties - some of these were undoubtedly real. Six worms were thought to arise in the sputum. They were all imaginary, bein g thought to be hairy with spots and tails; it was considered that they fed on the bone marrow and penetrated into the eyes, palate and ears. Finally, seve n imaginary worms arose from the blood, some of which were believed to feed on the roots of hairs which fell out as a consequence 93. A number of imaginary worms are detailed below. Undoubtedly th e imaginary worms which were most widely held to exist were the toothworms, but a number of others were frequently alleged such as eyeworms, earworms, nasal worms, corpse worms, umbilical worms and echo worms. Toothworms The belief that toothache and dental disease are caused by worms in or around the teeth goes back to ancient times. Perhaps the earliest literary reference to 765

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such parasites is in an Egyptian papyrus (Anastasi IV, 13.7) of the twentiet h dynasty (c.1200-1100 BC) in which an unhappy official at a desert outpost is recorded as complaining that a worm gnawed at this teeth 95. Such ideas were also prevalent in Mesopotamia. An Assyrian tablet in the library o f Asur-bani-pal (c.500 BC) mentions t oothworms and describes charms for their removal. Moreover, the tablet described the origins of these worms and their modus operandi: After Anu made the heavens, The earth made the rivers The rivers made the canals The canals made the marsh The marsh made the Worm. The worm came weeping unto Samas, Came unto Ea, her tears flowing, 'What wilt thou give me for my food, What wilt thou give me to destroy?' 'I will give thee dried figs and apricots.' 'Forsooth, what are dried figs to me, or apricots? Set me amid the teeth and let me dwell in the gums, That I may destroy the blood of the teeth, And of the gums chew their marrow. So shall I hold the latch of the door.'"(cited in 95)

Similarly, the Syriac Book of Medicine, written in the ninth century AD but largely a translation of Galen's De locis affectis (second century AD), contains prescriptions for the treatment of teeth with worms in them 101. Likewise, Scribonius Largus, physician to the Roman emperor, Claudius, associated worm s with dental disease in his De compositione medicamentorum 66. In the same manner in the Indian text, the Sushruta Samhita, it was considered that dental caries arose when the teeth were eaten by worms 93. Toothworms were also generally accepted in China. For example, a writer of the Ming dynasty (16th century AD) believed that worms recovered from patients with longstandin g toothache had black heads whereas those seen in acute cases had red heads 64. This concept that toothworms caused dental dise ase was accepted in Europe until the eighteenth century and was recorded in various leechbooks and books of herbal remedies 96. In the present century, such beliefs are still prevalen t among the poorly-educated in many parts of the world. It seems likely that these ideas arose spontaneously and independently in different places althoug h Townend96 has suggested that this notion ma y have begun in the Nile valley and spread from there to other communities. A variety of techniques have been used down the ages in diverse places in an attempt to deal with these mythical creatures. Many herbal remedies have been employed but the pride of place goes to henbane ( Hyoscamus species). The Assyrians recommended that it be p laced on a hollow tooth and Scribonius Largus described fumigation with the smoke of its burning seeds in order t o drive the worms out of decayed teeth. Similarl y, this formula was extolled in the

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Anglo-Saxon leechcraft: For toothworms, take acorn meal and henbane seed and wax of all equally much, mingle these together, work into a wax candle and burn it, let it reek into the mouth, put a black cloth under it, then will the worms fall on to it. 31

Other plants which have been recommende d from time to time included myrtle, tamarisk, sumach, leeks, onions, raisins and roses. A seventeenth centur y English poem mentions come of these: If in your teeth you hap to be tormented, By means some little wormes therin do breed, Which pain (if heed be tane) may be prevented, By keeping cleane your teeth, when as you feede; Burne Francomsence (a gum not evil sented), Put Henbane into this, and Onyon seed, And with a tunnel to the tooth that's hollow, Convey the smoke thereof, and ease shall follow. 8

In many instances, it seems that when seeds wer e heated, they cracked open and plant embryos were scattered and mistaken for worms. Meanwhile, hyo scyamine and related drugs, constituents of henbane, dulled the pain. As well as plants, various small animals including worms, caterpillars , weevils, ladybirds and small b eetles were used to "cure" toothache. This seems to have been based upon the principle of "similis similibus curantur", i.e. that the administration of worms or some such would cure the disease caused b y worms in the teeth. Thus, the Assyrian sufferer from toothache was recom mended to crush a caterpillar on the afflicted tooth while a Greek physicia n suggested that earthworms boiled in oil cured toothache. An alternative ploy was to invoke charms and incantations. This approach was based upon the belief that toothworm infection was associated wit h invasion and possession by a demon which could be driven out by invocation. For example, the pagan Brandenburgians supplicated the moon: Little moon, decrease, Go away from us, Little worm, go away And do me no more harm.9

Many of the toothache incantations had a Christian flavour: Abraham said to Jesus Christ As they walked on the slope of Bethris: 'I have not the power of walking Or of riding because of toothache' Said Jesus Christ to Abraham: 'Toothache will not be in that head; Out of the toothache! Out of the toothache! Known in heaven, known on earth. Known to thy King is thy disease. Toothworms and toothache to be placed under the earth.' 10

Besides being spoken, charms were sometimes written on paper or parchment and worn as an amulet.

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Gradually, however, doubts grew about toothworms. Jacques Houllie r (1498-1562) wondered whether they really existed and condemned th e widespread practice of fumigations (cited in 52). Pierre Fauchard (1690-1761) in his classical work on dental surgery described how he had tried to find these worms and had failed. Others confirmed his observations and toothworm s passed into the realms of mythology. Eyeworms, Earworms and Nasal Worms There have been many descriptions of worms in the orbital, aural and nasa l cavities. Some of these may not have been imaginary at all as it is well-known that flies may deposit eggs in these places from time to time and the resultant maggots may have been mistaken for worms. Indeed, some of those in the eye may have been true worms (Loa, Thelazia). Many, however, were imaginary and have been described by numerous authors since the time of Galen. In the case of the orbit, for example, blepharitis (inflammation of the eyelids) ma y have caused crusts which had the appearance of parasites. Moreover, som e enterprising quack "eye-specialists" have been known to breed fly larvae then insert them into the conjunctival sac thus permitting their removal from tha t site16. Many techniques have been described for flushing worms out of thes e domains and indeed may be the means of producing objects resembling worms. Thus, the Syriac Book of Medicine remarked concerning: Worms in the ears....boil strong onions in the urine of children, and drop the liquor into the ears. Or pound and mix together sumach, goat's milk, rings of pomegranates, and raisins with honey, heat the mixture and drop it into the ears. . Or pour juice of absinthe and old oil which is cloudy into the ears and the worms will come out.101

Another popular method for driving out the worms was fumigation and i s described under toothworms. Urine Worms Macroscopic worms have rarely been passed in u rine but sometimes coagulated blood in elongated form has been mistaken for worms. Umbilical worms This worm was thought to live within the umbilicus of small children and cause weakness and failure to thrive. Its presence could be "proved" by fastening a small fish to the umbilicus in the evening then noting whether some of it had been "eaten" in the morning. In reality, parts of the fish had been rubbed off by the movements of the child. Andry in 1741 recounted Ettmuller's technique for eradicating such parasites. Half of a nutsh ell containing a mixture of honey with

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powdered glass and juniper is fastened to the umbilicus then "the worm comes as usual and attracted by the honey eats of this mixture from which it dies" 3. A rather similar worm was the "Amao" described by Lusitanius (1575-1642 ) which was supposed to live in the intestinal canal of children and graduall y consume their strength so they died if the worm was not expelled by the proper treatment72. Corpse Worms These worms were also sometimes known as "food worms" or "phthisi s worms". In ancient China it was believed that up to 80,000 of these worm s were present in each human body and that without them the human body could not exist. It was believed that they began their life with the birth of their host. Furthermore, they were thought to undergo transformations in their appearance during six generations. For example, Ku Chin Yi T'ung Ta Chu'an described and illustrated the following: 1. Worms of the first generation: resembled an infant with hair on its back, a ghost or a frog. 2. Second generation: a ball of hair, a centipede, a lizard, a shrimp or a crab. 3. Third generation: a mosquito, an ant, a mantis, a hedgehog or a caterpillar. 4. Fourth generation: a ball of thread, a grub, the lungs of a pig or a snake. 5. Fifth generation: a hairless mouse. 6. Sixth generation: a tortoise, the t ail of a horse or a bird. Furthermore, it was believed that worms of this generation had either wings or feet and could therefore reinfect people at a distance of a thousand miles 64. Echoing Worms In ancient China, it was sometimes believed that people were made sick b y echoing worms which were supposed to produce an echo when the parasitized person spoke. These worms were thought to be expelled or killed when th e relevant part of the Chinese pharmacop oeia was read and the appropriate herbs taken. For similar reasons, some Chinese anthelmintic prescriptions required that silence should be maintained while preparing the medicines otherwise the worm may hear and not be expelled 54. Furia infernalis (Höllenwurm, Mordwurm) This parasite was listed by Linnaeus in his Systema Naturae and discussed by a number of writers including Solander 90 and Pallas79 . The parasite was supposed to be a very small worm, the thickness of a hair, yellowish-white in colour with one dark end, and have a single row of minute spines. It wa s thought to be carried by the wind and be found in northern Sweden, Lapland and Russia. It was said to attack humans, horse s and cattle in summer and cause

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A History of Human Helminthology

a burning feeling like a mosquito bite. This was followed by the development of a painless swelling, central necrosis and death within several hours to days. It is likely that in fact the writers were des cribing a number of bacterial diseases such as anthrax, glanders, tularaemia or plague 54. PSEUDOPARASITES Pseudoparasites seemed just as real as imaginary parasites. For example , Ambroise Paré (1510-1590), a famous French military surgeon, described and illustrated numerous fantastic creatures that had allegedly developed i n abscesses or had been passed from the gut. Thus, he cited a specime n recovered from a patient by Benenius, a physician in Florence: A worm the size of four fingers, with a red round head the size of a large weight; it had a body covered with downy hair, a bifid tail in crescent shape and altogether four feet, two before and two behind.80

In addition, many pseudoparasites wer e free-living animals that were thought to be found in the human stomach and intestines , the urinary bladder, the female genital tract, or in abscesses. These included frogs, salamanders, snakes , lizards, leeches and lice. They were supposedly vomited, passed in stool o r urine, or escaped in some othe r way. Some found their way into human excreta by chance while others were placed there by hysterics, mendicants o r charlatans. For example, an Ascaris may look like a snake to the uninitiated . Others are quite inexplicable in this way such as the extraordinary claims that a Russian vomited a dog and that a young boy passed a pup in his faeces 58. Normal or pathological human structures have al so been mistaken for worms. These include the secretions of sebaceous glands 3, hydatidiform moles in the vagina27 and even spermatozoa 69. Besides members of the animal kingdom, plants have also been thought to be worms. Thus, Seltzer of Strasbourg in a thesis described "worms" which h e found in the stools of a 26 year old woman that turned out to be the seeds o f Morus nigra 92. PARASITOPHOBIA Parasitophobia or, more properly, a delusion that a person is infected wit h parasites was apparently first described in 1872 (cited in 104). Some patients are convinced that they harbour parasites in the skin; these are usually confuse d with entomological ectoparasites. Others are certain that they are infected with internal parasites, frequently worms. This condition may be seen in the setting of a primary psychiatric disorder or in conjunction with a variety of organi c illnesses including vitamin deficiencies, chronic renal failure and toxi c psychosis. Those with primary psychiatric disorders may have parasitophobia as an isolated problem while in others it is part of a schizophrenic, depressive or compulsive illness.

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Wykoff104 reviewed cases reported in the literature and added many of hi s own. He remarked that this condition is seen most frequently between the ages of 40 and 60 years and occurs more commonly in females. Response t o treatment has been poor.

EARLY ILLUSTRATIONS OF WORMS Very few worms parasitic in humans we re known when printing became established in Europe in the latter half of the fifteenth century. Initially, illustrations were produced with the aid of woodcuts but during the seventeenth centur y copper engravings which permitted the renderin g of finer details were gradually introduced. In the early nineteenth century the new technique of lithograph y was adopted. FIFTEENTH AND SIXTEENTH CENTURIES Perhaps the first illustration of a parasitic worm is to be found in the Hortus Sanitas of Jacob Meydenbach published in Ma in, Germany, in 1491. This book had 1066 illustrations with one of them showing a man in a squatting position from whose anus large worms, presumably Ascaris, were passing out (cited in28). The first simple illustration of a tapeworm (without a head) was provided by Cornelius Gemma in 1575 46. This picture was copied by many author s including Aldrovandi 1, Spigelius (van der Spiegel) 91, Clericus 29 and Andry3. In 1596, The Dutch explorer van Lins choten illustrated the extraction of a Guinea worm70. SEVENTEENTH CENTURY The liver fluke, Fasciola hepatica, was figured by Redi in 1668 82 then by Ruyschius in 1691 86 and Bidloo in 1698 13. Velschius in 1674 showed Dracunculus medinensis protruding from various parts of the human body but gave no details of the parasite 100. He also drew filariae obtained from birds. In 1683 , Edward Tyson illustrated the anatomy of Ascaris lumbricoides 97 then in the same year he drew a Taenia saginata and reproduced the scolex of a dog tapeworm98. In the following year, Redi described 108 different parasites an d produced copper plates in wh ich he illustrated amongst other things Eustrongylus gigas, Cysticercus pisiformis , the reproductive organs of Ascaris lumbricoides, and the dog and cat tapeworms, each of the latter with a head 83. In 1691, Tyson illustrated Cysticercus tenuicollis from the omentum of an antelope99.

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EIGHTEENTH CENTURY Andry gave illustrations of fragments of Taenia and Diphyllobothrium in 17002 and again in subsequent editions of his book in 1718 and 1741 3. Clericus in 171529 copied the figures of previous authors in 14 plates. Included amongst them was a reproduction of Enterobius vermicularis by Contoli who had regarded it as a minute fish. In 1762, Roederer and Wagler 84 provided a simple drawing of Trichuris trichiura. A variety of worms were illustrated in 44 plates 17 by Goeze in 178248 and in 10 plates by Bloch in the same year . In 1789, Fischer drew Cysticercus cellulosae in the choroid plexus 42. NINETEENTH CENTURY Good illustrations of a number of worms were provided by Joerdens (1801) 58, Brera (1811) 22 and Bremser (1819)20. The last author illustrated Coenurus and Echinococcus. Owen drew the larvae of Trichinella spiralis in 183578 then Dubini illustrated Ancylostoma duodenale in 184337. Schistosoma haematobium was figured by Bilharz in 1852 14. Crude drawings of the worms sub sequently called microfilaria bancrofti and microfilaria volvulus were made by Demarquay (1863) 36 and O'Neill (1875)77 , respectively. Clonorchis sinensis was drawn by McConnell in 1875 73 then a figure of an adult Wuchereria was published by Cobbold in 1877 30 from material provided by Bancroft. UNORTHODOX MODES OF TREATMENT Massage Massage of the abdomen has been recommended for the treatment of intestinal worms in many countries but particularly in China. As a consequence of this procedure, worms were supposed to be passed in the stools: Abdominal pain in children accompanied by a palpable mass in the abdomen is due to worms. In this case, no drug is necessary: simply advise the parents to massage the abdominal mass for half a day. This kills the worms which will be passed out in the faeces.25

Acupuncture Acupuncture has been practised in China as a means of treating worms for many years: Heartache caused by the three kinds of worms is attended by profuse salivation and inability to turn the body into a recumbent position. In this case, the pit of the stomach is the proper place for acupuncture.56

This practice is based upon the theory that the inserted needles will transfe r energy to different parts of the body along hypothetical lines or "meridians". Moxibustion In this procedure, cones of the plant Artemisia (worm-wood) are applied to

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the skin and ignited. The smouldering fire burns into the skin and produces a blister. It was sometimes used in China as an anthelmintic measure 54. Music Music was advocated occasionally for the treatment of worms in Europe in the eighteenth century. According to Goeze 48, tapeworms could be expelled by the noise of a Jew's harp. Others believed that intestinal worms could sens e sound and recommended the use of certain musical instruments to mollif y tapeworms and thus relieve symptoms 21. Magic In diverse countries down the ages, magic in the form of incantations o r charms has been invoked to induce the expulsion of intestinal worms. Many of the incantations had quasi-religious overtones while charms were objects with written or engraved magic signs or words. THE MOON AND WORMS For many centuries and in many parts of the world, the moon has been held to have an influence on worms, particularly upon the efficacy of anthelminti c therapy. One of the first authors to deal with this subject was Nicola s Myrepsus, a Greek physician who lived in the thirteenth century. He advised that anthelmintics be given only during the waning of the moon 76. Andry at the beginning of the eighteenth century was sceptical at first about such an effect but then, following an investigation, gave some credence to the phenomenon. He treated 100 persons with intestinal worms during the days of the wanin g moon and found that more than 80% were cured. In contrast, the result wa s reversed if the therapy was given on the other days 2. Similarly, Hoffman55 advised giving anthelmintics when the moon changed its phase. Such ideas were not confined to Europe. Some ea rly Chinese writers believed that intestinal worms had their heads turned upwards during the first half of the lunar month and downwards in the second half. Further, they thought tha t anthelmintic therapy was more effective if the head of the worms was turned upwards 54. In recent times in Ruanda in Africa, it has been the practice t o administer anthelmintics when the moon is full 68. Some authors believed that the moon also i nfluenced symptomatology. Rosen de Rosenstein85 thought that the symptoms were worse in children wit h tapeworm infections during the waning moon and at the time of the new moon. Likewise, Wawruch 102 claimed that Taenia segments appeared in stools more regularly at this period. Some authors contended that Ascaris was more likely to be discharged around this time and believed that there may be a simila r influence on Enterobius. Küchenmeister, who was infected with these las t parasites, however, sought a relationship between the numbers of worm s discharged and the phases of the moon but could find no connection 63.

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WORMS AS THERAPEUTIC AGENTS The roundworm, Ascaris lumbricoides, has from time time been a popula r therapeutic device in both the Occident and the Orient. Pulverized, drie d worms were commonly used by both the medical profession and the populace at large in Europe as an anthelmintic. In China, worm extracts were recom mended for the treatment of a wide range of conditions such as ulcerativ e blepharitis, painful ophthalmitis, anal fistula, cancrum oris and boils e.g. "An Ascaris worm, washed clean, baked dry over a tile on a fire, and ground into a powder will, when applied to pustules and furuncles, effect a quick cure" 26. It was even used as an aphrodisiac: Grind the above (Ascaris) into powder, mix with grease and roll into pills of the size of barley seeds. Before coitus, introduce one pill into the urethra; it will help enlarge and stiffen the penis and prolong its periods of erection. 89

WORMS AND IMMUNITY In 1862, Casimir Davaine highlighted the phenomenon of natural resistance to helminth parasites. he took ov a of the common roundworm of humans, Ascaris lumbricoides, and fed them, first to a cow, then to rats. He failed subsequently to find adult worms in the intestine of these animals and concluded that, i n contrast to humans, they were not susceptible hosts to this parasite: Eggs of A. lumbricoides develop outside the body of man, but the embryo only hatches when it is brought by food or drink....in whichever animal supplies these conditions, the egg hatches if it remains in the intestine long enough; however, the embryo does not linger if the animal is not of the kind where the worm can acquire its final form.35

The accumulation of such data led to the development of two important concepts - the host specificity of a parasite and the parasite fauna characteristic of a given host species. Both of these aspects interact and ultimately ar e determined genetically. Despite over 100 years of investigation since the time of Davaine, we are little wiser as to the reasons why these variations in hos t responsiveness occur or as to what the mechanisms are by which suc h responses are generated. A variation on this theme is the effect of age on susceptibility to firs t infection. This probably applies to human s although it has never been definitely shown. This phenomenon was alluded to by Looss in 191171 then Ransom in 192181 observed that young chickens were infected easily with the gapeworm, Syngamus trachealis, while old chickens were difficult to infect. Likewise, it has been shown with a number of parasites that the sex of the host influences the susceptibility to infection with male animals in general being more prone to infection. The idea of acquired immunity to a worm, i.e. the development of resistance to a particular parasite following prior exposure was floated by Weinberg and Julien in 1911 103. They carried out experiments on ascarid infections in horses

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and concluded that horses infect ed with a certain number of parasites gradually immunized themselves against the actio n of the secretions of these worms. Five years later, Fujinami in a paper entitled (in translation) "Immunity t o macroparasitic disease: can it be acquired?" recorded the acquisition o f immunity against Schistosoma japonicum in horses45. In 1921, the development of acquired immunity against Trichinella spiralis was shown in rats by Ducas38. Blackwell and Thompson in 1923 observed that immunit y could be acquired by both man and animals against the larva of the tumbu fly, Cordylobia anthropophaga, which causes cutaneous larva migrans 15. Whether significant acquired immunity develops in most human helminth infections has been a matter of intense debate ever since, with the probability being that i t develops only to a limited degree 50. How worms manage to evade the host' s responses and persist has been a subject of earnest but largely unproductiv e speculation18. The possibility of developing vaccines against helminths has now been floated for a number of years 6,32 but success has hitherto eluded everyone's grasp. The development of immune responses, particularly the appearance of antibodies and skin reactivity has been put to diagnostic purposes for man y decades. The era of immunodiagnosis in human helminthology was probably ushered in by Isaac and von den Velden in 1904 when they reported th e presence of a precipitin reaction in the serum of a person with Diphyllobothrium latum infection and compared this with a negative in an uninfected 43 control individual57. In the same year, Fleckseder and von Stejskal found antibodies against Taenia saginata in the serum of immunized rabbits bu t Langer65 could not find such antibodies in humans infected with T. solium or T. saginata infections. In 1906, Ghedini described a complement fixation test for antibody directed against fluid from human hydatid cysts 47. In the following year, Fleig and Lisbonne 44 described a test for precipitating antibody i n echinococcosis. In 1911, Casoni described a skin test for echinococcosis in which delaye d hypersensitivity reactions occurred in infected persons after intraderma l injection of fluid obtained from a sheep hydatid cyst 23. Sophisticated immunological techniques have been developed in recent years and are no w frequently being employed in the immunodiagnosis of human helminthiases 7. Reactions to ascarids were described by Miram, Cobbold, Huber, Leuckart, Bastian, Railliet and many others in the nineteenth century. In 1910, Gold schmidt again described features r esembling hay fever after exposure to human and horse Ascaris and recognized its allergic nature49. The relationship between helminthiasis and the atopic d isorders, asthma, hay fever and eczema, has been a thorny one for many years. Herrick in 1913 may have been the first t o recognize an association between asthma and worm infection when he wrote: Common to both bronchial asthma and Ascaris infection is an increase of the eosinophils in the blood. One may well ask the significance of the eosinophilia in this association.53

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Paul Erlich had described these peculiar white cells in 1879 then Müller and Rieder in 189175 observed that they were increased in number in hookwor m infection. Similar findings were then made in other worm infections. Nevertheless, little attention was paid to this association until Johansson in 1967 59 discovered a new class of immunoglobulin (initially called IgND, now IgE) and found that increased levels were seen in the serum of patients with asthma. In the following year, he observed increased levels of the same antibody i n Ethiopian schoolchildren with Ascaris infection60. Similar elevations were then seen in a variety of helminth infections. These discoveries provided a further nexus between helminthiasis and atopy. A number of hypotheses wer e advanced including a belief that worms caused asthma, the concept that worm infection ameliorated asthma, and the proposition that atopic individuals ar e able to generate increased resistance to worms 51. The first major textbook of helminth immunology was written in 1929 b y Taliaferro who produced a 414 page work entitled The immunology of parasitic infections "94. This was followed in 1941 by Culbertson with hi s Immunity against animal parasites "33. WORMS AND CANCER Eli Metchnikoff, the generally-recognized discoverer of the phenomenon o f phagocytosis, in his Harben Lectures of 1906 advanced the proposition tha t there may be a relationship between entozoa, in particular intestinal worms, and cancer: Even in certain tumours the role of the entozoa would appear very probable....Might not the entozoa serve as gates for entry for the hypothetical parasites of those tumours?74

He drew attention to the recent studies of Borrel 19 who had described the presence of intestinal worms in the centres of intestinal tumours of mice an d had correlated cysticercosis and tumours in rats. Metchnikoff then went of to advocate a campaign against intestinal worms in order to prevent cancer in the same manner as the war which had just begun against disease-carryin g insects74. In 1913, Fibiger in Copenhagen claimed that a newly-recognized worm , Spirometra neoplastica (= Gongylonema neoplasticum), in rats from the West Indies and South America caused cancer of the stomach and suggested tha t cockroaches may be the intermed iate hosts39. He revived this idea in 1920 with further studies40,41. Nevertheless, an editorial writer in the British Medical Journal cautioned: It must not be assumed that spontaneous tumours of rats and mice are commonly caused by the ingestion of food containing Spiroptera neoplastica, still less that cancers of higher animals and man are produced by a similar, indeed by any, parasite.4

Nevertheless, this idea was taken up by enthusiasm by Sambon and Bayliss who, under the auspices of the Cancer Field Commission of the Tropica l Disease Prevention Association, investigated the relationship betwee n

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Gongylonema and cancer in certain districts in Italy. This led to the concept of "cancer houses" with the theory that Gongylonema was transmitted from person to person by cockroaches, resulting in cancer 87. This hypothesis was attacked by Leiper and a heated correspondence followed 11,67,88. In the event, Leiper was proven correct when it was finally concluded that Fibiger's tumours were in fact non-malignant 5. Nevertheless, time has been a little kinder in favouring associations between cancer and two parasites - Schistosoma haematobium and bladder cancer (see chapter 8), and Clonorchis sinensis and carcinoma of the bile ducts (se e chapter 6) THE GOD, "VERMINUS" The Romans apparently had a god of worms and worm diseases name d "Verminus". The little that is known about this deity derives from an inscription on an altar found near Rome in 1876. The inscription said: "Vermino A. Postumius A.F.A.N Albi Duovir lege Plaetoria" which has been translated as: "To Verminus Aulus Postumius Albinus, son of Aulus grandson of Aulus Duovir by the Plaetorian law" Apparently, the increasing seriousness of worm infections had caused thi s shrine to be erected and dedicated by the consul, Aulus 54.

REFERENCES 1. ALDROVANDI U. De animalibus insectis libri septem denuo impressum, Ferronius , Bononiae, pp 767, 1602 2. ANDRY R. De la génération des vers dans le corps de l'homme. Avec trois lettres sur les sujets des vers, les deux premières....par M. Nicolas Hartsoeker et l'autre....par M . Georges Baglivi, Laurent d'Houry, Paris, pp 468, 1700. An account of the breeding o f worms in human bodies etc., translated by H Rhodes and A Bell, pp 266, 1701 3. ANDRY R. De la génération des vers dans le corps de l'homme, third edition, Lauren t d'Houry, Paris, pp 1190, 1741. Partly translated in 54 4. ANONYMOUS. Helminths in cancer. British Medical Journal i: 777-778, 1920 5. ANONYMOUS. Fibiger's tumour of the rat's stomach. Lancet i: 735-736, 1938 6. ANONYMOUS. Immunisation against helminths. Lancet i: 685, 1960 7. ANONYMOUS. Immunodiagnosis in parasitic diseases. British Medical Journal 283 : 1349-1350, 1981 8. ANONYMOUS. Cited in 12 9. ANONYMOUS. Cited in 61 10. ANONYMOUS. Cited in 96 11. BAYLISS HA. Gongylonema and cancer. British Medical Journal ii: 503-504, 1926 12. BERDOE E. The origin and growth of the healing art. A popular history of medicine in all ages and countries, Swan Sonnenschein and Co., pp 509, 1893

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13. BIDLOO G. Observatio, de an imalculis, in ovino aliorumque animantium hepate detectis, J Luchtmans, Lugduni Batavorum, 1698 14. BILHARZ T., von SIEBOLD CT. Ein Beitrag zur Helminthographia humana, au s brieflichen Mittheilungen des Dr. Bilharz in Cairo, nebst Bemerkungen von Prof. C. Th. von Siebold in Breslau. Zeitschrift für wissenschaftliche Zoologie 4: 53-76, 1852-1853 15. BLACKLOCK DB, THOM PSON MG. Study of tumbu-fly, Cordylobia anthropophaga Gruneberg in Sierra Leone. Annals of Tropical Medicine and Parasitology 17: 443-510, 1923 16. BLANCHARD R. Charlatans et pseudo-parasites: les "vers des yeux". Bulletins de l a Société de Pathologie Exotique et de ses Filiales 11: 579-586, 1918 17. BLOCH ME. Abhandlung von der Erzeugung der Eingeweidewürmer und den Mittel n wider dieselben, Sigismund Friedrich Hesse, pp 54, 1782 18. BLOOM B. Games parasites play: how parasites evade immune surveillance. Nature 279: 21-26, 1979 19. BORREL A. Tumeurs cancére uses et helminthes. Bulletin de l'Académie de Médecine de Paris 41: 141-144, 1906 20. BREMSER JG. Ueber lebende Würmer im lebenden Menschen. Ein Buch für ausübende Aertze. Mit nach der Natur gezeichneten Abbildungen auf vier Tafeln. Nebst eine m Anhang über Pseudo-helminthen, Carl Schaumburg et Comp., Wien, pp 248, 1819 21. BRERA VL. Medizinische-practische Vorlesungen ueber die vornehmste n Eingeweidewürmer des menschlichen lebenden Koerpers und die sogennante n Wurmkrankheiten. Aus dem Italienischen uebersetz und mit Zusaetzen versehen von FA Weber, Breitkopf und Haertel, Leipzig, 1803 22. BRERA VL. Memorie fisico-mediche sopra i principali vermi del corpo umano vivente etc., Antonio Ronna, Crema, pp 452, 1811 23. CASONI T. La diagnosa biologica dell'echinococcosi umana mediant e l'intradermoreazione. Folia Clinica Chemica e Microscopica 4: 5-16, 1911 24. CASTIGLIONI A. A history of medicine. Translated from the Italian and edited by E.B. Krumbhaar, second edition, Alfred A. Knopf, New York, pp 1192, 1947 25. CH'EN FU-CHENG (A comp ilation of pediatrics.), 1750. In Chinese. Partly translated in 54 26. CH'I FAND LEI CHU (A classified collection of unusual prescriptions.) In Chinese . Partly translated in 54 27. delle CHIAIE S. Compendio di elintografia umana, second edition, Dalla Stamperia e Cartiera del Fibreno, Napoli, 1833 28. CHOULANT L. Graphische Icunabeln für Naturgeschichte und Medicin, Leipzig, 1858 29. CLERICUS D (LE CLERC). Historia naturalis et medica latorum lumbricorum intr a hominem et alia animalia, nascentium etc., Fratres de Tournes, Genevae, pp 449, 1715. A natural and medicinal history of worms bred in the bodies of men and other animals etc., translated by J Browne, printed for J Wilcox at the Green-Dragon, Little Britain, pp 436, 1721 30. COBBOLD TS. Discovery of the adult representative of microscopic filariae. Lancet ii: 495-496, 1877 31. COCKAYGNE O. Leechdoms, wort cunning and starcraft of early England etc. , Longman, London, three volumes, 1864-1866 32. COX FE. Specific and nonspecific immunisation against parasitic infections. Nature 273: 623-626, 1978 33. CULBERTSON JH. Immunity ag ainst animal parasites, Columbia University Press, New York, pp 274, 1941 34. DAVAINE C. Traité des entozoaires et des maladies vermineuses de l'homme et de s animaux domestiques, J B Baillière et fils, Paris, pp 838, 1860 35. DAVAINE CJ. Nouvelles recher ches sur le développement et la propogation de l'ascaride lombricoïde et du trichocéph ale de l'homme. Comptes Rendus Hebomadaires des Séances de l'Académie des Sciences, série 3, 4: 261-265, 1862. Translated in 62

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36. DEMARQUAY JN. Helminthologie. Gazette Médicale de Paris 18: 665-667, 1863 37. DUBINI A. Nuovo verme intestinal umano ( Agchylostoma duodenale ) costituente un sesto genere dei nematoidei proprii dell'uomo. Annali Universali di Medicina 106: 5-13, 1843 38. DUCAS R. L'immunité dans la trichinose. Thèse, Paris, Jouve et Cie, 1921 39. FIBIGER J. Ueber eine durch Nematoden ( Spiroptera sp. n) hervorgerufene papillomatöse und carcinomatöse Geschwulstbildung im Magen der Ratte. Berliner klinisch e Wochenschrift i: 289-298, 1913 40. FIBIGER J. Sur la transmission aux rats de la Spiroptera neoplastica (Gongylonema neoplasticum). Méthode pour la production expérimentale du cancer. Comptes Rendu s Hebdomadaires des Séances et Mémoires de la Société de Biologie 83: 321-324, 1920 41. FIBIGER J. Carcinome spiroptér ien de la langue du rat. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 83: 692-695, 1920 42. FISCHER JL. Taeniae hydatigenae in plexu chorioideo nuper inventae historia etc., J Haasio, Lipsiae, 1789 43. FLECKSEDER R, von STEJSKAL K. Biologische Reaktionen mit Bandwurmextrakt. Wiener klinische Wochenschrift 17: 793, 1904 44. FLEIG C, LISBONNE M. Recherches sur un sérodiagnostic du kyste hydatique par l a méthode des precipitins. Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 62: 1198-1201, 1907 45. FUJINAMI A. (Immunity to macroparasitic disease, can it be acquired?), 1916. I n Japanese. Abstracted in China Medical Journal 31: 81, 1917 46. GEMMA C. De naturae divinis characterismis seu raris et admirandis etc., Antverpiae, pp 225, 1575 47. GHEDINI G. Ricerche sul siero di sangue di individuo affetto da cisti da echinococco e sul liquid in essa contenuto. Gazzetta degli Ospedali et delle Cliniche 27: 1616-1617, 1906 48. GOEZE JA. Versuch einer Naturgeschichte der Eingeweidewürmer thierischer Körper , PA Pape, Blankenburg, pp 471, 1782 49. GOLDSCHMIDT R. Die Aska risvergiftung. Münchener medicinische Wochenschrift 57: 1991-1993, 1910 50. GROVE DI. Immunity in human helminth infections. In, Biology and control o f endoparasites, L.E. Symons, A.D. Donald and J.K. Dineen (Editors), Academic Press , Sydney, pp 375-400, 1982 51. GROVE DI. What is the relationship between asthma and worms? Allergy 37: 139-148, 1982 52. GUERINI V. A history of dentistry from the most ancient times until the end of th e eighteenth century, Lea and Febiger, Philadelphia, pp 355, 1909 53. HERRICK WW. Experimental eosinophilia with an extract of an animal parasite: it s relation to anaphylaxis and certain clinical features. Archives of Internal Medicine 11 : 163-186, 1913 54. HOEPPLI R. Parasites and parasitic infections in early medicine and science, University of Malaya Press, Singapore, pp 526, 1959 55. HOFFMANN FH. Opera omnia physico-medica etc. et supplementa, Genevae, pp 508, 1740-1753 56. HUAND-FU MI. (The classics of acupuncture and moxibustion.) In Chinese. Partl y translated in 54 57. ISAAK S, von der VELDEN. Eine spezifische Präzipitinreaktion bei Bothriocephalus latus behergergenden Menschen. Deutsche medizinische Wochenschrift 30: 982, 1904 58. JOERDENS JH. Entomologie und Helminthologie des menschlichen Koerpers etc., G A Grau, Hof, two volumes, pp 473, 1801-1802 59. JOHANSSON SG, BENNICH H. Immunological studies of an atypical (myeloma ) immunoglobulin. Immunology 13: 381-394, 1967 60. JOHANSSON SG, MELLBIN T, VAHLQUIST B. Immunoglobulin levels in Ethiopian pre-school children with special reference to high concentrations of IgE (IgND). Lancet i: 1118-1121, 1968

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61. KANNER L. Folklore of the teeth. Dental Cosmos 67: 259, 1926 62. KEAN BH, MOTT KE, RUSSELL AJ. Tropical medicine and parasitology. Classi c investigations, Cornell University Press, Ithaca, pp 677, 1978 63. KÜCHENMEISTER F. Die in und an dem Körper des lebenden Mensche n vorkommenden Parasiten. Ein Lehr- und Handbuch der Diagnose und Behandlung de r thierischen und pflanzischen Pa rasiten des Menschen, BG Teubner, Leipzig, two volumes, pp 486, 1855. On animal and vegetable parasites of the human body. A manual of their natural history, diagnosis and treatment. Volume 1. Animal parasites belonging to th e group Entozoa, translated by E Lankester, The Syndenham Society, London, pp 452, 1857 64. KU CHIN YI T'UNG CHU'AN. Cited in 54 65. LANGER J. Zur Frage der Bildung spezifischer Antikörper im Organismus vo n Bandwurmwirten. Münchener medizinische Wochenschrift 52: 1665-1665, 1905 66. LARGUS S. Cited in 52 67. LEIPER RT. Gongylonema and cancer. British Medical Journal ii: 504, 1926 68. LESTRADE. La médecine indigène au Ruanda. Académie Royale des Science s Coloniales. Classe des sciences morales et politiques. Nouvelle série, tome VIII, fasc. l. (Ethnographie), Bruxelles, 1955. Cited in 54 69. LEUCKART FS. Zoologische Bruckstucke, Stuttgart, Freiburg, three volumes, 1819 70. van LINSCHOTEN JH. Vera descriptio regni pars Indiae orientalis in qua Johann . Hugonis Lintscotani navigatio in orientem etc., Teucrides Annaeus Lonicer, Frankfort , 1599. Original Dutch edition, 1596 71. LOOSS A. The anatomy and life h istory of Agchylostoma duodenale Dub. A monograph. Part II. The development in the free state. Translated from the German by M Bernhard. Records of the School of Medicine, Egyptian Ministry of Education 4: 163-613, 1911 72. LUSITANIUS. Cited in 29 73. McCONNELL JF. Remarks on the anatomy and pathological relations of a new species of liver-fluke. Lancet ii: 271-274, 1875 74. METCHNIKOFF E. The Harben lectures for 1906. II. The hygiene of the alimentar y canal. Lancet i: 1554-1555, 1906 75. MÜLLER HF, RIEDER H. Ueber vorkommen und klinische Bedeutung der eosinophilen Zellen, Ehrlich, im circulirenden Blute des Menschen. Deutsche Archiv für klinisch e Medicin 48: 96-121, 1891 76. MYREPSUS N. De antid., sect. I, cap. 298. Cited in 35 77. O'NEILL J. On the presence of a filaria in "craw-craw". Lancet i: 265-266, 1875 78. OWEN R. Description of a microscopic entozoon infesting the muscles of the huma n body. London Medical Gazette 16: 125-127, 1835 79. PALLAS PS. Einige Erinnerungen die Bandwürmer bettrefend: in Beziehung auf de s zwölfte und vierzehnte Stück des N aturforschers. Neue nordische Beyträge physickalische und geographische Erd- und Volkerbeschriften 1: 113-131, 1781 80. PARÉ A. Les oeuvres d'Amroise Paré, onzième edition. Avec les voyages qu'il a faits en divers lieux: et les pourtraits & figures, tant l'anatomie que des instruments de chirurgie, & de plusiers monstres, Chez Pierre Rigaud, Lyon, pp 854, 1651. Partly translated in 54 81. RANSOM BH. United States Department of Agriculture Bulletin No. 939, 1921 82. REDI F. Esperienze intorno alla generazione del'insetti, Carlo Dati, Firenze, pp 177, 1668 83. REDI F. Osservazione intorno agli animali viventi che si trovano negli animali viventi , Piero Matini, Firenze, pp 244, 1684 84. ROEDERER JG, WAGLER CG. De morbo mucoso liber singularis, quem nupe r speciminis inauguralis loco ediderunt, B Bossigelium, Goettingae, pp 211, 1762 85. ROSEN de ROSENSTEIN N. Traité des maladies des infans etc. Traduit du Suédois par Le Febvre de Villebrune, P G Cavelier, Paris, pp 582, 1778 86. RUYSCHIUS (RUYSCH) F. Observationum anatomico-chirurgicarum centuria etc., H et T Boom, Amstelodami, pp 138, 1691 87. SAMBON LW. Observations and researches o n epidemiology of cancer made in Holland and Italy (May-September, 1925). Journal of Tropical Medicine and Hygiene 29 :

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233-287, 1926 88. SAMBON LW. Refutation of statements made by Professor R.T. Leiper M.D., D.Sc., F.R.S., concerning African schistosomes, "American Gongylonemes", zoo vermin and Italian cancer houses. Journal of Tropical Medicine and Hygiene 29: 314-322, 1926 89. SHÊH SHENG TSUNG YAO. (Essentials of Hygiene. A curious book on coitus.), 1638. In Chinese. Partly translated in 54 90. SOLANDER DC. Furia infernalis, vermis et ab eo concitari solitus morbus, descripti . Nova Acta Regiae Societatis Scientarum Upsaliensis 2: 44, 1775 91. SPIGELIUS (van der SPIEGEL) A. De lumbrico lato liber cum eiusdem lumbrici icone et notis, L Pasquati, pp 88, 1618 92. SULTZER C. Dissertation sur un ver intestinal nouvellement découvert et décrit sous le nom bicorne rude, JA Fischer, Strasbourg, pp 52, 1801 93. SUSHRUTA SAMHITA. An English translation, edited by Kaviraj Kunja La l Bhishagratna, Calcutta, 1911 94. TALIAFERRO WH. The immunology of parasitic infections, The Century Co, Ne w York, pp 414, 1929 95. THOMPSON RC. Assyrian medical texts, Pro ceedings of the Royal Society of Medicine 19: 29-78, 1926 96. TOWNEND BR. The story of the toothworm. Bulletin of the History of Medicine 19: 37-58, 1944 97. TYSON E. Lumbricus teres, or some anatomical observations on the round worm bred in human bodies. Philosophical Transactions of the Royal Society 13: 153-161, 1683 98. TYSON E. Lumbricus latus, or a di scourse read before the Royal Society, of the joynted worm etc. Philosophical Transactions of the Royal Society 13: 113-144, 1683 99. TYSON E. Lumbricus hydropicus: or an essay to prove that Hydatides often met with in morbid animal bodies, are a species of worm, or imperfect animals. Philosophica l Transactions of the Royal Society 17: 506-510, 1691 100. VELSCHIUS GH. Exercitatio de Vena Medinensi, ad mentem Ebnsinae sive dracunculis veterum etc., Theophili Goebelli, Augustae Vindelicorum, pp 456, 1674 101. WALLIS BUDGE EA. Syriac anatomy, pathology and therapeutics or, "The book o f medicines etc.", two volumes, Oxford University Press, London, 1913 102. WAWRUCH. Réflexions tirées de deux cent six o bservations de ténias. Gazette Médicale de Paris 9: 633, 1842. Extracted from Medizin Jahrbuch des Oesterreich Staates 103. WEINBERG M, JULIEN A. Sub stances toxiques de l'Ascaris megalocephala . Comptes Rendus Hebdomadaires des Séances et Mémoires de la Société de Biologie 70: 337-339, 1911 104. WYKOFF RE. Delusions of parasitosis: a review. Reviews of Infectious Diseases 9 : 433-437, 1987

Chapter 29

BIOGRAPHIES

ALEIXO de ABREU (1568-1630) Aleixo de Abreu was born in Alcáçovas, Portugal in 1568. He entered Evora University and graduated with a bachelor of arts degree in 1583. He then studied medicine at Coimba University and graduated seven years later. He first practised in Lisbon then in 1594 he was appointed physician to the governor of Angola. In 1604 he went to Brazil with the governor of that province, Diogo Botello. During this period he developed dysentery and jaundice which necessitated his return to Lisbon in 1606. In 1612 he was appointed physician to the treasury officials, a position which he held until 1629. During a serious illness in 1621 he began writing his Tratado de las siete enfermedades etc. (Treatise of the seven diseases), the first text on tropical medicine. It was published in 1623, partly in Latin and partly in Spanish, and described, amongst other things, the worms now known as Trichuris trichiura and Dracunculus medinensis. He died in Lisbon in 1630. NICOLAS ANDRY de BOISREGARD (1658-1742) Andry was born in Lyons, France in 1658. He studied medicine then later became professor of philosophy and dean of the faculty of medicine at the University of Paris. He was a man of letters and made notable contributions to both the humanities and science. He wrote the first textbook of orthopaedics, and indeed coined the word which is derived from the Greek words referring to straightening and the rearing of children. He also wrote on phlebotomy and helminthology, the latter book being an attempt to refute the doctrine of the spontaneous generation of worms. He died in 1742, one year after the last edition of his textbook on helminths. (Plate 1) ARETAEUS THE CAPPADOCIAN (c. 50 AD) Aretaeus was born in the Roman province of Cappadocia in Asia Minor, probably in the first century AD. He studied medicine at Alexandria in Egypt and became a prolific writer. His work, De causis et signis morborum [On the causes and signs of diseases], however, is the only extant treatise. Aretaeus was the first person to describe cardiac murmurs and may have been the first to practise direct auscultation of the chest. (Plate 2) DOUGLAS MORAY COOPER LAMB ARGYLL-ROBERTSON (1837-1909) Argyll Robertson was born in Edinburgh, Scotland, the son of an ophthalmic surgeon and lecturer in the medical school. He was educated at the Edinburgh Institution, at Neuwied in Germany, and at the Universities of Edinburgh, St. Andrews and Berlin. He graduated in medicine from St. Andrews in 1857 and became a fellow of the Royal College of Surgeons of Edinburgh in 1862, having studied ophthalmology under von Arlt in Prague and von Graefe in Berlin. From the beginning of his career, he devoted himself exclusively to ophthalmic surgery, becoming assistant ophthalmic surgeon

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(1867) then ophthalmic surgeon (1870) to the Edinburgh Royal Infirmary until 1897 when he became consulting surgeon. He investigated the role of an extract of the Calabar bean (physostigmine) in the treatment of certain eye conditions and in 1869 and 1879 published papers describing the pupillary changes in tabes dorsalis (syphilis) which now bear his name (Argyll Robertson pupil). He described the appearances of the adult Loa loa. He became president of the Royal College of Surgeons of Edinburgh in 1886 and was awarded the honorary degree of LL.D. by the University of Edinburgh in 1897. He married Miss Fraser in 1882 but had no children. He was a keen golfer, archer, shooter and fisherman. When he retired in 1904, he retired to the island of Jersey on account of its milder climate. In November 1908 he travelled to India to visit an old friend, the Thakur of Gondal. He died suddenly in Gondal on 3 January 1909. (Plate 3) ARISTOTLE (384-322 BC) Aristotle was born in Stagira, Macedonia, the son of a Greek physician. At the age of 17 he became a pupil of Plato at the Academy in Athens. He was a tutor to Alexander the Great who probably endowed a museum which allowed Aristotle to collect botanical and zoological specimens. Around 347 BC he moved to Asia Minor and married Pythias. After a period on the island of Lesbos, he returned to Athens in 335 BC and set up a school in a grove sacred to Apollo Lyceus, the school becoming known as the "Lyceum". He wrote many works on a wide range of subjects including logic, biology, psychology, physics, metaphysics, ethics, political science, aesthetics and literary criticism. In 323 BC he was forced to leave Athens because of anti-Macedonian feelings and he died at Chalcis in Euboea in the following year. BAILEY KELLY ASHFORD (1873-1934) Ashford was born in Georgetown, USA, the son of the professor of surgery there. He joined the United States Army and graduated from the Army Medical School and Georgetown University. The Spanish-American War took him to Puerto Rico where he met then married Maria Asuncion Lopez, daughter of the Marques de Villar, by whom he had a son and two daughters. He was at Ponce when a devastating hurricane struck and the Army was left to succour 800,000 persons. It was this that led him to define hookworm infection as the cause of much anaemia on the island. Ashford rose to the rank of colonel in the United States Army. He spent many years trying to establish a school of tropical medicine in Puerto Rico. He was eventually successful in 1926 and was appointed professor of tropical medicine and mycology, a post which he held until his death. Meanwhile, he had been a member of the Rockefeller Commission (on hookworm) to Brazil in 1916 and had sailed with the American Army to France in 1917. Subsequently, he became particularly interested in sprue and in candidiasis. He died in 1934 at the age of 61 years. (Plate 4) MAX ASKANAZY (1865-1940) Askanazy was born in Stalliponen, Germany in 1865. He studied medicine at Königsberg (Kaliningrad), now in the USSR (Lithuania), where he later became professor of pathology. In 1905 he was appointed director of the Institute of Pathology in Geneva, Switzerland. He held this post for 35 years until his death in 1940.

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EDWARD LEICESTER ATKINSON (1882-1929) Atkinson was born in England in November 1882. He studied medicine at St. Thomas's Hospital, London and qualified as a member of the Royal College of Surgeons and a licentiate of the Royal College of Physicians in 1906. He joined the Royal Naval Medical Service as a surgeon in 1908. He was medical officer to Captain Scott's ill-fated expedition to the South Pole in 1910, was left in charge of the base camp, and led the rescue team which found Scott's last remains. He was promoted to Staff Surgeon in 1913, and went with Leiper on his expedition to the Orient in 1914. Atkinson was wounded severely in July 1917 while serving with the Howitzer Brigade in France. In May 1918 he was awarded the Distinguished Service Order. In September 1918 he was awarded the Albert Medal for gallantry in saving life at sea following an explosion on H.M.S. Glatton ; he was gravely injured in the process and his life was despaired of for some time. He was a keen bacteriologist and parasitologist; he invented a method of disinfecting and deodorizing urinals in ships. His official biography recorded that his zeal, tact, kindly disposition and consideration made him a friend to all, and that his cheery optimism, versatility, pluck and determination brought him through many vicissitudes. In November 1928, he was placed on the retired list as medically unfit with the rank of Surgeon Captain, but died at sea on 2 February 1929 at the age of 46 years. (Plate 5) ERWIN OTTO EDUARD von BAELZ (1849-1913) Baelz was born in Bietigheim in Württemberg, (in present-day West) Germany on 13 January 1849, the son of a builder. From his youth, he was interested in natural history and travel and became fluent in French and English and read Italian and Spanish. He began tertiary studies at the University of Tübingen at the age of 17, but in 1869 he transferred to the University of Leipzig. At the outbreak of the FrancoPrussian War (1870), he joined the artillery and became a medical auxiliary. Baelz returned to Leipzig then graduated in medicine in 1872. Subsequently, he studied pathology at the Leipzig Polyclinic, went to Vienna where he became an assistant in pathology, then returned to Leipzig where he worked for four years under Wunderlich who at that time had the most famous clinic in Germany. While working there, he came in contact with some Japanese post-graduate students, and in April 1876 he went to the newly-created medical department at Tokyo Imperial University, Japan, where he later became professor of medicine. He married a Japanese woman and remained in that country for the next 29 years. Baelz made original observations on paragonimiasis, clonorchiasis, beriberi and leprosy. He was decorated both in Japan and in Germany. Von Baelz returned to Germany in 1905 and died in Stuttgart on 31 August 1913 at the age of 64 years. (Plate 6) JOSEPH BANCROFT (1836-1894) Bancroft was born on a farm at Stretford, near Manchester, England, the only son of Peter Bancroft and Mary Lane in 1836. He began his medical training as an apprentice of Dr Jeremiah Shaw in Sale, Cheshire. He then continued his studies at the Manchester Royal School of Medicine and Surgery and at the Manchester Royal Infirmary. He qualified as a member of the Royal College of Surgeons and a licentiate of the Royal Society of Apothecaries in London in 1859 then received a doctorate in medicine from the University of St Andrews. While still a medical student he married Ann Oldfield by whom he had three children, one daughter dying in infancy. Following graduation he

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practised in Nottingham for five years. He was a keen naturalist and was for three years president of the Nottingham Naturalists' Society. Because of illness (possibly nephrotic syndrome), he moved to the warmer climate of Queensland, Australia in 1864, settling on the outskirts of Brisbane in 1867. He became visiting surgeon to the Brisbane Hospital in 1867 then in 1868 he was appointed house surgeon, a post similar to that of medical superintendent. Two years later he resigned this post and became a visiting surgeon once more and developed a thriving private practice. He wrote on a variety of clinical topics, especially snake-bite, tick paralysis, typhoid fever, leprosy and filariasis. He was a keen horticulturist and was intrigued by the medicinal possibilities of Australian plants. He was interested in public health and was for a number of years Health Officer for Brisbane. He was said to be a kindly and approachable man, yet on the other hand it has been remarked that he was direct of speech and at times could be rather irascible. He died suddenly from a myocardial infarction on 16 June 1894 aged 58 years. (Plate 7) THOMAS LANE BANCROFT (1860-1933) Bancroft was born in Nottingham, England, the son of Dr Joseph Bancroft and Ann Oldfield in 1860. When he was four years of age he migrated to Brisbane, Australia with his family aboard the "Lady Young". He was educated at Brisbane Grammar School then in 1877 went with his father to Britain to begin training as a medical student in Edinburgh. Following his graduation in 1883, he returned to Brisbane and entered practice. He practised there until 1894 when he moved to Deception Bay 40 kilometres north of Brisbane where he managed a property inherited from his father that included a meatworks and experimental farm. When the meatworks closed in 1904 he returned to Brisbane. While at Deception Bay, he had considerable time to devote to research. Like his father, he was a devoted, talented and many-sided doctor-naturalist, making many contributions to knowledge of the Australian fauna and flora. He died in 1933. (Plate 8) CLAUDE HEMAN BARLOW (1876-1969) Barlow was born in Lyons, Michigan, United States of America and graduated with a doctorate in medicine from Northwestern University in l906. He married Grace Hawley in the following year and had four daughters. In 1908, he went to Huchow, China as a medical missionary for the Baptist Foreign Missions Society. From 1911-1925 Barlow was located mostly in Shaohsing (= Shaoxing), although he had a spell (as a patient) in a tuberculosis sanatorium at Saranac Lake, New York in 1913 and attended the London School of Tropical Medicine in 1914. He was released by the Society from his other duties in 1922 in order to pursue his researches on fasciolopsiasis in China using facilities provided by Johns Hopkins University. Between 1925 and 1928 he was appointed port physician for the Chinese Maritime Customs in Ningpo (= Ningbo). In 1929 he joined the International Health Division of the Rockefeller Foundation and went to Egypt where he worked on the snail control of schistosomiasis. Barlow remained with the Foundation for the next 21 years, apart from a period spent in South Africa where he also was concerned with schistosomiasis control. He died in New York State, USA, on 9 October 1969 aged 92 years. HENRY CHARLTON BASTIAN (1837-1915) Bastian was born at Truro in Cornwall, England on 26 April 1837. He received his

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education at University College, London graduating with the degree of master of arts in 1861, bachelor of medicine in 1863 and doctor of medicine in 1866. Shortly after graduation he was elected assistant physician to St Mary's Hospital and lecturer in pathology at its Medical School. In 1867 he was appointed professor of pathological anatomy then in 1887 professor of medicine and clinical medicine at University College Hospital, a post which he held until 1897. He was also a physician to the National Hospital for the Paralysed and Epileptic from 1882-1912. He was elected a fellow of the Royal Society in 1868 when only 31 years of age for his contributions to parasitology, having published two monographs on free-living nematodes in which he described 100 new species and investigated their physiology. His middle years were devoted to neurology but in his early and later years he was primarily concerned with the origin of life, being a staunch advocate of heterogenesis (spontaneous generation). This latter story is a remarkable example of misguided moral courage and scientific enthusiasm in the face of hopeless odds. He died at home on 17 November 1915 at Chesham Bois, Buckinghamshire aged 78 years leaving his widow, Julia (née Orane), three sons, and a daughter. (Plate 9) ARTHUR RÉNÉ JEAN BAPTISTE BAVAY (1840-?) Bavay was born on 29 April 1840 at Lamballe in Côtes de Nord, France, the son of François Bavay, a doctor, and his wife, Marguerite. He studied pharmacy between 1858 and 1860 and was appointed in the French Navy as pharmacist third class (1860), pharmacist second class (1864) and pharmacist first class (1869), serving in Brest and Lorient in France, New Caledonia in the South Pacific (1864-1869), and Guadeloupe in the Caribbean (1869-1875). In 1868 he married Anna Coz. In 1875 he was appointed professor of botany and natural history in Toulon. In 1877 he was made a Chevalier de la Légion d'Honneur (knight of the legion of honour). In 1881 he was appointed professor of pharmacy and therapeutics in Brest, becoming chief pharmacist in 1883. In 1896 he was transferred to the Conseil Supérieur de Santé (high council of health). He remained there until he retired in 1902. It is uncertain when he died. PAUL C BEAVER (1905-) Beaver was born in Indiana in the United States of America in 1905. He obtained the degrees of master of science and doctor of philosophy from the University of Illinois. He joined the department of parasitology at Tulane University in New Orleans, Louisiana in 1945, rising to the rank of professor of parasitology and director of the university's international centre for medical research in Cali, Colombia. He served as editor of the "American Journal of Tropical Medicine and Hygiene" for twenty years. (Plate 10) PIERRE JOSEPH van BENEDEN (1809-1894) PJ van Beneden was born on 19 December 1809 at Mechelen (Malines) in Belgium. He graduated in medicine in 1831 from the University of Louvain having first been apprenticed to Louis Stöffels, a great collector of natural history specimens, who inspired van Beneden to become a zoologist. In 1835 he was appointed professor of zoology and comparative anatomy at the Catholic University of Louvain then became curator of the Natural History Museum in that city. In 1843 he established, at his own expense, a marine aquarium which was one of the first of its kind. Van Beneden made many contributions to the knowledge of the biology of parasitic worms. He was much

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esteemed for his high character and was the recipient of many honours, including being elected president of the Royal Belgian Academy in 1881, a foreign corresponding member of the Royal Society of Britain, and being made a Grand Officer of the Order of Leopold in 1886. His son, Edouard, became professor of zoology at Liège in 1870; he was an embryologist who discovered the phenomenon of meiosis. The elder van Beneden died at Louvain on 8 January 1894, aged 84 years. (Plate 11) CHARLES ALBERT BENTLEY (1873-1949) Bentley was born at Chipping Norton, England on 25 April 1873. He studied first in Liverpool then in Edinburgh where he graduated with the degrees of bachelor of medicine and master of chirurgie in 1898. After two years as a resident at the Royal Southern Dispensary in Liverpool, he went to India for a number of years as chief medical officer for the Empire of India and Ceylon Tea Company in Assam. Not only did he discover the cause of "ground-itch", but he showed that the recently-discovered Leishman-Donovan bodies were present in kala azar, thus showing for the first time the true nature of this deadly disease. He took a diploma in public health from Cambridge and a diploma in tropical medicine and hygiene in 1905. In 1909 he undertook an extensive investigation of malaria in Bombay. In 1915 he was appointed director of public health in Bengal. In 1916 he married Gwendoline Harper by whom he had two sons and two daughters. The University of Calcutta conferred an honorary doctorate of medicine on him in 1931. In 1931 he left India for Egypt on being appointed professor of hygiene in the Egyptian University in Cairo. He remained there until 1937 when he retired to England. He was created a Companion of the Order of the Indian Empire (CIE) in 1929 and made a Commandant of the Order of the Nile in 1937. He died at Carshalton, England on 23 November 1949 at the age of 76 years after a short illness. GODEFRIDUS GOVERT BIDLOO (1649-1713) Bidloo was born in Amsterdam, Holland in 1649. He studied medicine at the University of Leiden and eventually became professor of anatomy, first at the Hague and then at Leiden. For a time he was physician to William of Orange, later King William III of England, and in 1692 became Inspector of Military Hospitals in England. Bidloo published an Atlas of Anatomy in Amsterdam in 1685 with 105 plates by the artist Gerard de Lairesse. These plates were plagiarized by the English anatomist and surgeon, William Cowper in his Anatomy of Human Bodies published in 1698 in Oxford. Two years later, an irate Bidloo wrote a scathing attack on the latter in a tract entitled "Guglielmus Cowper, criminis literarii citatus". Bidloo died in Leiden, Holland in 1713. THEODOR BILHARZ (1825-1862) Bilharz was born on 23 March 1825 at Sigmaringen on the Danube in Württemberg, (present-day West) Germany. He was the eldest of nine children and showed his taste for natural history as a youngster, collecting plants, insects and minerals. In 1843 he entered the University of Freiberg, then in 1845 transferred to Tübingen where he began the study of medicine. After his graduation in 1849, Bilharz returned to Freiberg where he was appointed prosector at the Anatomical Institute; there he was able to study the comparative anatomy of lower animals and to attend von Siebold's lectures on helminthology. In June 1850, he went to Egypt as an assistant to another former teacher, Wilhelm Griesinger, who had been appointed, amongst other things, physician to the Viceroy of Egypt. When Griesinger departed from Egypt in 1852, Bilharz became

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successively chef-de clinique in the surgical division of Kasr-el-Aini Hospital, chief surgeon of the division for internal diseases, professor of medicine and professor of comparative anatomy (1856), then in 1861 he moved to the department for syphilis and diseases of the skin. In 1862, Bilharz accompanied the Duchess of Saxe-CoburgGotha and her party to Massaua (also Massowah, now Mesewa) on the Red Sea in the Eritrean province of Ethiopia, while the Duke and his companions went on an expedition to the interior. While in Massaua, Bilharz attended a German lady who was living in that place and who was suffering from a febrile illness, variously recorded as being typhus and typhoid. Bilharz contracted the disease himself, returned to Cairo and died there shortly afterwards on 9 May 1862 at the age of 37. Bilharz remained unmarried, was a modest man and painfully shy in the presence of strangers, but was a valued friend to many. Not only did he make major contributions to helminthology (schistosomiasis, hookworm infection, heterophyiasis, taeniasis nana), but he was also an authority on the fauna (describing, for example, the electric organ of the eel) and flora of Egypt, and on its inhabitants and their customs. (Plate 12) DONALD BREADALBANE BLACKLOCK (1879-1955) Blacklock was born at Oban in Argyllshire, Scotland on 7 January 1879, the son of the Rev. John Blacklock, a presbyterian minister. He was educated at the University of Edinburgh where he graduated with the degrees of bachelor of medicine and bachelor of chirurgie in 1902. He practised for a few years in South Africa. He took the diploma in public health (London) in 1907, degree of doctor of medicine (Edinburgh) in 1909, and diploma in tropical medicine (Liverpool) in 1911. In that same year he was appointed research assistant to the Liverpool School of Tropical Medicine's research laboratory and worked mostly on trypanosomiasis. In 1914 he was made director of the laboratory and was later appointed lecturer in parasitology. During World War I he served in the Royal Army Medical Corps. In 1921 he was created professor of the tropical diseases of Africa by the University of Liverpool and appointed first director of the Sir Alfred Lewis Jones Research Laboratory in Freetown, Sierra Leona where he remained for the next eight years. In 1922 he married Dr Mary Georgina Thompson; they had no children. In 1929 he returned to Liverpool as professor of parasitology, then from 1934 until his retirement in 1945 he was professor of tropical hygiene. In 1940 during World War II he was sent as a Surgeon-Captain in the Royal Navy Volunteer Reserve to Freetown, Sierra Leone to control a malaria outbreak which was threatening shipping convoys; for these services he was made a Commander of the Order of St Michael and St George (C.M.G.) He retired to Cornwall and died at his home at Mawnan on 10 June 1955 at the age of 76 years. (Plate 13) RAPHAEL ANATOLE BLANCHARD (1857-1919) Blanchard was born on 28 February 1857 at Sainte-Christophe (Indre-et-Loire) in France. His father, a poet and author, died at the age of 26, but his grand-uncle, Jean Pierre Blanchard, was famous for devising the first parachute and for having been the first person to cross the English Channel in a balloon (1785). Blanchard began the study of medicine and natural science at the University of Paris in 1875, graduating as a doctor of medicine in 1882. He was appointed associate professor of medicine at the Paris Faculty of Medicine in 1883. In 1876, Blanchard had helped found the Société Zoologique de France, of which he became the secretary-general and moving spirit for twenty years. He and Milne-Edwards organized the first International Congress of

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Zoology, and Blanchard was appointed president of the International Commission on Zoological Nomenclature in 1898. In the previous year he had been appointed professor of medical zoology, a title which was changed in 1906 to parasitology. He founded the Archives de Parasitologie in 1898, then became the first president of the Société Française d'Histoire Médicale and helped found the Institut de Médecine Coloniale in 1902. He was a prolific author, publishing 603 books, brochures, original papers, notes and articles. He had a considerable command of languages and was an eloquent speaker, an indefatigable researcher and a good organizer. He had many warm friends but, as one biographer wrote, "that he should have some enemies is natural for such is the fate of most leaders of men". He died suddenly on 7 February 1919 at the age of 62 years. (Plate 14) LUDWIG HEINRICH BOJANUS (1776-1827) Bojanus was born on 16 July 1776 at Buchsweiler in Elsass, Germany, now Alsace, France. He studied medicine at Jena and graduated there in 1797. After travelling for a year studying natural science, he began medical practice in Darmstadt where he was admitted as a member of the College of Medicine in 1801. In 1806 he was appointed professor of veterinary medicine in Wilna (now Vilnius, Lithuania, USSR), becoming professor of anatomy there in 1816. His major work was a monograph on the anatomy of tortoises, which remained an essential zoological text for many years. He died in Darmstadt on 2 April 1827 aged 50 years. CHARLES BONNET (1720-1793) Bonnet was born in Geneva, Switzerland on 13 March 1720. He was the son of wealthy parents, his family having emigrated from France during the persecution of the Huguenots. As a young person he was hindered by increasing deafness. He studied law and was elected to the council of his native city, but he also had a lively interest in natural science and eventually devoted himself entirely to that pursuit. He made major contributions to the understanding of insect biology and was the first person to describe the phenomenon of parthenogenesis when he showed that each female aphid produced 95 offspring without mating (1746). Likewise he studied regeneration and showed that each section of Lumbriculus worms when cut into many pieces became perfectly reconstituted into an adult worm. A serious eye disease, however, compelled him to give up making direct observations, and he spent the rest of his days engaged in theoretical speculations, frequently with effusive religious overtones, about natural science and philosophy. In 1756 he married Jeanne-Marie de la Rive, the daughter of a wealthy landowner. He died at his estate near Geneva on 20 May 1793 at the age of 73 years. MAXIMILIAN GUSTAV CHRISTIAN CARL BRAUN (1850-1930) Braun was born in Germany in 1850. He was educated at the Universities of Greifswald and Würzburg where he studied zoology and medicine. He graduated with the degree of doctor of medicine from Wurzburg in 1874 then three years later he was awarded a doctorate of philosophy. In 1880 he was appointed a professor in comparative anatomy at the University of Dorpat (now Tartu in Estonia, USSR) then in 1883 was made professor of zoology in that institution. In 1886 he moved to Rostock then in 1891 he was appointed professor of zoology and comparative anatomy and director of the zoological museum at the University of Königsberg (now Kaliningrad, Lithuania) where he remained until his retirement in 1922. After a number of years of ill health he

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died on 19 February, aged 80 years. (Plate 15) JOHANN GOTTFRIED BREMSER (1767-1827) Bremser was born on 19 August 1767 at Wertheim, (present-day West) Germany. He studied zoology at Jena and graduated in 1792. He then undertook further studies in medicine in Vienna, Austria. In 1806 he became associated with the museum of natural history in Vienna, and in 1811 was appointed its curator. In 1815 he went to Paris in order to pursue studies in his field of interest. Apart from helminthology, Bremser published papers on a number of infectious diseases including scarlet fever, cowpox and measles. He died in Vienna on 21 August 1827, aged 60 years.

JEAN de BRIE (1349-?) Jean de Brie was born at Villiers-sur-Rougnons, near Coulommiers, France in 1349. He had the reputation of being one of the best breeders of sheep and cattle in the country. He was commissioned by King Charles V of France to write a book on the proper management of sheep and the best means of wool production. This was completed in 1379, and in it de Brie described the liver fluke. JOHN JOSEPH CRONIN BUCKLEY (1904-1971) Buckley was born in Dublin, Ireland in 1904, the son of J J Buckley, the acting director of the National Museum of Ireland. He graduated with the degree of master of science from the National University of Ireland then went to the London School of Tropical Medicine in 1928. While in the West Indies between 1931 and 1933 he worked out the life cycle of Mansonella ozzardi. He studied onchocerciasis in Kenya in 1938 and in the 1950s undertook a number of experiments with Brugia, inoculating himself on three occasions with B. malayi and concluding that he had developed tropical eosinophilia. In 1963 he developed a lower limb paresis associated with intolerable pain. His biographer has said that his modesty was such that he belittled his own achievements and he invariably gave more credit than was really due to his collaborators. He died in 1971. GEORGE BUSK (1807-1886) Busk was born on 12 August 1807 in St Petersburgh (Leningrad), Russia, (USSR) where his father was a merchant in the English colony. He was educated at Dr Hartley's school in Yorkshire, England, then was apprenticed for six years to George Beaman, being articled at the Royal College of Surgeons. He spent some time at St Thomas's Hospital, then graduated in 1830. In 1832, Busk was appointed Assistant Surgeon to the Grampus, the Seamen's Hospital ship at Greenwich, and afterwards to the Dreadnought which replaced it. He served in this capacity for 25 years, during which time he made important observations on cholera and scurvy. He was elected a fellow of the Royal Society in 1850. He resigned his post as surgeon to the Dreadnought in 1855 and became Hunterian professor of anatomy and physiology at the Royal College of Surgeons between 1856 and 1859. Busk turned his attention to more general aspects of biology, paying particular attention to the Bryozoa and becoming interested in ethnology. He was the first Home Office Inspector under the Cruelty to Animals (Vivisection) Act, a post which he held with tact and impartiality. He married his cousin Ellen in 1843 and had two daughters. A biographer wrote that "Busk was full of knowledge,

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an unwearying collector of facts, a devoted labourer in the paths of science, and cautious in the conclusions he drew from his observations. He was a man of unaffected simplicity and gentleness of character, without a trace of vanity, a devoted friend, and an upright, honest gentleman". He died at his home in Harley Street, London on 10 August 1886, aged 79 years. (Plate 16) JOHN CATTO (1878-1908) Catto was born in August 1878 in Britain. He studied medicine at the University of Aberdeen and graduated with the degrees of bachelor of medicine and bachelor of chirurgie in 1900 and he later obtained a diploma in public health from the University of London. While employed as a resident medical officer in Singapore, he obtained the specimen in which he eventually found Schistosoma japonicum adult worms. He returned to England in 1904, then joined the Indian Medical Service as a lieutenant on 1 September 1905. He died of cholera at Imphal, Manipur State, India on 7 May 1908 aged 29 years. AULUS CORNELIUS CELSUS (30 BC-50 AD) Celsus lived during the reign of Tiberius Caesar at the height of Roman civilization immediately after the founding of the Empire. He was a landowner, nobleman and medical historian. He was probably a scholar with limited clinical experience, but he held most of the contemporary knowledge of medicine within his grasp. He wrote an encyclopaedia, "De artibus", which contained sections on agriculture, military arts, rhetoric, philosophy and jurisprudence. Only the last section, De medicina, is extant; it was re-discovered in 1443 when a copy of the manuscript was found in the papal library in Milan. (Plate 17) ADELBERT von CHAMISSO (1781-1838) Von Chamisso (also known as Charles Adélaïde Chamisso) was born, the son of a count, at Schloss Boncourt in the Champagne district of France on 30 January 1781. In 1798 he entered military school in Berlin and was commissioned in the Prussian Army as a lieutenant in 1801. Following the surrender of his regiment in 1806, he returned to France. His interests lay in the realms of writing lyrics and in natural science. In 1812 he went back to Berlin to study medicine and science. In 1815 he sailed around the world as naturalist with the Russian, Captain Otto von Kotzebue on the brig Rurik, following which he wrote a book on his experiences and observations. In 1819 he was appointed adjunct curator of the Royal Botanical Gardens in Berlin, then became curator in 1833. In 1820 he married Antonie Piaste by whom he had seven children. Von Chamisso was elected a member of the Academy of Science in 1835 and died in Berlin on 21 August 1838 aged 57 years. RICHARD HAVELOCK CHARLES (1858-1934) Charles was born in 1858. He was educated at Queen's College in Cork, Ireland then entered the Indian Medical Service in 1882. He was soon appointed to the Afghan Boundary Commission then at an early age was made professor of anatomy and surgery at the Lahore Medical College. Subsequently he became professor of surgery in Calcutta. He reached the rank of Major-General in the Indian Medical Service and was appointed medical adviser to the Indian Office. He was knighted in 1912. He was said to have a forceful personality but was a good friend to all who gained his confidence.

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After several years of failing health he died on 27 October 1934, his wife having pre-deceased him by several years. (Plate 18) JOHN BRIAN CHRISTOPHERSON (1868-1955) Christopherson was born at Bakley, Yorkshire, England on 30 April 1868, the son of a clergyman. He went to Cambridge University then continued his medical studies at St. Bartholomew's Hospital, London. After graduating in 1893, he took several resident positions in that hospital, gained the fellowship of the Royal College of Surgeons in 1897 and proceeded to the degree of doctor of medicine from Cambridge in the following year. Between 1896 and 1902 he was on the surgical staff of the Albert Dock Hospital, but then went to South Africa as surgeon to the Imperial Yeomanry Hospital during the Boer War. In 1902 he was appointed physician to the Governor-General of the Sudan, then two years later became Director of Medical Services to the Sudan Government. In 1909 he resigned these appointments to become Director of the Civil Hospitals in Khartoum and Omdurman. Meanwhile, his main clinical interests had evolved from surgery to medicine; he took the membership of the Royal College of Physicians in 1905 and was elected a fellow of that College in 1913. In 1912 he married Joyce Ormerod, a daughter of one of the physicians at St Bartholomew's Hospital. In 1916 during World War I he went with a Red Cross unit to Serbia (now part of Yugoslavia) but was taken prisoner-of-war by the Austrians. On his release shortly afterwards, he went to France, serving as the secretary to the War Office Commission on Medical Establishments in the British Expeditionary Force. Near the end of that year, he returned to the Sudan where he was to make his observations on the efficacy of antimony in the treatment of schistosomiasis. He settled in London after the war and was honoured by being made a Commander of the Order of British Empire (C.B.E.) in 1919. Although he did not lose interest in tropical medicine, he turned his attention to respiratory diseases and became a member of the staff of the London Chest Hospital. He was described as being a kind, considerate soul with a keen, inquisitive look and an enquiring mind. He died at his home in Lydney-on-Severn in Gloucestershire, England on 21 July 1955 at the age of 87 years. (Plate 19) THOMAS SPENCER COBBOLD (1828-1886) Cobbold was born on 28 May 1828 at Ipswich, Suffolk, England, the son of Richard Cobbold, a well-to-do clergyman. At the age of 16, he became apprenticed to J G Crosse, a surgeon in Norwich, for three years then in 1847 he went to Edinburgh to study medicine and graduated with the degree of doctor of medicine in 1851. After a short period in Paris, he became curator of the Anatomical Museum of the University in Edinburgh and remained there for several years while working on comparative anatomy. In 1852 he married a Miss Amyss of Suffolk by whom he eventually had several daughters and a son. In 1856 he went to London and was appointed lecturer in botany, zoology and comparative anatomy, first at St. Mary's Hospital and then (1861) at the Middlesex Hospital Medical School. Cobbold did not practise medicine for many years but in 1865, following the success of his book, began a consultative practice in helminthology. He wrote the first major English textbook on parasitic diseases: Entozoa: an introduction to the study of helminthology, more particularly to the internal parasites of man which was published in 1864. In the same year he was elected a fellow of the Royal Society, then was appointed professor of geology at the British Museum in 1868 and professor of botany and helminthology at the Royal Veterinary College in

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1872. He was said to be of a kind and affectionate disposition (although his often dogmatic writings at times appear to belie this), made and kept many friends, was devoted to music, and possessed a remarkable alto voice. He died from cardiac disease in London on 20 March 1886 at the age of 57 years. (Plate 20) CHARLES WILBERFORCE DANIELS (1862-1927) Daniels was born on 9 May 1862, the third son of the Rev. Thomas Daniels, rector of Hulme near Manchester, England. He was educated at Trinity College, Cambridge and at the London Hospital, graduating from the University of Cambridge with the degree of bachelor of medicine in 1886. After three years in various posts in the London Hospital, he entered the Colonial Medical Service in 1889 and was sent to Fiji. In 1894 he was transferred to British Guiana (now Guyana). In 1899 he went to Calcutta on behalf of the Royal Society to study Ross's work on the transmission of malaria then later that year he proceeded to Nyasaland (Malawi) as a member of the Royal Society's Commission on blackwater fever. On his return to London he was made superintendent of the London School of Tropical Medicine but two years later he was sent to Malaya (Malaysia) to direct the new Institute of Medical Research in Kuala Lumpur. In 1905 he retired from the Colonial Service and returned to the London School of Tropical Medicine as Director. In 1912 he was appointed adviser to the Colonial Office where he remained until 1920 when ill health forced him to retire. A progressive and disabling illness dogged his last years in Ilford until his death on 6 August 1927, aged 65 years. He never married. (Plate 21) CASIMIR JOSEPH DAVAINE (1812-1882) Davaine was born on 19 March 1812 at Saint-Amand-les-Eaux in France, the sixth child of Benjamin Joseph Davaine, a distiller. He entered the Collège of Tournai in 1828 then moved to Lille. In 1830 he went to Paris to study medicine, spending his clinical years at the Paris Hospital. He received his doctorate in 1837 for a thesis on haematocoele in the tunica vaginalis. He began the practice of medicine in Paris but developed an interest in natural history, especially parasitology; for example, he published a paper on lice in 1839. In 1844 he wrote a work on the development of the fetal human brain between the ages 5 weeks and 7 months. He was elected a member of the Société de Biologie in 1848 and became its treasurer and archivist. The first edition of his great textbook of parasitology appeared in 1860 and the second edition was published in 1877. Davaine described the causative organism of anthrax and was the first to recognize the pathogenic role of bacteria. In 1869, 14 years before Metchnikoff, he described phagocytosis by human leucocytes. All this research was carried out while Davaine practised medicine for he never had a laboratory of his own, nor did he hold an official university position. Because of his fame, he was appointed physician to the French Emperor. In 1869 he married an Englishwoman, Maria Forbes, by whom he had a son. Outside of medicine, he was a rose-fancier. He died in Garches from an abdominal malignancy on 14 October 1882, aged 70 years. (Plate 22) JEAN NICHOLAS DEMARQUAY (1814-1875) Demarquay was born in Longueval, a small village in the department of Somme, France in 1814, the son of a farmer. He graduated in medicine and specialized in surgery becoming a famous exponent of the art. He was surgeon to the Maison Municipale de Santé and a member of the Academy of Medicine in Paris. Demarquay never married,

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and although born of poor parents, died a millionaire. He was a man of literary pursuits and possessed a very extensive library. He invented many surgical devices and published papers on surgery, pharmacology and hypnosis. Because of his contributions, he was made a Commandant of the Legion of Honour. He died in Longueval, having left Paris two weeks earlier, of cancer of the stomach on 21 June 1875, aged 60 years. FÉLIX DÉVÉ (1872-1951) Dévé was born at Beauvais, France on 10 November 1872. He studied medicine at Paris, and while there in 1900 began his long series of investigations on echinococcosis. In 1902 he went to Rouen and entered clinical practice. During the first World War he joined the French Army Medical Service. In 1924 he was appointed professor of clinical medicine in Rouen. He wrote three books and more than 300 articles on hydatid disease. He received much recognition for his work; he was a member of the Academy of Medicine in Paris and corresponding member for the academies in Rome, Lima and Buenos Aires and was an honorary professor of the Faculty of Medicine in Montevideo, Uruguay. He died suddenly in Paris on 1 September 1951 aged 78 years. (Plate 23) HAROLD ROBERT DEW (1891-1962) Dew was born in Melbourne, Australia on 14 April 1891. He studied medicine at the University of Melbourne and graduated in 1914. He immediately joined the Royal Army Medical Corps and served in Palestine and France. In 1920 he took the fellowship of the Royal College of Surgeons. In 1923 he was jointly appointed to the surgical staff of the Royal Melbourne Hospital and made assistant director of the adjacent Walter and Eliza Hall Institute of Medical Research. He wrote his classic monograph on echinococcosis in 1928 then two years later he was appointed to the Royal Prince Alfred Hospital as the first full-time professor of surgery in Australia by the University of Sydney. He became president of the Royal Australasian College of Surgeons in 1954-55, was knighted in 1955, and retired in 1956. He died on 17 November 1962, aged 71 years. (Plate 24) ANGELO DUBINI (1813-1902) Dubini was born, of a poor family, in Milan, Italy on 8 December 1813. He studied medicine at the University of Pavia and received his degree in 1837. He spent the next two years at the Milan Hospital (Ospedale Maggiore), during which time he discovered hookworm, then in 1840 was appointed an assistant in the Medical Clinic of the University of Pavia. In 1841 he travelled to Paris, London, Vienna and Heidelberg in order to study French, English and German. He took his microscope with him on his travels and expanded his interest in pathology. He returned to Milan and was appointed as an assistant at the Ospedale Maggiore. In 1847, he was promoted to become head of the pathological services in the hospital, and in 1849 was appointed a member of a commission for the study of rabies. In 1865, he became chief physician and head of the department of dermatology in the same hospital and remained there until his retirement in 1878. In his retirement, he wrote a cookbook which received popular acclaim, and another work on the keeping of bees. He spent the last few years of his life at Cassano Magnago where he indulged these hobbies. He fractured a femur and died in that place on 28 March 1902, aged 88 years. (Plate 25)

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FÉLIX DUJARDIN (1801-1860) Dujardin was born at Tours in France on 5 April 1801, the son of a watchmaker. He was a versatile and gifted person who applied his talents to a number of vocations, becoming an engineer, bookseller, then professor of geometry then of chemistry at the University of Tours from 1826. In 1823 he had married Clémentine Gregoire. He did not turn his attention to zoology until he was over 30 years of age. In 1839 he was appointed professor of geology in Toulouse but in the following year he was called to the chair of zoology and botany at Rennes; he remained there until his death. Being a person of catholic and wide-ranging interests, he made important contributions in a number of areas. He improved the performance of the microscope by developing a system of lenses beneath the stage which became the fore-runner of the modern condensor. He proved that sponges were animals and first observed the motility of leucocytes. He made a number of contributions to parasitology, the most notable being his book, Histoire naturelle des helminthes ou vers intestinaux. He spent the last few years of his life almost as a recluse, having been persecuted by his colleagues. He died in Rennes on 8 April aged 59. PAUL VAN DURME (1877-1947) Van Durme was born in Ghent, Belgium in 1877. He graduated in medicine from the University of Ghent in 1901 then studied at the Liverpool School of Tropical Medicine in England. He visited the centres of tropical medicine in London, Hamburg, Marseilles and Paris. He was appointed a professor of legal medicine in 1910 and professor of medicine in 1919. He retired in 1934, dying 13 years later in 1947. NEIL HAMILTON FAIRLEY (1891-1966) Fairley was born in Melbourne, Australia in 1891 and graduated in medicine from the University of Melbourne in 1915. Almost immediately, he joined the Army and was posted to Egypt with the Australian Expeditionary Force. While in the Middle East he made original observations on schistosomiasis, cerebrospinal fever, dysentery and typhus. He returned to Australia but in 1921 was appointed professor of tropical medicine in Bombay where he researched on tropical sprue. In 1924 he returned to the Walter and Eliza Hall Institute of Medical Research in Melbourne and worked on snake bite. In 1928 he went to London as physician to the Hospital for Tropical Diseases. During World War II he was commissioned a brigadier in the Australian Army and was appointed director of the Land Headquarters Medical Research Unit at Cairns, Queensland where he proved that mepacrine was a valuable prophylactic for malaria. After the war he was appointed to the chair of clinical tropical medicine in the University of London, but illness forced him to retire in 1948. He was knighted in 1950. He died in Sonning, England on 19 April l966 leaving a widow and three sons, one of whom became a well-known oncologist before he was killed by a terrorist bomb in London. (Plate 26) ERNEST CARROLL FAUST (1890-1978) Faust was born in Carthage, Missouri in the United States of America on 7 September 1890. He obtained a bachelor of arts degree from Oberlin College, Ohio in 1912 then went to the University of Illinois to study parasitology. He was awarded a master of arts degree in 1914 and obtained the doctorate of philosophy in 1917. He served as an instructor in the same institution for the next two years then went to the Peking Union

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Medical College in China in 1919. He remained there until 1928, rising to the rank of associate professor of parasitology. During this period he wrote classic monographs on clonorchiasis and schistosomiasis japonica. In 1928 he returned to the United States as professor of parasitology at Tulane University in New Orleans, Louisiana. In 1947 he was appointed professor of tropical diseases and hygiene in that institution. He is perhaps best remembered for his text on helminthology which became incorporated into Craig and Faust's Clinical Parasitology, still the bible of medical parasitology. He married Lola Swift by whom he had one daughter. He died in New Orleans on 2 November 1978, aged 88 years. ALEKSEJ PAWLOWICH FEDCHENKO (FEDTSCHENKO) (1844-1873) Fedchenko was born on 7 February 1844 at Irkutsk near Lake Baikal in Russia (USSR). After the death of his father, his mother sold the estate and moved to Moscow to facilitate the family's education. Following graduation, he taught at Moscow University then in 1866 became assistant dean of the student body. He married a fellow student, OA Armfeld, then travelled to Scandinavia where he collected insects and worked on the measurement of Finnish skulls. He studied for a short period with Leuckart then between 1868 and 1871 sojourned with his wife, in Turkestan, Samarkand and Tashkent in south central USSR. He visited Cobbold in London in 1873 then went to the French Alps. On 15 September 1873 he was killed, aged 29 years, in an accident while climbing Mont Blanc; he is buried in the English cemetery at Samoëns. The Fedchenko glacier in Turkestan is named after him. He was the first explorer of Central Asia and his work on the geology, flora and fauna of the region was published posthumously between 1873 and 1876 as Fedchenko's Journeys in Turkestan. (Plate 27) WINTHROP DAVENPORT FOSTER (1880-1918) Foster was born in the United States of America in 1880. He worked as a zoologist at the Bureau of Animal Industry, United States Department of Agriculture. He died in 1918. AKIRA FUJINAMI (1870-1934) Akira Fujinami (also known as Kan Fujinami) was born in the Aichi prefecture of Japan in 1870. He graduated from the Faculty of Medicine of the Tokyo Imperial University in 1895, then spent the next four years studying pathology in Germany. In 1899 he was appointed professor of pathology at the Imperial University of Tokyo and held this position until his retirement in 1930. In 1918 he was awarded the prize of the Imperial Academy of Japan for his researches in schistosomiasis. He was said to be a man of fine character and delightful personality and was admired by his students and colleagues. He died on 18 November 1934. (Plate 28) FRIEDRICH FÜLLEBORN (1866-1933) Fülleborn was born on 13 September 1866 at Kulmbach in (present day West) Germany. He studied medicine at Berlin University. He was a voluntary assistant in anatomy with Virchow and studied anthropology. In 1894 he went to North America to study the embryology of certain fishes on behalf of the Royal Prussian Academy of Science. Between 1896 and 1900 he was a medical officer in the German Colonial Army in German East Africa (now Tanzania, Uganda). During this period he studied the

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fauna and ethnology of the Nyasa and Kinga mountains. This was to lead to books on the Nyasa tribes and the people of Tanganyika (Tanzania). In 1901 he joined the newly-formed Institute for Naval and Tropical Diseases in Hamburg, Germany. In 1908-9 he led an expedition to the South Pacific to make anthropological observations. On the outbreak of World War I he was called up for military service and shortly afterwards was severely wounded at Mons in France. Thereafter he was appointed an expert on malaria and hygiene to the German troops operating in Macedonia. In 1920 he undertook research in the West Indies and South America while later travels carried him to East Africa, India and Japan. In 1930 he was appointed director of the Hamburg Institute and professor in the University of Hamburg. Fülleborn was a great raconteur and linguist, a fine cook and a persistent smoker. He married relatively late in life and died on 9 September 1933, aged 66 years. (Plate 29) GALEN (129-c.200 AD) Galen was born in 129 AD at Pergamum in Turkey, the son of Nicon, a landowner, architect and mathematician. Galen was taught in the local temple of Aesculapius, an institution for medical teaching and healing, then studied in succession in Smyrna, Corinth and Alexandria. He returned to Pergamum and began the practice of medicine, being appointed surgeon, amongst other things for the gladiators at their summer games. Subsequently, he became more interested in anatomy, experimental physiology and general medicine. Eventually, he was summoned to Rome by the emperor to become his personal physician. He was a prolific writer on medicine, philosophy, mathematics and grammar. Such was his authority, that he was quoted endlessly and with finality for the next 1400 years until the dawn of modern clinical investigation. (Plate 30) KONRAD GESNER (1516-1565) Gesner was born in Zurich, Switzerland on 26 March 1516. His father was a protestant artisan who fell at the battle of Kappel in 1531 in which the civic guard of Zurich under Zwingli were defeated by the Catholics. Subsequently, his friends sent him to study at their expense in Basle, Paris and Montpellier, where he read many subjects including classical and oriental languages, natural science and medicine. He was professor of Greek at the Lausanne Academy from 1537-1540, then was appointed the first town-physician of Zurich. He had a quiet nature and a constant struggle with financial difficulties but his energy was marvellous. He wrote on many subjects but his masterpiece was his immense four volume Historia animalium in which the animal world was arranged according to the principles of Aristotle. He died on 13 March 1565, aged 48 years, of the plague that ravaged Zurich in that year. JOHANN AUGUST EPHRAIM GOEZE (1731-1793) Goeze was born in Ascherleben, (East) Germany on 28 May 1731. He studied theology in Halle between 1747 and 1951 and was a preacher in Quedlinburg (East Germany). He became a hospital chaplain in 1755, then in 1762 he was appointed minister to the protestant church of St. Blas in Quedlinberg. In 1786 he was made dean of the cathedral in that city. Goeze acquired a microscope and made major contributions to the knowledge of natural history, particularly in the fields of entomology and helminthology. His great work on parasitic worms was submitted to the Academy of Science in Copenhagen in response to its call for communications on the origins of intestinal

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worms and received second prize (silver medal). He died in Quedlinberg on 27 June 1793 aged 62 years. GIOVANNI BATTISTA GRASSI (1854-1925) Grassi was born on 27 March 1854 in the small Italian town of Rovellasca in Lombardy. In 1872 he entered the Faculty of Medicine at the University of Pavia to both learn the practice of medicine and to embark upon a career in research. While still a medical student in 1878, he found that hookworm infection could be diagnosed by finding eggs in the faeces. Following his graduation, he turned to research rather than clinical practice. In 1880 Grassi won a scholarship to the University of Messina to study zoology. Subsequently, he went to Heidelberg and Würzburg in Germany to study under first, the anatomist, Gegenbauer, then the zoologist, Butschli. It was in Germany that he met his future wife, Maria Koenen. In 1883 Grassi returned to Italy and was appointed professor of zoology, comparative anatomy and physiology at the University of Catania. In 1895 he moved to the same chair in Rome. He and Ronald Ross had a great controversy over which of them first discovered that malaria was transmitted by Anopheles mosquitoes. Grassi has been eulogised as an "indefatigable (who) showed great enthusiasm and perseverance in his work and granted first-hand importance to originality, truthfulness, zeal and exactness" by some, but damned as a plagiarist, liar and fraud by others. In 1908 Grassi was appointed a Senator of the Kingdom of Italy for life. He died in Rome on 4 May 1925 aged 71 years and was buried in the small village of Fiumicino where he had conducted a malaria control campaign for the last seven years of his life. (Plate 31) WILHELM GRIESINGER (1817-1868) Griesinger was born on 29 July 1817 in Stuttgart, (present day West) Germany. He began his medical studies at Tübingen University in 1834 but, because he was a member of a banned student organization, had to move to Zurich in 1837 to complete his training. He began a practice at Friedrichschafen at Bodensee (Lake Constance) in 1839 then a number of appointments in Paris, Winnenthal (where he received his psychiatric training), and Stuttgart followed. In 1843 he returned to Tübingen. In 1845 he published a major textbook Die Pathologie und Therapie der psychischen Krankeiten (Pathology and treatment of psychiatric illness), which was to have a seminal role in neuropsychiatry. In 1847 he was appointed lecturer in pathology, materia medica and the history of medicine in Tübingen. In 1849 he was appointed professor of pathology and therapeutics at the University of Kiel. At this time, a political change of great importance occurred in Egypt; the francophile Viceroy, Mehemed Ali, died and his successor, Abbas, replaced Clot Bey and other French administrators and teachers with persons of German nationality. The triple post of Director of the Medical School, President of the Sanitary Council, and personal physician to the Viceroy was offered to Griesinger who went to Cairo in 1850. Although he made major contributions to the knowledge of hookworm disease and schistosomiasis, his time there was not altogether a happy one and he returned to Germany in 1852. Subsequently, he became a major force in psychiatry, especially in the linking of that discipline to physiology and internal medicine. He was professor of medicine in Zurich from 1860-1864, then devoted the last three years of his life to full-time psychiatric practice. He died on 26 October 1868 aged 51 years. (Plate 32)

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JOHN HARLEY (1833-1921) Harley was born in Shropshire, England in 1833. He received his medical education from King's College, London and qualified in 1858. He was elected an assistant physician to King's College Hospital in 1863 and held this post until he was appointed to the same position at St. Thomas's Hospital. He was promoted to full physician at the latter institution in 1879 and was created consultant physician in 1893. He also served on the staff of the London Fever Hospital. He received a doctorate of medicine from the University of London and was elected a fellow of the Royal College of Physicians in 1867. He expounded views on the origins of certain diseases that were entirely unwarranted by contemporary discoveries in pathology and bacteriology with the result that he lost the respect of his professional colleagues. His habit of smiling, bowing and shaking hands on every possible occasion with every acquaintance that he met became an easily caricatured joke. Outside of medicine, he was interested in botany and geology. He died in Sussex on 9 December 1921. PHILIPP JACOB HARTMANN (1648-1707) Hartmann was born in Stralsund in Pomerania, Prussia (now East Germany) in 1648. He studied letters, theology and medicine in Königsberg, East Prussia (now Kaliningrad, USSR) from 1669 and received his degree in the last subject in 1678. He travelled through France, Holland and England in order to further his knowledge. He returned to Königsberg and was appointed, successively, professor of history and of medicine. In 1685 he was elected to the Academia Naturae Curiosorum under the pseudonym of Aristotle II. He made many contributions to comparative medicine and wrote a history of anatomy. He died in Königsberg in 1707. WILLIAM HARVEY (1578-1657) Harvey was born at Folkestone in Kent, England on 1 April 1578, the son of a yeoman farmer. He was educated at King's School in Canterbury then entered Caius College, Cambridge, where he graduated with a bachelor of arts in 1597. He then travelled through France and Germany to Padua, Italy where he received a doctorate in arts and medicine in 1602. He then returned to England and received the degree of doctor of medicine from the University of Cambridge. In 1604 he married Elizabeth Browne but had no children. In 1607 he was admitted to the College of Physicians then in 1609 he was appointed to the staff of St Bartholomew's Hospital in London. In his Lumleian Lecture of April 1616, "Exercitatio anatomica de motu cordis et sanguinis in animalibus" (Study on the motion of the heart and blood in animals), he described the circulation of the blood; this work was not published until 1628. In 1851 he published his treatise on embryology, Exercitationes de generatione animalium (Studies on the generation of animals). Even though he was one of the greatest physiologists of all time, he was also a successful practitioner and was appointed physician to King James I and his son Charles I. He died near London on 3 June 1657, aged 79 years, probably from a stroke. (Plate 33) ERNST FRIEDRICH GUSTAV HERBST (1803-1893) Herbst was born in Göttingen in present-day West Germany in 1803. He was educated at the University of Göttingen and spent most of his professional life in that city. He died in 1893.

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HIPPOCRATES (c.460-375 BC) Hippocrates was born on the Greek island of Cos, the son and grandson of physicians, and was himself to be given the accolade of "Father of Physic". He rejected mysticism and emphasized the role of clinical observation in the study of disease. A large number of writings have appeared under his name but they probably represent the labours of many. Adams's translation, "The genuine works of Hippocrates", contains Prognostics, Aphorisms, First and third books of epidemics, Regimen on acute diseases, On airs, waters and places, On the articulations, On fractures, On wounds of the head, The oath, and The law. Hippocrates' lectures were said to be given under a plane tree in a village on the island of Cos. He was accorded honorary Athenian citizenship and is believed to have died in Thessaly. A marble bust of Hippocrates was found in 1940 near the ruins of Ostia Antica, the seaport of imperial Rome. (Plate 35) ISAO IJIMA (1861-1921) Ijima was born in Hamamatsu, Shizouka prefecture in Japan in 1861. He studied zoology at the University of Tokyo and graduated in 1882. He went to Germany for post-graduate studies, then returned to his own university where he became professor of zoology and director of the Marine Experimental Station at Misaki, Kanawaga prefecture. He was awarded the degree of doctor of science in 1892. He made many contributions to ornithology and the study of sponges. He published an Outline of Zoology in 1918 and is generally considered to be the father of Japanese parasitology. (Plate 36) CONSTANTIN JANICKI (1876-1932) Janicki was born in Moscow, Russia (USSR) in 1876, the son of a famous engineer. He began his studies at the University of Warsaw, Poland, but Russian domination was so oppressive to him that he went to Leipzig in 1894. Here he fell under the influence of Leuckart and studied there for four years. He then moved to Freiburg, Germany and finally to Basel, Switzerland where he received his doctorate in 1906. Following working in Grassi's laboratory in Italy for five years, he went back to Basel as privatdocent in 1911. In 1919 he returned to Warsaw to take up the post of professor of zoology. He committed suicide in 1932. (Plate 37) FUJIRO KATSURADA (1867-1946) Katsurada was born in Japan in 1867, the son of a samurai. He studied at Ishikawa Prefecture School of Medicine and was licensed in 1887. He then continued his education at the Faculty of Medicine of the Tokyo Imperial University. He spent several years in Germany and received the degree of doctor of medicine from the University of Freiburg in 1901. He was appointed professor of medicine at Okayama Medical College in 1903 and remained there until 1914. Subsequently, he became director of the Seamen's Institute in Kobe and director of the Japanese Hospital for Tropical Diseases. (Plate 38) KENJI KAWANISHI (1868-1927) Kawanashi (also known as Kasai) was born in Japan in 1868. He began the study of medicine at the Tokyo Imperial University but in 1889 was drafted into military service during the Sino-Japanese War. He then resumed his medical studies at Kyoto Imperial University. He remained in the army as a medical officer and was stationed in Taiwan, Manchuria, and Germany. In 1908 he received the degree of doctor of medicine. He

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became head physician of the South Manchurian Railway Hospital in Dairen, then was appointed the first director of the South Manchurian Medical School. COENRAAD KERBERT (1849-1927) Kerbert was a student in Amsterdam, Holland then undertook post-graduate studies with Rudolf Leuckart in Leipzig in present-day East Germany. In 1876 he wrote a dissertation on reptile skin, then in the next year was appointed as an assistant at the Zoology Laboratory in Amsterdam. He became a lecturer at the University of Amsterdam and chief curator of the Aquarium. In 1890 he succeeded CF Westerman (after whom he had named Distoma westermanni) as director of the Royal Zoological Society. MOHAMED KHALIL (1895-?) Khalil was born in Cairo, Egypt on 23 May 1915. He studied medicine at the Government Medical School in Cairo and graduated in 1918. He was appointed as a clinical assistant at the Kasr-el-Aini Hospital in Cairo in that year, then spent between 1920 and 1922 at the London School of Tropical Medicine. In 1922 he was appointed sub-director for parasitic diseases at the Public Health Laboratories in Cairo, then in 1925 he was made professor of parasitology at the Cairo Medical School. (Plate 39) HARUJIRO KOBAYASHI (1884-1969) After graduating from the Kyoto Imperial University in Japan, Kobayashi studied schistosomiasis japonica at the University of Tokyo. In 1916 he went to Korea where he made a number of original investigations on clonorchiasis, paragonimiasis, trichostrongyliasis and malaria. He published several books on parasitology, including an account of the parasites of Korea. He died in 1969. (Plate 40) SHIMESU KOINO (1897-1971) Koino was born in 1897 at Tomiyama-cho, Awagun in Chiba Province near Tokyo, Japan. He studied medicine at the University of Manchuria, graduating in 1920. He investigated plague then returned to the department of parasitology of the Keio University Medical School in Tokyo. In 1927 he joined the department of paediatrics in Keio University Hospital. He began private practice in pediatrics in 1929. He died in 1971. GOTTLOB FRIEDRICH HEINRICH KÜCHENMEISTER (1821-1890) Friedrich Küchenmeister was born on 22 January 1821 in Buchheim near Lausigk in Saxony, (present day West) Germany, the son of a protestant pastor. Initially, he was destined for the ministry and began the study of theology, but then changed to medicine which he studied first in Leipzig, then later in Prague. In 1846 he began the practice of medicine in Zittau (East Germany) and became particularly expert in the fields of obstetrics and gynaecology. In 1859 he moved to Dresden (East Germany) where he continued both his medical practice and his research; here he was given the title of "medicinalrat" or medical councillor. All of his experiments were done at his own behest and without the benefits and facilities of a university environment. He was a dynamic man of catholic interests. Parasitology was never the same after his demonstrations of the importance of experimentation. His experiences led him to write his famous textbook of parasitology. He introduced the operation of ovariotomy to Germany and displayed considerable ingenuity in inventing and modifying surgical instruments; perhaps the best

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known of these was an apparatus for plugging the nostrils in epistaxis. He was one of the first advocates of the official inspection of meat and meat markets. He investigated the propagation and treatment of cholera, and the frequency of consumption in Saxony. For some years he edited a journal of his own entitled Periodical of Epidemiology. He popularized the treatment of diphtheria with lime water, investigated the toxins of mushrooms and the grafting of fruit trees, and was an avid bee-keeper. His study was said to be littered with theological texts and he was a masterly exponent of the scriptures. He wrote papers on Luther's last illness and on the latter's famous hymn "A mighty fortress is our God". During the last fifteen years of his life he came much before the public eye as an ardent apostle of cremation; in Dresden in 1874 he began the practice of the placement of ashes in urns. He gave the appearance of being a rough person, but underneath he was said to have a heart of gold and, as a doctor, was much loved and respected. He died in Dresden on 30 April 1890, aged 69 years. As he wished, he was cremated at Gotha in the crematorium of which he was a founder. (Plate 41) CLAYTON ARBUTHNOT LANE (1868-1948) Lane studied medicine at St. Mary's Hospital in London, England and graduated with the degree of bachelor of medicine in 1893. He obtained a doctorate in medicine in 1895 and entered the Indian Medical Service, rising to the rank of lieutenant-colonel. He died in London on 2 January 1948. (Plate 42) EDWIN LANKESTER (1814-1874) Lankester was born on 23 April 1814 at Melton, in Suffolk, England. He was articled to a surgeon then studied medicine at University College, London between 1834 and 1837. He was appointed lecturer in materia medica and botany at St. George's Hospital Medical School in 1843 and was elected a fellow of the Royal Society in 1845. In 1850 he was made professor of natural history at New College, London. In 1862 he was appointed coroner for Central Middlesex, a post which he held until his death. He was a voluminous writer on aspects of natural history and, amongst other things, translated Küchenmeister's two volume text Animal Parasites from the German, and in an appendix to that work named the fluke now called Fasciolopsis buski. He died from diabetes and a carbuncle on 30 October 1874 aged 60 years. DANIEL LE CLERC (CLERICUS) (1652-1728) Le Clerc was born in Geneva, Switzerland in 1652, the son of a doctor. He studied in Montpellier and in Paris, France, then received the degree of doctor of medicine from the University of Valencia, Spain. He returned to Geneva and began to practise, but his great interest was in medical history, his History of Physick being published in 1696. He wrote a monograph in Latin on helminthology in 1715 which was translated to English as well as a monograph with Manget on anatomy. He became a councillor of state in 1702 and held this position until his death in 1728. (Plate 43) ANTONY van LEEUWENHOEK (1632-1723) Van Leeuwenhoek was born in Delft, Holland on 24 October 1632, the son of Philips Thoniszoon, a prosperous basket-maker. Antony took his surname (Lion's corner) from the house near the Leeuwenpoort (Lion's gate) at Delft owned by his father. As a boy he was sent to Amsterdam to receive a business training while he worked in the cloth trade. When he was 22 years old, he returned to his native town and began work as a

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shopkeeper. In 1660 he received a sinecure office with the municipal authorities as City Chamberlain of Delft. This employment provided him with ample leisure to indulge in his scientific interests. He taught himself the art of lens grinding and used simple biconvex lenses to magnify the world around him. It is said that, at his death, more than 400 microscopes and magnifying glasses were found. He was extremely jealous of his inventions and never sold or lent them to anyone, although he did allow visiting scientists to use them. He never received a formal scientific training and could not write or read Latin, the medium in which most natural philosophers of his day published their works. He communicated many of his findings in letters to friends and published many of his original observations in the Proceedings of the Royal Society of London, of which he became a foreign member in 1680. He made numerous observations of biological interest, discovering spermatozoa, erythrocytes, the capillary circulation, Infusoria and Rotifera in water, and was the first to demonstrate a parasitic protozoon when he found Giardia lamblia in his own stools. He married Barbara de May, the daughter of a merchant in Norwich, England in 1654, by whom he had five children. She died in 1666 then he married Cornelia, the daughter of a Calvinist minister, in 1671. He died in Delft on 26 August 1723 at the great age of 90 and lies buried in the Oude Kerk. (Plate 44) JOSEPH LEIDY (1823-1891) Leidy was born in Philadelphia in Pennsylvania, United States of America in 1823, the son of a prosperous hatmaker of German parentage. He began the study of medicine at the University of Pennsylvania and took the degree of doctor of medicine in 1844 with a thesis on the comparative anatomy of the eye of vertebrates. In 1845 he was appointed a prosector in anatomy then in 1853 he was made professor of anatomy. Shortly afterwards, the disciplines of zoology and comparative anatomy were added to this position. He published widely in a number of areas ranging from the structure of the liver to the fossil horse of America. Indeed, he became the father of palaeontology in the United States. In 1853 he advanced a theory of natural selection, anticipating Darwin by several years. He was a modest and retiring man, but popular with his students. In 1886 he was awarded the degree of doctor of laws by the University of Harvard. He died after a short illness in 1891. (Plate 45) ROBERT THOMSON LEIPER (1881-1969) Leiper was born at Kilmarnock, Scotland on 17 April 1881. He began the study of biology and medicine at the University of Birmingham but then transferred to Glasgow where he graduated with bachelor degrees in science, medicine and surgery in 1904. He obtained the degree of doctor of science from that University in 1911 and its doctorate of medicine in 1917. His interest in helminthology began soon after graduation. He joined the staff of the London School of Tropical Medicine in 1905 to found the department of helminthology. He visited the Gold Coast (Ghana) in 1905, worked with Looss in Egypt in 1907 and visited Uganda in the same year, worked in Nigeria in 1912 and went on an expedition to China and Japan in 1914. Between 1912 and 1914 he was Wandsworth Scholar at the London School. Following the outbreak of World War I, he was sent to Egypt in 1915 with the rank of lieutenant-colonel in the Royal Army Medical Corps to investigate the mode of transmission of schistosomiasis and advise on prophylaxis for the troops. In this task he was successful, finding the snail vectors of Egyptian schistosomiasis. Soon afterwards, he was appointed to the chair of hel-

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minthology in the University of London; he held this position until his retirement in 1946. He founded and edited the Journal of Helminthology and Helminthological Abstracts, was director of the Institute of Agricultural Parasitology at St. Albans, and made many other contributions to helminthology, including discovery of the insect vector of Loa loa. He was elected a fellow of the Royal Society in 1921 and was made a Companion of the Order of St Michael and St George (C.M.G.) in 1941. He married Ceinwen Jones in 1908 and had a son and two daughters. It has been said that he had an unpredictability that was the delight of his friends and the despair of his opponents. His biographers have written that he was a man of gentle voice and charm of manner who had a great sense of humour, but also remarked that he did not suffer fools gladly and that at times his criticisms could be acidulated. His dedicated and unparalleled career over half a century inspired a fierce loyalty among his countless students and colleagues. He died on 21 May 1969 aged 88 years. (Plate 46) NATHANIEL GOTTFRIED LESKE (1751-?) Leske was born on 22 October 1751 at Muskau in lower Lausitz. He studied in Leipzig then was appointed successively professor of natural history in 1775 then professor of economy in 1778 in the University of Leipzig.

KARL GEORG FRIEDRICH RUDOLF LEUCKART (1822-1898) Leuckart was born on 7 October 1822 in Helmstadt in Brunswick, (present-day West) Germany where his father was a business man. He began his studies in Göttingen in 1842 and graduated with a medical degree in 1845. In 1847 he was appointed a lecturer in zoology at Göttingen. In 1850 he became associate professor of zoology at Giessen and married soon after his arrival. He remained in Giessen until 1869 when he took the chair of zoology at Leipzig; in 1880 he established a new Zoological Institute which became famous. He made major contributions to the comparative anatomy and classification of many invertebrates but became attracted particularly to parasitic worms, perhaps through the influence of his uncle, FS Leuckart (1794-1843), who was professor of zoology in Freiburg. Much of Leuckart's original work is contained in his Die Parasiten des Menschen und die von ihnen herrührenden Krankheiten (Parasites of Man) which was partly translated into English. Among his important contributions were his observations on the life cycles of Trichinella spiralis, Fasciola hepatica and Strongyloides stercoralis and the recognition of Onchocerca volvulus. He attracted a large number of brilliant pupils to Leipzig, including Fedchenko, Janicki, Kerbert, Looss and Lutz. He was a helpful, warm-hearted and good-humoured man, and was universally praised by his colleagues and former students after his death in Leipzig on 6 February 1898, aged 75 years. (Plate 47)

TIMOTHY RICHARD LEWIS (1841-1886) Lewis was born at Llanboidy in Carmarthenshire in Wales on 31 October 1841. After leaving school at the age of 15, he was apprenticed to a pharmacist in Narbeth. Four years later he went to London as a dispenser in the German Hospital but also attended classes at University College between 1863 and 1866. He then went to Aberdeen and graduated in 1867 with the degrees of bachelor of medicine and master of chirurgie. In 1868 he was commissioned as an assistant surgeon in the Medical Department of Her

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Majesty's Army, being promoted to surgeon in 1873 and surgeon-major in 1880. Lewis and DD Cunningham, having received the highest marks for the British Army and Indian Medical Services, respectively, were sent to Germany for 3 months then to India to study the cause of cholera. He worked on this and other subjects in India from 1869 until 1883, usually in conjunction with Cunningham until the latter's appointment as professor of physiology in the University of Calcutta. Many of his findings were published as appendices to the Annual Reports of the Sanitary Commissioner with the Government of India. In 1879 he married and had two children. In 1883 he was appointed assistant professor of pathology at the Army Medical School, Netley, England. In 1886 he was recommended for election as a fellow of the Royal Society. Two weeks later, on 7 May 1886, he died at his home in Woolston in Southampton, aged 44 years, from pneumonia and septicaemia following an accidental wound which he received while performing a post-mortem examination. (Plate 48)

CARL LINNAEUS (1707-1788) Linnaeus, the first child of Nils and Christina Linnaeus, was born at Råshult in Sweden on 23 May 1707. His father came of peasant stock from the province of Småland and had no family name early in life, as was common with many rural people in that country. While at school, Nils Ingemarsson adopted the name Linnaeus after a great linden tree which was regarded as sacred and grew near his home. After much tribulation, Nils was ordained a minister in 1704 and appointed curate of Råshult in 1706. This permitted him to indulge himself in horticulture and a study of herbs, and he established a large garden filled with many rare and exotic plants. This interest and enthusiasm was transmitted to his son Carl and provided him with an opportunity for developing his powers of observation. One of his teachers, recognizing his talent for natural science, urged his family to allow him to study medicine rather than theology. In 1727 Linnaeus began to study medicine at the University of Lund, but in the following year he moved to Uppsala. There he secured patrons and, although not a graduate, obtained permission to lecture in botany and attracted large audiences. With financial assistance from his future father-in-law, a wealthy physician in Falun, he travelled to Holland and took the degree of doctor of medicine from the University of Harderwijk. He remained in that country for three years, publishing a number of works, including his Systema Naturae (1735), which brought him immediate fame. After visiting England and France, he returned to Stockholm where he practised as a physician until he was appointed to the chair of botany at Uppsala University in 1741. There Linnaeus devoted himself to teaching, the reorganization of the botanical gardens, and to the production of scientific works. He never attempted to formulate any elaborate theory of the phenomena of life, but conceived nature as being created by God for His honour and for the blessing of mankind. He was far more interested in systematics than in mechanisms and, even in the twelfth edition of his Systema Naturae, still averred that the universe consisted of the four ancient elements of fire, air, water and earth. Further, his systematic classification of the animal kingdom was less successful than his arrangement of the botanical world. Nevertheless, by establishing the concept of species, which he regarded as immutable, he laid down the foundations for the modern system of classification and he facilitated its implementation by developing the binary system of nomenclature, first for plants in 1753, then for animals in 1758. He became acknowledged throughout Europe as an authority on natural sciences. When his own

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country ennobled him, he took the name of von Linné. Illness progressively impaired his powers from the 1750's, then during the eighth decade of his life he was subjected to repeated strokes which dulled his intelligence and finally paralysed him entirely. He died in Uppsala on 10 January 1778 aged 70 years, and is buried in its cathedral. Following his death, there was an acrimonious dispute between his son, who had unfortunately been appointed his successor, and the rest of his family over his herbarium, library and correspondence. They were eventually sold to England where they were preserved by the Linnean Society which was founded for that purpose. (Plate 49) ARTHUR LOOSS (1861-1923) Looss was born at Chemnitz in Saxony, (present day East) Germany on 16 March 1861, the son of a local manufacturer. In 1880 he entered the University of Leipzig where he studied natural science for four years under a number of authorities, including Leuckart. He received a doctorate of philosophy in 1885 for his thesis on certain trematodes. He lectured at the University of Leipzig for some years and in 1889 presented a thesis on the role of phagocytes in the degeneration of the tadpole's tail as a prelude to his appointment as Privat-docent in the Faculty of Philosophy. In 1891 he married Elise Lohse, but remained childless. He visited Egypt in 1893 although he did not settle there until 1896 when he accepted an invitation from the government to remain in Cairo as professor of biology and parasitology, a post created especially for him in the Egyptian Government School of Medicine. He was particularly concerned with trematodes, but he made the major discovery of showing that hookworm larvae penetrated the intact skin. Looss remained in Cairo for 18 years until he was dismissed in November 1914 following the outbreak of World War I. He volunteered for military service and appears to have spent some time in Belgium as a captain. In 1919 a post was found for him as an assistant in the Zoological Institute at Giessen. In 1921 he became an honorary doctor of medicine of the University of Giessen. His dogmatic manner and acrid, controversial style brought him into conflict in turn with Railliet, Stiles, Manson, Leiper and Sambon, but in private life Looss was said to be a man of simple and lovable character who had many friends of many nationalities. He was an accomplished linguist and philatelist. In his later years he was troubled greatly with asthma and he died at Giessen on 4 May 1923 at the age of 62 years. (Plate 50)

GEORGE CARMICHAEL LOW (1872-1952) Low was born at Monifieth in Forfarshire, Scotland in 1872. He studied medicine at the University of Edinburgh, qualifying in 1897 and obtaining the degree of doctor of medicine in 1912. He was a resident at the Royal Infirmary in Edinburgh then went to London to study under Manson. In 1900 Low, together with LW Sambon and Signor Terzi, a well-known artist, lived for 3 months in a screened hut erected at Ostia near Rome, Italy, in order to demonstrate that malaria could be prevented by sleeping by night in a mosquito-proof house. In 1901 he travelled to the West Indies and British Guiana (Guyana) to study filariasis then in 1903 he went to Uganda with the Royal Society's Commission to seek the cause of sleeping sickness. Shortly afterwards he was appointed superintendent of the London School of Tropical Medicine, where he remained for the next 34 years. Together with Sir James Cantlie, he founded the (Royal) Society of Tropical Medicine and Hygiene in 1907. He was a keen ornithologist. In 1906 he married Elizabeth Nash but remained childless. He died at his home in London on 21

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July 1952, aged 79 years. (Plate 51) ADOLPHO LUTZ (1855-1940) Lutz was born in Rio de Janeiro, Brazil in 1855 into a family which had emigrated from Switzerland in 1849. He was the fifth of ten children and was taken to Switzerland when two years old. He studied medicine at Berne University where he graduated in 1878. He studied for short periods in Paris, Leipzig and London then in 1881 returned to Brazil and began to practise in São Paulo. In 1889 he went to Hawaii in charge of the leprosy colony on Molokai. It was there that he met his future wife, Ann Fowler, an English nurse; they were married in 1891 and had a son and a daughter. In 1892 he returned to São Paulo where he was appointed director of the Bacteriological Institute. In 1908 he became chief of the department of medical zoology of the Instituto Oswaldo Cruz in Rio de Janeiro where he remained until 1938 when he was forced to retire after a series of strokes and failing health. He died in 1940 following an attack of influenza. (Plate 52) JAMES FREDERICK PARRY McCONNELL (1848-1895) McConnell was born in Agra, India, the son of a Scot, James F McConnell, on 13 January 1848. He studied medicine at Aberdeen University and at St. George's Hospital and graduated with the degrees of bachelor of medicine and master of chirurgie with high honours in 1869. Subsequently he acquired a doctorate of medicine from that University. He became a member of the Royal College of Surgeons and in 1888 was elected a fellow of the Royal College of Physicians. In 1870 he joined the Indian Medical Service in Bengal where he served for the remainder of his life, rising to the rank of surgeon lieutenant-colonel. His first post was as house surgeon at the Calcutta Medical College and his last was as professor of pathology and physician at that same institution. He died in Calcutta on 24 August 1895 aged 47 years. STEPHEN MACKENZIE (1844-1909) Stephen Mackenzie was born on 14 October 1844 in Leytonstone, England, the seventh child of Stephen Mackenzie, a surgeon, and his wife, Margaret Frances, née Harvey. He began his medical training as an apprentice in Wellingborough then entered medical school at the London Hospital. He qualified as a member of the Royal College of Surgeons in 1869 but then continued his studies at the University of Aberdeen, graduating with the degree of bachelor of medicine and master of chirugie in 1873. He proceeded to the degree of doctor of medicine of that University in 1875 and became a member (1874) then fellow (1879) of the Royal College of Physicians. After a period in Berlin, he became assistant physician to the London Hospital, being in charge of the skin department in 1874, lecturer in pathology in 1877, physician and lecturer in medicine in 1886 and consulting physician in 1905. In addition, he was physician to the London Ophthalmic Hospital (Moorfields) from 1884-1905 and was one of the first to make routine use of the ophthalmoscope. He became an authority of diseases of the skin and of the blood. He married Helen Dulley, the daughter of the doctor with whom he had served his apprenticeship, and had two sons and a daughter. He was knighted in 1903 as had been his older brother Morell who was also on the staff of the London Hospital. Stephen Mackenzie developed chronic lung disease in middle age which greatly restricted his activities and he was forced to spend the winters in Egypt. He died at Dorking in Surrey on 3 September 1909 aged 64 years.

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MARCELLO MALPIGHI (1628-1694) Malpighi was born at Crevalcore near Bologna, Italy where his father was a small landowner, in 1628. At the age of 17, he began the study of philosophy and medicine at the University of Bologna. He graduated in 1653 and remained in Bologna for several years. In 1656 he accepted the chair of theoretical medicine (equivalent to physiology) in Pisa then in 1662 moved to the University of Messina. In 1666 he returned to Bologna. He made many contributions to medicine and science including observations on the circulation of blood through the lungs, the structure of the kidney (Malpighian corpuscles) and the liver, recognition of lymphadenopathy, and studies of the anatomy of fishes and silkworms. He maintained a regular correspondence with the Royal Society in England and was elected a fellow in 1668. In 1691 he went to Rome as personal physician to Pope Innocent XII. He died there in 1694, his body being subjected to post-mortem examination at his own request; it disclosed a scarred kidney, a small bladder calculus, left ventricular hypertrophy, and an old cerebral infarction. (Plate 53) PATRICK MANSON (1844-1922) Manson was born on 3 October 1844 in Oldmeldrum, Aberdeenshire in Scotland, the second son of nine children, his father being laird of Fingask and manager of the local branch of the British Linen Bank. At school, he was said to be studious but not brilliant and fond of cricket, fishing and carpentry. At the age of fourteen he was apprenticed at the ironworks of his mother's relatives, Messrs Blaikie Bros. in Aberdeen, but developed curvature of the spine and paresis of the right arm so was committed to bed for five months, during which time he studied natural history. In 1860 he entered the medical course at the University of Aberdeen and graduated with the degrees of bachelor of medicine and master of chirurgie in 1865. In 1866 he was assistant medical officer at the Durham Lunatic Asylum in England and during this time wrote a doctoral thesis entitled A peculiar affection of the internal carotid artery in connexion with diseases of the brain. Later that year he joined the Chinese Imperial Maritime Customs and was posted to Takao, Formosa (Taiwan) where his duties were to inspect ships at port, treat crews, maintain a meteorological record, attend the native missionary hospital and conduct a private practice. In 1875 he went on leave to England and married Henrietta Isabella Thurburn, by whom he had two sons and three daughters. On his return to the Orient, he was posted to Amoy in China. Despite a lack of professional and literary contact, Manson carried out many important helminthological studies while in Amoy; he observed the development of Wuchereria bancrofti microfilariae in mosquito intermediate hosts, found periodicity of microfilaraemia in the blood, discovered Spirometra mansoni and was associated with the recognition of Paragonimus westermani. He went on leave to Britain in 1882 then moved to Hong Kong in 1883. He took a leading part in the foundation of the Hong Kong College of Medicine for the Chinese and was appointed its Dean in 1887. In 1889 he returned to England and commenced practice in London the following year. In 1891 he discovered the microfilariae of Loa loa and of the worm now known as Mansonella perstans. He was appointed physician to the Albert Dock Hospital of the Seamen's Hospital Society in 1892 and medical adviser to the Colonial Office in 1897. Shortly afterwards he described Filaria ozzardi, was intimately associated with Ronald Ross between 1894 and 1898 in the discovery of the mosquito transmission of malaria, founded the famous London School of Tropical Medicine in 1899 and drew attention to the lateral spines of

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the eggs later recognized as Schistosoma mansoni in 1902. In 1898 the first edition of his Manual of tropical diseases appeared; successive editions have continued to appear down to the present day. Manson was the first president of the Society of Tropical Medicine and Hygiene (now the Royal Society) and has been acclaimed frequently as the "father of tropical medicine". He was made a Companion of the Order of St Michael and St George (C.M.G.) in 1900 then was knighted in 1903. He was elected a fellow of the Royal Society in 1900 and received honorary doctorates from the Universities of Aberdeen (LL.D., 1886) and Oxford (D.Sc., 1904). For the last thirty years of his life he was affected by recurrent attacks of gout. Manson was, by all accounts, a most impressive man in appearance, intellect and personality who was universally mourned after his death in London on 9 April 1922 at the age of 77 years. (Plate 54) YONEJI MIYAGAWA (1885-1959) Miyagawa was born in Japan in 1885. He graduated in medicine from the Tokyo Imperial University in 1917 then was an assistant for four years at the Hospital Clinic. He then transferred to the Government Institute for Infectious Diseases. In 1921 he was appointed clinical director to the hospital of the Institute, then in 1927 he was made professor of medicine at the University of Tokyo. In 1934 he became director of the Government Institute for Infectious Diseases. (Plate 55) KEINOSUKE MIYAIRI (1865-1946) Miyairi was born in Nagano-Ken, Japan in 1865. He studied medicine at the Tokyo Imperial University and graduated in 1890. He worked in public health for a number of years then was sent to Germany between 1902 and 1904. Upon his return to Japan, he was appointed professor of Hygiene at the Fukuoku College of Medicine of the Kyoto Imperial University. (Plate 56) GIOVANNI BATTISTA MORGAGNI (1682-1771) Morgagni was born in Forli, Italy on 25 February 1682. He studied medicine in Bologna where he graduated in 1801. He remained in Bologna until 1707 when he moved to Venice. In 1909 he returned to Forli and practised medicine with great success. At the age of 29 in 1711 he was elected to the chair of theoretical medicine (equivalent to physiology) at Padua then four years later he was appointed professor of anatomy in the same University, a position which he was to hold for over 50 years. He was a scholar, teacher, physician, philosopher, medical historian and pathologist. He published widely but his greatest work was De sedibus et causis morborum per anatomen indagatis (The seats and causes of diseases, investigated by anatomy) which appeared when he was 79 years old; it summarized a lifetime study of clinical observations and of pathological studies. Morgagni was the founder of the discipline of pathological anatomy. He died at Padua on 5 December 1771, aged 89 years. (Plate 57) OTTO FREDERIK MÜLLER (1730-1784) Müller was born on 2 March 1730 in Copenhagen, Denmark, where his father was a musician. Although he grew up in poverty, he was able to study theology then jurisprudence at the University of Copenhagen by working as a tutor for certain aristocratic families. During visits to their estates he became interested in natural history and acquired a collection of insects. While tutor of a young count, he journeyed through

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Europe, increasing his knowledge and widening his collections. Upon his return to Denmark, he married into money and thereafter was able to devote himself to scholarly pursuits until his death at the age of 54 years in Copenhagen on 26 December 1784. He was generally regarded as an amiable, kind-hearted but somewhat vain man.

MASATOMO MUTO (1886-1967) Masatomo Muto (also known as Shochi Muto) was born in Yamanashi prefecture, Japan in 1886. He studied medicine at the Aichi Prefectural College of Medicine, graduating from there in 1913. He studied pathology in Kyoto and later became professor of pathology at Aichi University. He died in 1967. (Plate 58) KOAN NAKAGAWA (1874-1959) Nakagawa graduated in 1894 from the department of medicine, Fourth High School (which was the predecessor of the Kanazana Medical College). He practised medicine in Tokyo, Japan until 1904 when he entered the medical service of the Formosan (Taiwanese) Government. By 1926 he was chief medical officer to the Government and director of the largest hospital on the island. He died in 1959. (Plate 59) BERNHARD NAUNYN (1839-1925) Naunyn was born in Germany in 1839, the son of a well-to-do Berlin burgomaster. He apparently suffered from hydrocephalus as a child and did not learn to speak until he was four years of age. He began his university training at Bonn, intending to prepare for the law. He turned his attention to physics and chemistry, however, and in 1860 returned to Berlin to begin the study of medicine. In 1862 he presented his inaugural thesis for the degree of doctor of medicine on the development of Echinococcus in the dog. After several early appointments, he joined the department of medicine at universities in Dorpat (1969), Bern (1871), Königsberg (now Kaliningrad) (1872), Strasbourg (1888) and retired to Baden-Baden in 1904 as professor emeritus. He was recognized as one of the great clinical teachers in Germany. He made major contributions to the understanding of diabetes mellitus, but his interests were catholic and he wrote on many clinical subjects, especially the nature of jaundice and the formation of gallstones. He made little attempt to develop a private practice, preferring instead to devote his great energies to the furthering of the understanding of diseases which could be studied in animals and by quantitative chemical procedures at the bedside and in the experimental laboratory. He died in 1925. (Plate 60) ALEXANDER von NORDMANN (1805-1866) Von Nordmann was born of a Germanized Finnish family in Wiborg, Finland in 1805. He studied at Åbo (now Turku) then went to Berlin where he became a pupil of Rudolphi. While in Berlin, he wrote Mikrographische Beiträge which dealt chiefly with parasitic crustaceans but which also considered certain parasitic trematodes. Following this he was called to a chair in Odessa where he investigated the living and fossilized world of South Russia. In 1849 he was appointed a professor in the University of Helsingfors (Helsinki) and he died there in 1866. LOUIS ALEXIS NORMAND (1834-1885?) Normand was born on 7 September 1834 at Clermont in Argonne, France, the son

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of a music teacher. He enrolled in the Naval Medical School and became successively a surgeon, third class (1855), surgeon second class (1861), physician first class (1865) and principal physician (1878). His first appointment in 1855 was in the Naval Hospital (Hôpital de la Marine) in Toulon. Between 1855 and 1880 he served on 20 warships. He had 20 periods of service on land including at Toulon, Cherbourg, Paris, Marseille, Rochefort and Lorient. He was made a Chevalier de la Légion d'Honneur (knight of the legion of honour) in 1863. He served with distinction against two epidemics of yellow fever on the Normandy and the Massena and took part in campaigns in the Crimea, Italy and Mexico. He retired at his request in 1884 while based at Lorient and is thought to have died in 1885. JOHN O'NEILL (1848-1913) O'Neill was born on 31 July 1848. He undertook his medical studies at Queen's College in Cork, Ireland, graduating with the degrees of doctor of medicine and master of chirurgie in 1870. In 1872 he entered the Royal Navy, serving in the Ashanti War of 1873-1874. On 30 September 1875 he joined the Indian Medical Service as a surgeon, being promoted to surgeon-major in 1887 and surgeon lieutenant-colonel in 1895. Most of this period was spent in civil service in the Punjab Sanitary Service. In 1883 he led a team of surgeons from the Bengal Army that was sent to Egypt during the cholera outbreak of 1883. He retired from the Indian Medical Service in 1896. He died in England on 15 October, 1913, aged 65 years. RICHARD OWEN (1804-1892) Owen was born at Lancaster, England on 20 July 1804, the son of a West Indies merchant who died while his son was still an infant. He was apprenticed for four years to a doctor in Lancaster then matriculated as a medical student at the University of Edinburgh in 1824. He left Edinburgh prematurely, however, not taking his degree. He became a prosector for surgical lectures at St Bartholomew's Hospital in London and two years later became a member of the Royal College of Surgeons. Although he set up in practice in 1826, his first love was anatomy and in the same year he became assistant conservator of the Hunterian museum of the Royal College of Surgeons. At around the same time, he also became lecturer on comparative anatomy at St Bartholomew's Hospital. In 1836 he was made Hunterian professor of anatomy and physiology at the College. In 1856 he resigned to become the first superintendent of the natural history department of the British Museum, and oversaw its transfer to new premises in South Kensington. He became famous in the eyes of the British public for his work on fossils. Owen attacked Darwin in 1860 over the theory of evolution, but he defended creationism in terms so ambiguous that no-one understood him. He was knighted in 1884, having retired in the previous year to a residence in Richmond Park that had been donated by Queen Victoria. A biographer has recorded that he was a tyrant and a prima donna possessed of deviousness, duplicity and ambiguity. He died in London in December 1892, aged 88 years. (Plate 61) ALBERT TRONSON OZZARD (?-1929) Ozzard became a member of the Royal College of Surgeons in 1886 and a licentiate of the Society of Apothecharies in the following year. He joined the Colonial Medical Service and spent 40 years from 1887-1927 in British Guiana (Guyana) holding various posts including district medical officer and resident surgeon to the Suddie and George-

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town Public Hospitals. However great the demands of work, he always found time to call in the aid of his microscope in the diagnosis of obscure cases. He lived a strenuous life in a tropical climate, broken by attacks of grave illness. His last work was the investigation of a severe epidemic of malaria in the upper reaches of the Demerara River. Unfortunately he contracted the infection and he remained in poor health until his death on 1 February 1929, leaving his widow, daughter, and two sons. JAMES PAGET (1814-1899) Paget was born at Great Yarmouth in Norfolk, England in 1814, the eighth child of the 17 children of Samuel and Sarah Paget. His father was a brewer and shipowner and mayor of the town. In 1839 he was apprenticed to Mr Charles Costerton, a surgeon in Yarmouth. In 1834 at the age of 21 he entered St. Bartholomew's Medical School in London then in 1836 he became a member of the Royal College of Surgeons. The next few years were very difficult for him financially; he was curator of St. Bartholomew's museum and did much writing including being sub-editor of the Medical Gazette and translating medical articles from German, French, Dutch and Italian. In 1839 he nearly died of typhus. In the same year he was appointed demonstrator in morbid anatomy then in 1841 he became surgeon to the Finsbury Hospital. From 18431851 he was warden of St. Bartholomew's College. In 1844 he married Lydia North, the daughter of an Anglican minister. In 1847 he was appointed assistant surgeon to St. Bartholomew's Hospital, having been made a fellow of the Royal College of Surgeons when the fellowship was instituted. From 1847-1852 he was professor of human anatomy and surgery. He was appointed surgeon to St. Bartholomew's and kept that post until he resigned in 1871 following a near fatal attack of cellulitis which left him weakened. In that year he was knighted. He described Paget's Disease of the Nipple in 1874 and osteitis deformans (Paget's Disease of Bone) in 1877. He was president of many learned societies. He died after two years of enfeebling illness on 30 December 1899, aged 85 years. (Plate 62) PETER SIMON PALLAS (1741-1811) Pallas was born in Berlin in Germany on 3 October 1741, the son of a doctor. He studied medicine at the universities of Halle, Göttingen and Leiden. He received his degree from the last university in 1760 with a thesis on intestinal worms. He then spent some years in Holland and England working on zoological collections from the tropics. In 1767 he was invited by the Russian government to take part in an expedition which was being sent to explore Siberia. He spent six years from 1768-1774 travelling in that region, then went to St. Petersburgh (now Leningrad) where he worked, as professor of natural history, on the immense quantity of scientific material that he had brought back with him. In 1793 he was sent to explore the Crimean district which had just then become a part of Russia and he stayed there for a long time living on an estate that the Empress Catherine II had given him. Pallas was also an accomplished linguist and geologist. Finally, he moved back to Berlin in order to be in closer touch with the scientific world and he died there on 20 Septemer 1811, aged 69 years. (Plate 63) LOUIS PASTEUR (1822-1895) Pasteur was born at Dole in Jura, France on 22 December 1822, the son of a tanner and a retired sergeant in Napoleon's Army. He studied at the University of Besançon, where he received the degree of bachelor of arts in 1842. He continued his education

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in the physical sciences in Paris at the École Normale Supérieure, from which he received a doctorate of philosophy in 1848, and at the Sorbonne. In 1849 he was appointed professor of physics at the Lyceum in Dijon. In 1852 he moved to Strasbourg as professor of chemistry. In 1854 he became professor of chemistry and dean of the Faculty of Sciences in Lille. It was here that he studied fermentation and showed that yeast cells were required for the production of alcohol. In 1857 he was recalled to Paris to direct the scientific studies of the École Normale. It was during this period that he established the causal relationship of micro-organisms with infectious diseases. In 1863 he was professor of geology and chemistry at the École des Beaux Arts, then from 1867 to 1899 he was professor of chemistry at the Sorbonne. When only 46 years of age in 1868 he had a stroke which left him partially paralysed on one side of his body, and with impaired speech. As the years passed, he became more interested in infectious diseases, identifying Staphylococcus aureus in boils and Streptococcus pyogenes fever, and developed a vaccine against rabies. In 1888 the Pasteur Institute was opened as a monument to Pasteur funded by public subscriptions. He died seven years later on 28 September 1895, aged 72 years, at the Chateau Villeneuve-l'Étang near Paris. (Plate 64) EDOARDO PERRONCITO (1847-1936) Perroncito was born on 1 March 1847 at Viale d'Asti in Italy. He studied at the University of Turin and received a degree in veterinary medicine in 1867. He was appointed professor of veterinary pathological anatomy in the University of Turin in 1874 and remained there until his retirement 48 years later in 1922. He studied a variety of parasites, particularly hookworm, Taenia saginata, Echinococcus and Trichinella. After he left the University, he served as director of the International Museum for the study of bees and wine-making. He died in Pavia, Italy on 4 November 1936, aged 89 years. (Plate 65) MANOEL AUGUSTO PIRAJÁ DA SILVA (1873-1961) Pirajá da Silva was born in the town of Camamn near Bahia, Brazil in 1873. His early education was undertaken in Salvador then he studied medicine at the University of Bahia. After a period of private practice he was appointed professor of clinical medicine in the University of Salvador in 1902. A few years later he was appointed professor of parasitology in the medical school in Bahia, where he remained until his retirement in 1935. His interests were wide-ranging and in addition to parasitology he studied a variety of microbiological and botanical problems. He died in 1961. FELIX PLATTER [PLATERUS] (1536-1614) Platter was born in Basel, Switzerland, the son of a well-known printer in October 1536. After receiving a classical education, he began the study of medicine in Montpellier, France in 1552 and graduated in 1556 as a bachelor of medicine. He then toured France and Germany before returning to Basel where he conducted a public dissection and received the degree of doctor of medicine in 1557. In 1571 he was appointed to the chair of the practice of medicine, then his election to the position of city physician made him overseer of the public health and director of the city hospitals. In this capacity, he displayed exceptional courage during successive outbreaks of plague. He sponsored a botanical garden and established chairs in anatomy and botany at the University in Basel. He was a prolific author on medical subjects, proposed a classification of psychiatric disorders (unlike most of his contemporaries, he refused to consider mental disturbances

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to be the work of demons), and described cretinism, amongst many other observations. He died in Basel on 28 July 1614, aged 77 years. (Plate 66) FRANZ PRUNER (1803-1882) Pruner was born on 8 March 1803 at Pfreimdt in Oberfalz, Germany, the son of a civil servant. He studied medicine in Munich from 1826, graduating in 1830. He travelled to Paris then in 1832 was appointed professor of anatomy and physiology in Cairo, Egypt. Two years later he became the director of the Military Hospital in Esbegyeh near Cairo then subsequently director of the Kasr-el-Aini Central Hospital in Cairo where he was also professor of ophthalmology. He died on 29 September 1882, aged 79 years. (Plate 67) BRAYTON HOWARD RANSOM (1879-1925) Ransom was born in Iowa, United States of America in 1879. He was educated at the University of Nebraska from where he received the degree of doctor of philosophy in 1908. In 1902 he moved to George Washington Medical School in Washington, D.C. He then joined the Bureau of Animal Industry, United States Department of Agriculture, becoming chief of the zoology division in 1906. He was a reticent person and fastidious about his appearance. He died in 1925. (Plate 69)

WILLIAM HENRY RANSOM (1823-1907) Ransom was born at Cromer, England on 19 November 1823, the son of Henry Ransom, a master mariner. He went to school in Norwich, then after an apprenticeship with a doctor at King's Lynn, studied at University College, London where he graduated with the degree of bachelor of medicine in 1848. After travelling through France and Germany on a study tour, he settled in Nottingham in 1850 and became physician to the General Hospital between 1854 and 1890. During this period he gained the degree of doctor of medicine from the University of London and was elected a fellow of the Royal College of Physicians in 1869. In 1860 he married Elizabeth Branwell by whom he had four sons and one daughter. During the early years of his practice, he devoted much of his spare time to studying the embryology of fishes and the development of galls in plants; for this work he was elected a fellow of the Royal Society in 1870. He died in Nottingham on 16 April 1907 at the age of 83 years. (Plate 70) FRANCESCO REDI (1626-1697) Redi was born at Arezzo, Tuscany in Italy on 18 February 1626, the son of a doctor. When he was a boy he was educated in the Jesuit schools then he took the degrees of doctor of medicine and doctor of philosophy from the University of Pisa in 1647. He spent the next five years in travelling, studying languages, and writing poetry. He became an intimate of the court of the Grand Duke of Tuscany at the age of 26, but was not made "medico primo" until 1666 when his father died. He was a wise and skilful physician and had a healthy scepticism about the value of many of the therapeutic agents then available. His greatest work, however, lay in other directions. He was a great man of science and a brilliant investigator. He was the first to experiment with snake venom, finding that it was innocuous by mouth but toxic when applied parenterally. He proved that worms in rotting meat arise, not in consequence of putrefaction, but from eggs laid

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by flies on the meat. Some of Redi's experiments were inconclusive and he accepted that certain intestinal worms and gall-flies may arise by spontaneous generation. According to his translator, Bigelow, his "constant friendship for the Jesuits must have had a maleficent effect on (his) mind, as it exacted blind faith and put a limit to his logic". Redi never married. During the last nine years of his life he suffered much from epilepsy, and his death occurred suddenly on the night of 28 February 1697 when he was with the court at Pisa. He was accorded a public funeral and was buried in the church of San Francesco at Arezzo, aged 71 years. (Plate 71) RODOLFO ROBLES (1878-1839) Robles was born in Quezaltenago in Guatemala in 1878. Most of his schooling was undertaken in Guatemala but he spent a brief period in California, United States of America. He studied medicine in France, graduating in 1904. Here he came under the influence of the famous French parasitologist, Émil Brumpt. He returned to his home town to practise but in 1911 moved to Guatemala City where he carried on a private practice while holding various positions in the Faculty of Medicine. He died in 1939. JOHANNES GEORGE ROEDERER (1726-1763) Roederer was born in Strasbourg, France in 1726. He studied medicine in Paris, graduating in 1750. Subsequently he studied in England and Holland. He returned to Strasbourg as an obstetrician. In 1754, he was appointed professor of obstetrics at the University of Göttingen in (West) Germany. He died in Strasbourg in 1763. CARL ASMUND RUDOLPHI (1771-1832) Rudolphi was born in Stockholm, Sweden of German parents on 14 July 1771. His father was a schoolmaster who later became a pastor near Stralsund in the part of Pomerania which was then within the Swedish kingdom (now East Germany). He studied at Greifswald University where he took the doctorate of philosophy in 1793. He then studied medicine in Jena, Dresden, Erlangen and Göttingen, then presented his thesis entitled Sur les vers intestinaux for the degree of doctor of medicine at Griefswald. In 1801, having finished a course at the Berlin Veterinary School, he was appointed a professor in the Veterinary Institute in Griefswald. He was appointed professor of medicine at that University in 1808, then was called to Berlin as professor of anatomy and physiology in 1810. Here he founded the Berlin Zoological Museum and under his influence Berlin became a great centre for the study of human and comparative anatomy. He could never persuade himself to perform vivisections, but laboured hard for the abolition of the mysticism that natural philosophy had introduced into biology. He made important contributions in three main areas - parasitology, comparative anatomy, and physiology. His first parasitological opus, Entozoorum, sive vermium intestinalium historia naturalis, appeared between 1808 and 1810, then his Entozoorum Synopsis was published in 1819, but his most important work may have been his textbook on physiology, Grundriss der Physiologie, which occupied his old age and was still unfinished at his death. Rudolphi married twice, first to his cousin, Friederike Eleonore Wilhelmi, by whom he had two daughters. She died in 1801, then he later married Charlotte Friederike Wilhelmie Meyer, the eldest daughter of the Burgomaster of Greifswald. After his second wife died in 1821, Rudolphi's own health became poor and he died in Berlin on 29 November 1832, aged 61 years. (Plate 73)

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LOUIS WESTENRA SAMBON (1866-1931) Sambon was born in London, England in 1866, the son of an Englishwoman and a Frenchman. He received his preliminary medical training at St. Bartholomew's Hospital in London but then went to the University of Naples where his father had Italian relations. He graduated from there with the degree of doctor of medicine in 1891. While still a student in Naples, he worked through a terrible cholera epidemic which afflicted the city; for this service he was decorated by both the French and Italian governments. He began his professional career as a gynaecologist in Rome, but the lure of England proved too strong and he went to London, much against the wishes of his father. There, he met Manson and a strong friendship sprang up between them. He nearly ruined his career at the outset by publishing an article on acclimatization in which he held, contrary to universal opinion at the time, that parasites, and not the climate, killed the white man in the tropics. He was eventualy vindicated in this matter, but time did not deal so kindly with his attempts to prove that pellagra was caused by an insect-borne parasite, or in his beliefs concerning the parasitic nature of cancer and in the existence of cancer houses and cancer streets. Nevertheless, he was an accomplished epidemiologist and, according to a biographer, a warm-hearted and courteous man. He died suddenly in Paris on 31 August 1931 at the age of 65 years. (Plate 75) CARL THEODOR ERNST von SIEBOLD (1804-1885) Von Siebold was born on 16 February 1804 at Würzburg, (present day West) Germany, the son of Adam Elias von Siebold, a famous obstetrician who was later to found the Lying-in Hospital in Berlin. He studied medicine at Göttingen and Berlin and took his degree from the latter university in 1828. After the death of his father he had financial problems and practised medicine for some years at Heilsberg, East Prussia (now Lidzbark, Poland). In 1831 he married Fanny Nöldechen; she died in 1854 and in the following year he married her younger sister, Antoynie. In 1834 went to Königsberg (Kaliningrad) but after a short period he became director of the midwifery school in Danzig where he remained for six years. During this period he devoted much of his spare time to zoological studies and the collection of insects and helminths. In 1836 he discovered ciliated epithelium in man when examining an extirpated nasal polyp. In 1840 he was called to Erlangen as professor of zoology, comparative anatomy and veterinary medicine. In 1845 he established the class Protozoa which he characterized as unicellular animals. In the same year he moved to Freiburg as professor of zoology, comparative anatomy, physiology and special physiology. There he founded in 1848, with Albert Kölliker, the journal Zeitschrift für wissenschaftliche Zoologie. In 1850 he became professor of physiology and director of the Physiological Institute at Breslau, Germany (now Wroclaw, Poland), then moved to Munich where a chair of physiology and comparative anatomy was established in 1856. After some years of ill-health with his mental faculties gradually deteriorating, he died in Munich on 7 April 1885, aged 81 years. (Plate 76) PROSPERO SONSINO (1835-1901) Sonsino was born on 6 August 1835 at Tunis, Tunisia of Italian parents. While still young he went with his family to Italy then studied medicine at the University of Pisa. Between 1860 and 1864 he practised in Turkey and other parts of Asia minor. He then settled in Florence, working in public health and editing a medical journal called Imparziale. In 1873 he went to Cairo, Egypt and studied aspects of parasitology at the

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Khedivial Laboratory. He worked heroically during the cholera epidemic of 1882, being one of the few Europeans who refused to leave Cairo. He left Egypt in 1885 and travelled as a ship's doctor to South America and eastern Asia. He then returned to Africa to study schistosomiasis and in 1897 he once more visited Egypt. He finally retired to Montepiano in Italy, where he died on 19 November 1901, aged 66 years. (Plate 77) LAZZARO SPALLANZANI (1729-1799) Spallanzani was born in Scandiano in northern Italy on 12 January 1729, the son of a lawyer. He attended the Jesuit College at Reggio where he was ordained a priest; he was eventually made an abbott. He then studied law at the University of Bologna but his interest turned to science and he became a brilliant investigator in geology, biology and experimental physiology. He studied the Infusoria with the microscope and rejected the theory of spontaneous generation. These investigations led to a chair in natural history at the University of Pavia in 1769. His interests were catholic and his investigations widespread. He made many contributions to medical science including observations on the digestive power of saliva and gastric juices and he discovered the passage of blood through the capillaries. He died in Pavia on 11 February 1799, aged 70 years. (Plate 78) DIMTRY F SSINITZIN (1871-1937) Ssinitzin was born in Symferolpol in the Crimea in the Russian Empire (now Simferopol, USSR) in 1871. He studied at the University of Warsaw, which was then part of Russia, and later received his doctorate in zoology from the University of St. Petersburgh (Leningrad). He was appointed a professor in Shanjasky University in Moscow, then became Chancellor of Nijny-Novgorod University from 1918-1919. Political change forced him to leave the USSR in 1923 and he sought asylum in the United States of America at the age of 52 years. He lived in poverty for some time but then obtained employment as a technician at the American Museum of Natural History. Later, he became an associate zoologist at the Bureau of Animal Industry in Washington, D.C. Finally, he moved to California where he engaged in private research. He died in 1937. JOHANNES JAPETUS SMITH STEENSTRUP (1813-1897) Steenstrup was born, the son of a minister, at Vang in Jutland in Denmark on 8 March 1813. He studied in Copenhagen then became a schoolmaster for some years. He took no university degree but undertook journeys of exploration in Ireland, Scotland, Jutland and Norway in which he gathered material for his courses on mineralogy and botany at the Soro Academy where he taught for six years. In 1842 he published two books which brought him fame; the first was a classic work on Scandinavian bog research and the second was his Alternation of Generations (Om Fortplantning og Udvikling gjennem vexlende Generations Raekker, en saeregen Form for Opfostringen i de lavere Dyreklasser) in marine life and trematode worms. In 1846 he was appointed professor of zoology at the University of Copenhagen, then in 1848 became director of the Museum of Natural History. He was an extraordinarily gifted and many-sided investigator, working in diverse fields of research, including botanical, geological and archaeological studies of peat moss and the discovery of ancient Stone Age shell mounds. He died on 20 June 1897. (Plate 80)

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FRANCIS HUGH STEWART (1879-1951) Stewart was born in 1879. He studied medicine at the University of St Andrews and at the University of Edinburgh from which he graduated in 1904 with the degrees of bachelor of medicine and bachelor of chirurgie. He immediately joined the Indian Medical Service. He was medical officer to a number of regiments and saw active service on the northeastern frontier of India from 1911-1912 and in several Asian and African fronts during World War I. He was Officer Commanding of the Indian Station Hospital in Quetta (now in Pakistan) before his retirement from the Service in 1921. He died in 1951. CHARLES WARDELL STILES (1867-1941) Stiles was born in the United States of America in 1867, the son of a methodist minister. His tertiary education was undertaken in a number of institutions in America and Europe including the Wesleyan University in Connecticut (1885-1886), and Leipzig (1889-1890). He obtained his doctorate of philosophy in 1890 in the last-named, having worked under Leuckart. Subsequently he spent some time at the Trieste Zoological Institute and the Pasteur Institute. He then returned to the United States in 1892 as a zoologist in the Department of Agriculture's Bureau of Animal Industry. In 1898 he returned to Berlin for two years as a scientific attaché. In 1902 he joined the United States Public Health Service, ultimately becoming its medical director in 1930. He served as secretary of the International Commission on Zoological Nomenclature for many years. His time abroad, especially in Germany had stamped a military bearing on him, together with a delight in wearing uniforms adorned with a sword and other embellishments. He died in 1941. (Plate 81) JAN SWAMMERDAM (1637-1680) Swammerdam was born in Amsterdam, Holland on 12 February 1637, the son of an apothecary who was also a keen student of natural history. He studied medicine at the University of Leiden and qualified as a candidate in medicine in 1663 but was plagued by chronic ill-health. In 1665 he visited France seeking a cure then returned to Holland to continue his studies and graduated with the degree of doctor of medicine in 1667. He did not practise medicine but continued the collection and anatomical investigation of lower forms of life, especially insects, of which he classified more than 3,000 forms. He was a skilled sketcher and those drawings formed the basis of his masterpiece General History of Insects. He anticipated Galvani in an experiment that was not published until many years later, in which he showed that stimulation of the nerve caused contraction of an isolated frog muscle. Five years or so before his death, he came under the spell of a religious fanatic and renounced science, destroying many manuscripts. He was disinherited by his father, and died in Amsterdam of a wasting disease at the early age of 43 years on 17 February 1680. (Plate 82) WILLIAM ST. CLAIR SYMMERS (1863-1937) Symmers was born of Scottish parents in South Carolina, United States of America in 1863. When he was seventeen years of age he followed in his father's footsteps and was sent to Aberdeen University to study medicine. While in Aberdeen, his sight became affected and he had to depend upon lectures and his fellow students reading to him. He qualified in 1887, then assisted a country practitioner in Shaftesbury, Dorset. He subsequently worked at Pasteur's laboratory in Paris, in Birmingham, and at the Lister

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Institute. While employed as an assistant bacteriologist at the latter institution, he was sent to Egypt to study the problem of cattle plague, being allowed l8,000 pounds sterling per annum for his laboratory and all his expenses. In 1897 he was appointed professor of pathology and bacteriology at the Government Medical School in Cairo and pathologist to the government hospital. He returned to the United Kingdom in 1904 and was appointed professor of pathology at Queen's College, Belfast in Ireland. He was a voracious reader and had an amazing memory, being able, for example, to recite most of the Aeneid in Latin. His students nicknamed him "The Man". He died in Belfast at the age of 70 years. (Plate 83) ALGERNON PHILLIPS WITHIEL THOMAS (1857-1937) Thomas was born in England in 1857 and received his training in biology at the University of Oxford. While a demonstrator there, he discovered the intermediate host of Fasciola hepatica, independently of Leuckart. Shortly afterwards, he was appointed as the first professor of biology and geology at the University in Auckland, New Zealand, where he remained for the next thirty years. Shortly before his death in 1937, he was knighted for his contributions to education. (Plate 84) DYNESHVAR ATMARAN TURKHUD (1868-1926) Turkhud was born in India in 1868 but studied medicine at the University of Edinburgh, Scotland. Between 1908 and 1915 he held a number of appointments as doctor on plague duty at the Bombay Bacteriological Laboratory, at the Matunga leprosarium, and as professor of bacteriology at the Grant Medical College. In 1916 he became officiating director of the Bombay Bacteriological Laboratory and in 1926 was acting director of the King Institute of Preventive Medicine in Madras. He died later that year. EDWARD TYSON (1650-1708) Tyson was born in Bristol, England on 20 January 1650 (according to the English calendar of that period, or 30 January 1651 in the Gregorian calendar). He entered Oxford University in 1667 and graduated with a bachelor of arts (1670), then master of arts (1673). He then studied medicine and graduated as a bachelor of medicine in 1677. Thereupon he went to London to practise medicine, was elected a fellow of the Royal Society in 1680, and received the degree of doctor of medicine from Cambridge University in the same year. In 1684 he was appointed reader in anatomy at Surgeon's Hall and appointed physician to Bethlehem and Bridewell Hospitals. Tyson made major contributions to medicine, human anatomy, and comparative anatomy, perhaps the most important publication in the last discipline being his monograph on the orang-utan. In this work, published in 1699, Tyson distinguished for the first time the anthropoid apes as a group separate from both monkeys and man. Tyson died, a bachelor, on 18 August 1708 in London, aged 58 years, and is buried in St. Dionis Backchurch, Lime St., London. (Plate 85) VILLANOVANUS (ARNALD OF VILLANOVA, ARNAULDT DE VILLENEUVE) (c.1240-1311) Villanovanus was born in Aragon, Spain around 1240 AD. As a young man, he studied in Montpellier, France. By 1281 he was physician to Peter III of Aragon. In 1291 he took up residence in Monpellier but was called back repeatedly to Spain. He translated many works, including those of Galen and Avicenna from Arabic into Latin. His

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commitment to medicine was gradually replaced by a concern for theological matters and he spent much time travelling between Provence and Rome. In 1305 he became an adviser to Pope Clement V. His principal work, the Parabolae, contains many aphorisms. He died on 6 September 1311 at sea off Genoa, Italy. RUDOLPH VIRCHOW (1821-1902) Virchow was born in Schivelbein in Pomerania in present day East Germnay on 13 October 1921. He graduated in medicine from the University of Berlin in 1843 then served as a house officer and assistant to Froriep at the Charité Hospital in Berlin. In 1847 he was appointed prosector at the same hospital. In the same year Virchow and Reinhardt founded the Archiv für pathologische Anatomie und Physiologie and fü r klinische Medicin; in 1852 Reinhardt died and Virchow continued the journal on his own. In 1859 he accepted the chair of pathological anatomy at the University of Würzburg then in 1866 he returned to Berlin as professor of pathology and director of the Pathological Institute. Virchow championed the principle of cellular pathology, the fundamental concepts of which were embedded in his 1858 work, Cellular Pathology. He advanced the ideas that the basic components of tissues and organs were cells, that cells begat cells, and that diseased cells were altered in structure and biochemistry. These views revolutionized pathology and he became known as the "Father of Modern Pathology". In 1848 he had participated in an uprising in Berlin. His liberal political leanings led him into politics and in 1862 he joined the Prussian Lower House. He served in the Reichstag from 1880 to 1893. He died in Berlin on 5 September 1902, aged 80 years. The Virchow Institute and the Virchow Hospital in Berlin are memorials to him. (Plate 86) JOHANN JACOB WEPFER (1620-1695) Wepfer, the son of a Canton councillor, was born at Schaffhausen, Switzerland on 23 December 1620. He studied humanities and medicine at Basel and Strasbourg and spent two years in Italy before receiving his medical degree from Basel University in 1647. He returned to Schaffhausen, was appointed city physician, and was allowed to perform post-mortem examinations. He also became an army medical officer and personal physician to the Duke of Wirtemberg and other notables. He described the anastomotic blood vessels at the base of the brain, later known as the circle of Willis, and showed that cerebral haemorrhage was a cause of apoplexy (stroke). In formulating his deductions from the pathological findings, Wepfer rejected the speculations of his predecessors and developed an admirable scientific approach, correlating clinical features with pathological findings. He was elected as Machaon III of the Academia Naturae Curiosorum. He died at Schaffhausen on 26 January 1695, aged 74 years. (Plate 87) HELENOR CAMPBELL WILDER (1895-) Wilder was born at Baltimore in Maryland, United States of America. She worked for thirty years in the section of ophthalmic pathology of the Armed Forces Institute of Pathology until her retirement in 1953. Not medically qualified, she was made an honorary member of the American Academy of Ophthalmology and Otorhinology in view of her contributions to eye pathology.

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OTTO EDWARD HENRY WUCHERER (1820-1873) Wucherer was born in Oporto, Portugal on 7 July 1820. His mother was Dutch and his father was German. The family had a business in Brazil and he lived in Bahia for seven years as a young child. He was educated in Hamburg, Germany where he took up an apprenticeship in pharmacy. He then studied medicine at the University of Tübingen where he received his doctorate in 1841. He was then an assistant for a short period at St. Bartholomew's hospital in London, England following which he practised in Lisbon, Portugal then in Nazareth, then Cachoeira, Brazil. In 1847 he returned to Bahia as the doctor to the German colony there. He was confronted by epidemics of yellow fever (1849) and cholera (1855). His wife, Dorothea Frederica Louiza, died of yellow fever in 1854. He wrote on hookworm, filariasis, ainhum and poisonous snakes. After 24 years in Bahia, he returned to Germany in 1871 and went to Stuttgart where his second wife (a sister of the first) and son were living. Possibly because of financial difficulties, he returned to Bahia in 1873. He was said to be of noble character, serious, modest and caring. He suffered a stroke while attending a patient in labour, and died soon afterwards on 7 May 1873, aged 52 years. He is buried next to his first wife in the cemetery for foreigners in Salvador, Brazil. (Plate 88) SADAMU YOKOGAWA (1883-1956) Yokogawa was born in Okayama Prefecture in Japan in 1883. He graduated with honours from Okayama Medical College in 1908. After working for some time in Okayama, he went to Formosa (Taiwan) as a lecturer in pathology, becoming professor of pathology there in 1918. He died in 1956. (Plate 89) FRIEDRICH ALBERT ZENKER (1825-1898) Zenker was born in Dresden in present day East Germany in 1825. He studied medicine in both Leipzig and Heidelberg. He received an appointment in the department of pathology in the University of Leipzig but returned eventually to Dresden where he was appointed professor of pathology in the Medical-Surgical Academy. In 1862 he became professor of pathology at Erlangen where he remained until his retirement in 1895. He died in 1898. (Plate 90)

PERSON INDEX

Numbers in bold refer to the page on which a biography can be found.

Abbotts-Smith 405, 460 Abdallah 531 Abildgaard 41, 106, 400-1, 480 Abreu de 455-6, 783 Ackert 740 Actuarius 455 Adams 727 Aetius 356 Africa 310-1, 731 Agatharchides 694 Aitken 643 Akashi 427 Al-Qazwini 31 Albarran 207 Albertus Magnus 31-2 Albrecht 408 Alcock 609 Aldrovandi 771 Alessandrini 723 Alexinsky 335 Ali-Khan 684 Alicata 724 Allan 195-6, 213 Alves 216 Amato Neto 487 Amatus Lusitanius 471, 694-5, 709, 769 Amin 629 Anaxagorus 32 Anazawa 301 Anderson R 724, 730, 739 Anderson W 486 Ando 166, 168-70, 172, 301 Andreev 335 Andrews 520, 526 Andry 37-8, 356, 359, 386, 398, 695, 768, 771-3, 783 Annandale 203, 275

Annett 613, 645 Anthony 740 Apt 744 Araoz 735 Aretaeus 320, 338 783 Argyll-Robertson 643, 645, 647, 649-50, 653, 783 Arinus 119 Aristophanes 362 Aristotle 3, 30, 32, 356, 362, 439, 469, 784 Arizono 300 Arme 631 Arthur 558 Artigas 309 Arzube 177 Asada 59, 300, 304, 479 Ash 59, 605 Ashburn 87, 579, 604 Ashford 500, 515, 529, 784 Ashton 119 Askanazy 306-7, 551, 554, 784 Aspöck 461 Atkinson 56, 145, 372-4, 743, 785 Attygale 514-5 Aubert 653 Auchincloss 625 Augustine 517, 528 Austin 90, 526 Austrageliso 509 Avicenna 4, 31, 77, 356, 439, 444, 480, 521, 694-5, 707, 709 Azarova 684 Aziz 680 Babione 618 Bacigalupo 425, 433

823

Baellstaedt von - see Albertus Magnus Baelz 142, 161-2, 171-2, 176, 279, 785 Baer von C 11, 43, 108 Baer J 414, 426 Baermann 528, 530 Baglivi 38 Baillet 432 Bain 735, 737-8 Bajon 642, 652 Baker 516 Balfour 199 Bancroft J 14, 601-4, 608-9, 772, 785 Bancroft T 55, 610-1, 613, 726, 786 Barbier 288 Barbot 616 Barlow C 131-8, 210, 221, 786 Barlow N 558 Barry 441 Barton 629 Basch 302 Bascome 618-9 Basnuevo 85 Bastian 53, 606, 696-7, 710, 737, 786 Batsch 325, 433 Baumler 81 Bavay 544-6, 550, 787 Baylis 203, 286, 776 Beal 560 Beale 728 Beaujean 149 Beaurepaire Aragão de 624 Beaver 16-7, 252, 461, 684, 745, 787 Beer 463 Behrer 744

824

A History of Human Helminthology

Bekhti 91 Belleli 246, 248 Bellingham 460, 746 Bemrick 739 Beneden van 25, 46-7, 328-9, 331, 361, 368, 424, 580, 643, 787 Bennington 311 Benoit 671 Bentley 83, 509, 524, 788 Bequaert 203, 275, 670 Bérenger-Férand 392 Berghe van den 670, 677, 681 Bergouie 709 Berkeley 484 Berkowitz 150-1, 252 Bernard, 207 Bernstein 346 Berrio 81 Berry 281 Bertolus 400-1 Bhaduri 731 Bhalerao Bidloo 37, 104-7, 115, 771, 788 Biermer 407 Biggam, 519 Biglieri 735 Bijlmer 444 Bilharz 13, 22, 187-9, 191-2, 205-8, 211-2, 233-4, 245, 251, 303, 424, 500, 506, 772, 788 Billet 709 Biocca 502, 742 Bischoff Bishop 525 Blackie 288, 562 Blacklock 58, 204, 66970, 675, 681, 789 Blackwell 775 Blair 84, 92, 216, 680 Blanchard E 360 Blanchard R 14, 17, 121, 142, 267, 303,

306, 308, 311, 389, 421-4, 426, 441, 4745, 500, 551, 642, 668, 728, 734 789 Bloch 40, 305, 387, 422, 772 Boase 678 Bobillier 339 Boerhaave 39 Bojanus 42, 107-8, 790 Bonetus 338 Bonnal 431 Bonne 300-1, 629 Bonnet 386, 399, 790 Bonnsdorf von 405, 409-10 Bonyun 617, 625 Bordeu de 33 Borel 105 Borrel 776 Borrichius 370 Bour 197 Bourges de 713 Bourne 603 Boycott 516-7, 519 Bozzolo 514, 524, 527 Brackett 287 Brady 445 Branden van den 666, 668, 678 Braun 15, 25, 54, 108, 163, 309, 401-3, 405, 790 Bray 86 Brayer 78 Bremser, 9-10, 41-2, 105, 325, 365, 388, 399, 440-2, 448, 470, 772, 791 Brenes 178 Brera 772 Breton 550 Brett 701 Brie de 103-4, 114, 119, 121, 791 Bright 335 Brock 195 Brown A 676

Brown H 485, 487, 526, 561 Brown N 129 Brown P 374-5 Brown R 562, 572, 724 Brown TR 585 Browne 33 Bruce 699 Brudastov 483 Brug 16, 283, 300, 604, 613, 618, 705, 712 Brugmans 91 Brumpt, 289, 431, 487, 521, 663-4, 666-7, 672, 682, 746 Bruning 81, 524 Brunner 485 Bry de 641-2 Bryant 675-6, 678 Bucholz 105, 298 Buchwalder 745 Buckley 287, 605, 630, 682, 733, 735, 740, 791 Budd 127 Bueding 87 Buffon 5, 39 Bui-Quoc-Hong 487, 526 Bumbalo 90 Bunnag 136, 308 Burch 678-9 Burrass 90 Busk 127-8, 601, 789 Bylund 92 Caelius Aurelianus 480 Caius 525 Calandruccio 54, 458, 463, 473-4 Calderón 664, 668, 6734 Caldwell 462, 490, 509 Cameron 59 Campbell A 429 Campbell W 92, 574, 585, 680 Camuset 500, 513

Person Index Cannon 728 Capp 88 Cardanus 31 Cardoso 243 Carneri de 463 Carnochan 625 Carter H 247, 629, 701 Casaux 429 Casoni 337, 775 Castellani 302, 643 Castle 409, 519 Catto 266-7, 278, 283, 792 Cawston 203-4, 211 Celsus 3, 30, 356, 469, 792 Cerf 89, 217 Cerqueira Falção de 240 Céspedes 724 Ch'en 177-8, 297 Chabaud 724, 735, 7378 Chabert 106, 118, 218 Chaia 526 Chambers 302, 643 Chamisso von 43, 109, 792 Chandler 221, 287, 4278, 517, 729-30 Chang 302 Chapin 311 Chardome 58, 738-9 Charles 697-8, 792 Chastang 545, 550 Chatin 739 Chaudhuri 745 Chauvin 545-6 Chen 723 Cherry 195 Chesterman 288 Children 572 Chisolm 699, 713 Chitanondh 732 Chitwood 721, 726, 745 Cho 449 Choi 151 Chopra 626

Chow 152, 170 Choyce 676-7 Christenson 286 Christopherson 83, 214, 221, 793 Chu 136 Chuckerbutty 600 Chung 88-9, 173, 177-8 Church 471 Ciurea 58, 301, 305, 307 Claparède 441 Clericus - see Le Clerc Clot 642 Cobb 729, 732 Cobbold 12-3, 22-3, 25, 121, 128, 130, 135, 142, 160-1, 189-90, 371, 390, 399, 441, 447-8, 500, 575-6, 588, 599, 602, 606, 608-10, 614, 618, 643, 703-4, 737, 772, 793 Cockin 201 Codvelle 121 Cole 134 Coleman 214 Coles 212 Collet-Meygret 728 Colomiati 514 Coneato 522 Connal 56, 648-9 Connor 709 Conor 197 Contoli 440, 772 Conyngham 311 Cook 250 Corre 599 Correa 464 Corson 667-8, 738 Cort 177, 286, 303-4, 479, 485, 528 Coulaud 92 Coulet St. 439 Coulston 429 Coventry 485 Craig 604 Cram 421 Creplin 43, 108, 400,

825 500, 725, 740 Crevaux 599 Crewe 649, 177 Crilly 523 Crocker 722 Cross 59, 726 Cruz 519 Cuckler 585 Culbertson 776 Cunha 526 Cunningham 309, 599 Cupp 16-7 Currie 645 Curtis 218 Cuvier 6 D'Alessandro 346 Da Cruz Ferreira 89 Dacunha 252 Daengsvang 59, 730-1 Daland 560 Dalgetty 509, 530 Danaraj 85, 629 Daniels 266, 427, 604, 705, 734-7, 794 Darling 530, 549, 558 Date 445, 460, 482 Davaine 3, 13-4, 50, 77, 128, 334, 370, 372, 397, 410, 426-7, 458, 461, 472, 484, 598, 774, 794 Davey 725 David 605 Davies 736 Davis 449 Day 213-4, 247, 526 Deguy 663 Delafond 729 Delpert 588 Demarquay 14, 597-600, 619, 623, 772, 794 Democritus 32 Deschiens 550 Desnos 218 Desoil 671 Desowitz 90 Deunzer 731

826

A History of Human Helminthology

Dévé 333-6, 339, 341, 344-5, 795 Dew 333-5, 337, 344-5, 795 Dhayaguda 629 Diamantis 212, 215-6 Diaz 682 Dick 710 Diesing 3, 11, 110, 162, 189-90, 325, 399, 428, 431, 500, 578, 664, 726, 728, 737, 738, Dietz 299-300, 305, 309 Dimier 709 Dinnik 463 Dioscurides Anazarbeus 77 Do Nascimento 91, 487, Dobson 514-5 Doeveren van 359 Dollfus 297, 427 Dougherty 722 Douglas 212 Dounon 550 Dove 722 Drebbel 36 Dryden 338 Dubini 499-500, 502, 512, 643, 772, 795 Dubois 423, 652, 666, 670, 672, 678, 681 Ducas 775 Dujardin 3, 10, 45, 298, 327, 361, 365, 424, 489, 577, 643, 725, 739, 742, 796 Duke 655, 680-1, 738 Dukes 739 Duncan 700 Dunsterville 190 Dunus 397 Duque Lince 462 Durme van 55, 552, 796 Dutcher 622 Dutt 712 Dyce Sharp 58, 646, 651, 671-2, 679, 737-8

Ebell 520 Eberhard 735. 737-8 Edeson 58, 605, 615 Edgar 280 Edwards 613 Ehrenberg 243 Elgood 195 Elliot 711 Elliotson 446, 448, 461, 485 Elmes 310 Enzer 679 Epicurus 32 Epstein 474 Ercolani 722 Erian 216 Erlich 776 Eschricht 44, 342, 360, 399 Espejo 92 Esslinger 738 Ettmuller 768 Eustis 560 Fain 739, 310, 432 Fairley 203, 208, 212, 242, 244, 248, 373, 624, 652, 678, 708, 711, 796 Falção 298 Farber 104, 114 Faria de 502, 721 Farid 210 Farquet 213 Farre 572-3, 576-7, 582 Fauchard 768 Faulkner 710 Faust 16, 86, 153, 243-4, 267, 275, 277-9, 285, 429, 431, 549-50, 556, 561, 729, 735, 737-8, 743, 796 Fayard 87, 486 Fayrer 620 Fedchenko 51, 696, 702-4, 732, 797 Fehr 357 Feng 613, 732

Ferg 699, 712 Ferguson 207, 246, 247 Fernán-Nuñez 460 Ferrara 402 Fibiger 776-7 Fiedler 581 Figueroa Marroquin 682 Filippi de 108 Finlayson 266 Finsen 335 Fischer 529, 772 Fisher 288 Fitch 616 Fitzherbert 104, 114, 117, 119, 121 Fleckseder 775 Fleig 337, 775 Flu 239 Foley 646 Forbes D 46, 700-1 Forbes J 707-8 Foster 90, 253, 477-8, 797 Fox 620, 706 Foy 740 França 204 Friedheim 215 Friedreich 584 Frimodt-Müller 629 Fritz 485 Froelich von 301, 742 Fromman 104 Fujii Y 279 Fujii D 268, 279, 283-4 Fujinami 56, 266, 26870, 273, 284, 775, 797 Fukutuni 284 Fülleborn 459, 478-9, 510, 517, 519, 552-4, 556-8, 615, 646-7, 663-5, 675, 678, 682, 737, 747, 797 Gabucinus 31, 104 Gage 554-5, 558, 560 Galen 3, 30, 319-20, 356, 439, 443, 469, 694, 766, 798

Person Index Galgey 734-5 Gallandat 698-9 Galli-Valerio 404 Galliard 147, 559 Galvin 489 Garcia 310-1 Garnham 683 Garrison 300, 427 Gault 629 Gayer 603 Gelpi 483 Gemma 104, 119, 771 George de St. 49 Gerritson 210 Gervais 432, 544, 643 Gesner 104, 362, 798 Ghalioungi 519 Ghedini 337, 485, 522, 775 Ghose 732 Giaquinto Mira 670, 676 Gibbins 682 Gibbons 670 Giles 505-6, 508, 515, 746-7 Gillet 289 Girardeau 562 Girges 247, 249-50 Giroud 87, 449 Gleichen-Rusworm 399 Gmelin 6, 363, 696 Goddard 129, 133 Godfrey 617 Godoy 739 Goebel 442 Goeze 5, 40, 48, 106, 324-5, 327-8, 334, 337, 359-60, 363, 365, 370, 386-8, 400, 426, 432, 440, 456, 728, 772-3, 798 Goldberger 312 Goldman 673 Goldsmid 743 Goldsmith 253 Golgi 549-50 Gönnert 89, 216, 375, 646-7

Gonzalez 244 Goodsir 334 Goodwin 487, 526 Gordon 91, 216, 517, 649, 654 Gorter 625 Goto 277 Gouillon 737 Gouvêa de 121 Graefe von 371 Graham C 446 Graham W 713 Grassi 54, 402, 422-5, 441, 458, 473-4, 503, 506, 521, 524, 546, 549-50, 553, 560, 611, 799 Gravière de la 544 Greany 252 Grene 286 Grenet 513 Grew 36 Griesinger 190, 192, 2056, 208, 211-2, 234, 245, 500, 512-3, 521, 799 Gros 443, 472 Grove 559 Gruby 729 Grüntzig 642 Gubler 684 Guerrero 674 Guillemard 195, 213 Guiness 644 Gulland 623 Gullstrand 678 Guret 578 Guyon 641-3 Guyot 642-3 György 744 Häckel 52-3 Hairston 627 Hales 92 Hall 83, 87, 432, 446, 525, 722 Hallez 474 Hampton 525

827 Handley 625 Harada 522 Hardy 212 Harinasuta 177, 308 Harley 189-90, 193-4, 209, 212, 234, 606, 710, 799 Harris 672 Harrison 207 Hartmann 321, 331, 362-3, 402, 800 Hartsoeker 38 Hartz 459, 559 Harvey 21, 800 Harwood 87 Hasegawa 459, 747 Hassal 163, 176, 303, 308, 421, 470, 550, 643 Hatch 197 Haubner 333, 368-9 Hawking 84, 626, 679 Heanley 129, 144, 148-9 Heath 699-700 Heckenroth 653 Héricourt d' 78 Heiner 745 Heller 368, 446, 476, 579 Henle 575 Hennessy 728 Henrard 681 Henry 431, 664, 726, 729, 739-40, 742-3, 746 Herbst 50, 578-81, 800 Herman 524 Herrick 581, 584, 775 Hewitt 85, 626, 679 Heydon 730 Hien 288 Highby 728 Hilton 575 Hinchcliffe 287 Hinman 559 Hippocrates 3, 30, 32, 319, 356, 444, 469, 480, 521, 800

828

A History of Human Helminthology

Hirasawa 299 Hirsch 176, 711 Hisette 670, 675-6, 678 Hjaltelin 335, 340, 342 Ho-Thi-Sang 487 Hodgkin 605 Hoekenga 462 Hoelz 424 Hoeppli 149, 480, 693-5 Hoffman 408 Hoffman F 733 Hoffman W 624, 733 Hoffmann 670 Holcomb 239 Hollenbach 367 Hood 663 Hoof van 87, 679 Hoogstraten 740 Hooke 36 Hopkins 737 Houghton 144-5, 431, 743 Houllier 767 Howard 510 Hsia 177 Hsieh 172 Hsu 146-7, 152 Huart 519 Huber 389 Hudullet 709 Huffman 643, 646 Humbert 48, 367 Humphreys 221 Hungerford 164, 166 Hunter 335, 338 Hutcheson 281 Hutchinson H 248 Hutchinson J 339 Huxley 53 Ibn Sina - see Avicenna Ijima 143, 152, 422, 430, 831 Ikeda 173 Imai 281 Imamura 173 Inouye 174 Irvine 745 Isaac 775

Ishii 178 Issajev 705 Iturbe 243-4 Iwata 429 Jacobson 700 Jacoby 515 Jaegoerskiöld 730 James 55, 611, 613 Janeway 581, 584 Janicki 58, 403-5, 801 Janson 302 Jayewardene 487 Jeanselme 711 Jefferys 129 Jener 374 Jennes 642 Jiménez-Galán 178 Joannidès 213 Johansson 776 Johnson 281 Johnston 425, 744 Jophnstone G 128 Johnstone R 651 Joyeux 423-5, 507 Judas 389 Julien 774 Jung 16-7, 460 Junod 84 Kagei 743 Kahane 460 Kakami 168 Kalantarian 747 Kalm 81 Kamo 178, 422 Kan 281 Kartulis 246 Kasai - see Kawanishi Kasimov 741 Katamine 173 Kato 252 Katsurada 15, 174, 264-8, 271, 305, 801 Katsuta 303 Katz 90, 217, 251, 253 Kau 170 Kawamura 172

Kawanishi 270, 279, 283, 801 Keller 430, 479 Kellicott 176 Kennard 611 Kenney 464 Kérangel 513 Kerbert 162, 163, 174, 802 Kerr 128, 308 Kershaw 676 Kevy 745 Khalil 215, 221, 304, 521, 525, 802 Kholokowsky 306 Kikuiko 173 Kikuth 85, 561 Kimuri 170 King 733 Kingery 309 Kirby-Smith 722 Kirchner 298 Kirk 672 Kitchener Lord 200 Kleine 56, 648-9 Klemm 344 Kloetzel 251 Knoch 400-1 Knott 624-5 Knox 389-90 Kobayashi Harujiro 57, 144-7, 152-3, 168, 304-6, 429, 742, 802 Kobayashi Hisao 166, 169, 176 Koch 443-4 Kofoid 449 Koford 744 Koino 478, 482-3, 485, 489, 746, 746 Kölliker 400 Kondo 173, 479 Kondoléon 625 Koppisan 248 Kosaka 426 Kosuge 552 Kothari 711 Kouri 119

Person Index Kouwenaar 525, 629 Koyama 743 Krabbe 322, 341-2 Krause 523 Krehl 357 Kreis 549 Krull 59, 116, 298 Küchenmeister 11-3, 24-5, 46-9, 110, 118, 325, 327-30, 332-3, 342, 364-70, 372-3, 376, 388, 392, 400-1, 410, 432-3, 441, 445, 448, 457-8, 481, 483, 500, 579, 584, 694-5, 699, 706, 773, 802 Kudiche 85, 261 Kuhne 589 Kuipers 725 Kumagawa 274 Kurata 281 Kurimoto 264, 422 Kurlow von 554 Kuwabara 151 Kwan 129 Kynsey 505, 515 Labadie-Lagrave 663 Lacroix 666-7, 671, 677 Laennec 325 Laigret 668 Lambert 87, 217 Lambinet 510 Lämmler 89 Lamson 86-7, 486, 525 Lane 303, 309, 488, 502, 517, 522, 524-6, 615, 747, 803 Langen de 86, 510, 5601 Langer 775 Laning 280 Lankester 127, 130, 803 Lapage 741 Lapierre 288 Larumbe 682 Lasbrey 214 Lautner 205

Laveran 545, 550 Lavoipierre 649 Lawless 747 Laurie 679 Lawrie 625 Lawton 249 Le Bas 405-6 Le Clerc 38, 82, 771-2, 803 Leach 440 Leared 342 Lebeder 335 Lebied 649 Lee R 721-2 Leeuwenhoek 25, 33, 36, 104-7, 803 Leichtensern 54, 504-5, 507, 549, 618 Leidy 128, 423, 577-8, 729, 804 Leiper 23-4, 56, 129, 145, 190, 195, 201-4, 218, 220, 239-42, 255, 264, 272-4, 301, 305, 308-9, 406, 431, 440, 470, 502, 506, 527, 647-8, 668, 697-8, 703-5, 709, 713, 731, 733, 735, 740-4, 746, 776, 804 Lemoine 598 Lentz 447 Leon 301 LeRoux 288 Leske 432, 805 Leuckart F 11 Leuckart R 48-51, 53-4, 110-1, 113, 115, 120, 128-9, 161, 163, 325, 333, 357, 367, 369, 388-90, 400-1, 422-4, 427, 441, 446, 458, 472-4, 502-3, 547-8, 575, 581-3, 609-10, 662, 665, 677, 702, 805 Levine 89 Levinson 731

829 Lewis 14, 55, 362, 599601, 603, 606, 609, 619, 623, 665, 805 Li 146-7, 302 Libby 282 Libermann 545, 550 Lichtenstein 16, 302, 309 Lie 301 Lim 90 Lin 723 Lind 699, 713 Linnaeus 1, 4, 18, 40, 105-6, 359, 362, 286, 422, 440, 457, 469-70, 696, 769, 806 Linné von - see Linnaeus Linschoten van 616, 641, 698, 710, 771 Linstow von 298, 473, 562, 740-1 Lisbonne 337, 775 Lister 707 Liston 708, 711 Little 605 Liu 89 Livois 325 Lobo-Sanahuja 725 Locke 338 Loeper 83 Löffler 483 Logan 283, 645 Lombard 527 Loney 642 Looss 54-5, 129, 142-3, 163, 195, 197, 199200, 218, 220, 236-40, 298, 301-3, 500, 502, 504-11, 518, 527, 548, 552, 553, 643, 746-7, 774, 807 Lopez 642 Loria-Cortes 725 Lortet 196-7, 199 Lotsy 212 Low 55, 288, 611-2, 622, 645-6, 650, 665-6,

830

A History of Human Helminthology

735-7, 807 Lowenthal 670, 682 Lu 171 Lucretius Carus 616 Ludlow 170 Lühe 309, 399, 422 Luschka 577 Lyle 195 Lýsek 490 MacArthur 371, 726 MacCowen 561 MacCowen 88 MacDonald 505 MacFadden 668 MacFie 667-8, 711, 738 MacKay 706 Mackenzie 614, 643, 646, 652, 736, 808 Mackerras 59, 723 Mackie 207, 235, 248-9, 252 MacLaurin 339 Maddern 210-1, 246, 249, 508 Maegraith 285 Magalhães de 255, 604, 733 Magath 337, 374-5, 413 Maisonneuve 700 Maitland 625 Majima 263, 278, 301 Malebranche de 33 Malpighi 33, 36, 105, 322, 359, 363, 808 Manalang 722 Mann 280 Manson 15, 55, 159-62, 164, 171-2, 175, 2356, 252, 254, 267, 428, 508, 530, 603-4, 60611, 613-5, 619-20, 622-3, 626, 643-7, 650-2, 662-3, 665, 667-8, 670, 677, 704, 706, 709, 734-7, 809 Manson-Bahr 87, 203, 242, 449, 599, 604-5,

609, 622, 703 Mantey 196 Mapes 59, 298 Maplestone 86, 510, 605, 731, 737 Maren 84 Margolis 414 Markovic 309 Martin de la Calle 118 Martin 118, 173, 252 Martinéz Báez 178 Martins 244 Martirani 91, 561 Matsuura 270 Matthes 745 Maung 479 Mauss 216 Maxwell 621 May 365 Mayer 216 Mazzotti 85, 678-9 McAdam 740 McConnell 15, 141-3, 146, 149, 302, 514, 722, 808 McCoy 136 McDonagh 215 McGregor J 707 McGregor W 142-3, 148 McKinley 622 McLelland 700 McMahon 681, 683 McMullen 310 Mebius 149 Medicus 33 Meerovitxh 684 Mehlis 43, 105, 108 Mehrez 87, 449 Meillon de 627 Meinhof 646, 651 Mekel 423 Meleney 267, 275, 2779, 282 Melnikov 422 Mercer 744 Mercurialis 31 Metchnikoff 445, 776

Meydenbach 771 Meyers 629, 738 Meyner 421 Mhaskar 525 Milne 695 Milton 218, 251, 253 Minchin 58, 425 Minet 212 Minett 622 Minning 281, 483 Minot 409 Mitter 730 Miura 252, 485 Miyagawa 272, 276-7, 289, 510, 810 Miyairi 56, 168, 268, 270-2, 274, 281, 284, 810 Miyakai 422 Miyazaki 177-8, 731 Molin 500, 732, 739-40 Mongin 642, 652 Monnig 746 Monson 178 Monti 549-50 Montpellier 666-7, 671, 677 Moore 59, 196, 649 Moorthy 697, 706, 713 Moquin-Tandon 189, 361, 706 Morenas 118 Morera 59, 724 Morgagni 322, 456, 810 Mori 522 Morin 344 Morishita 299 Moriyasu 172 Mornex 733 Mosler 50, 390, 473, 482, 585 Mossbrugger 460 Motte Lambert de la 698 Moty von 445 Moura de 513 Mouriquand 449 Mozley 221

Person Index Muangmanee 308 Muhleisen 722 Mühlens 305 Mukerji 86, 731 Mukoyama 147-8 Müller H 523, 776 Müller J 426, 430-1 Müller O 41-2, 107, 664, 810 Muller R 703 Müller W 727 Mullins 722 Murgatroyd 653 Murphy 409 Musgrave 460 Mustafa 483 Muto 57, 145-6, 148, 151-2, 306, 811 Myers B 743 Myers W 614, 625 Myrepsus 773 Nag 525 Naganori - see Majima Nakagawa 57, 130, 132, 137, 165-7, 169, 811 Nakahama 162-4 Nakamura 56, 268, 269, 270, 284, 422 Napier 520 Narabayashi 276 Natterer 162 Naunyn 332, 334, 811 Needham 39 Neghme 86 Nelson 273, 672, 735 Newsham 734 Nicholas 737 Nicholl 58, 425 Nicholls 525 Nickerson 411 Nicolai 388 Nietzsch 42, 107, 282 Nishigori 303, 555-6, 726 Nishio 57, 303-4, 310-1 Noè 611 Nöller 298

Nomura 723 Nordmann von 43, 108, 811 Normand 543-6, 550, 553, 556-9, 560, 811 Nouffer 77. 373 Noya Benitez 253 Nwako 178 Nwokola 178 Nybelin 485 Nyberg 410 O'Connor 622 O'Neill 661-5, 671-2, 677, 681, 812 Ochoterena 676 Odhner 129, 171, 300 Ogata 276 Ogawa 555 Ohba 478 Oisio 510 Okada 510 Oken 42, 108 Okumura 428-9 Oleinikov 446 Oliver 48, 391 Oliver-Gonzalez 85, 487 Onabamiro 706 Onji 57, 303-4, 310-1 Onuigbo 178 Ophüls 551, 556 Oribasius 30 Orihel 59, 649, 735, 737-9 Ortiz 673 Ostertag von 741 Östling 410 Otsuru 747 Ottesen 630 Otto 84, 479 Oudendal 459 Owen H 728 Owen R 572-7, 582, 730, 772, 812 Ozaki 301, 304 Ozzard 506, 734-5, 812 Pachecho 59

831 Pachecho Luna 674 Paget 572-6, 582, 813 Pagliani 514, 527 Pallas 40-1, 105, 323-4, 364-5, 386, 769, 813 Palmer E 423 Palmer ED 86 Pampiglione 562 Panarolus 362, 471 Pane 732 Paracelsus 31, 33, 78 Pardani 711 Paré 31, 695, 770 Parona C 503 Parona E 423, 503, 524, 546, 553 Parsons 663 Pasco 59, 300 Pasteur 51-2, 813 Paulus Aegineta 356, 480, 694 Payne A 176 Payne F 489-90, 740 Payne G 538 Peacock 575 Peel 58, 738-9 Peiper 510 Pellegrino 217 Pene 91 Penner 287 Perez 309 Perez-Santiago 92 Perlingiero 744 Perrin 84 Perroncito 49, 376, 391, 393, 503-4, 514, 521, 524, 529, 546, 560, 562, 814 Peruzzi 739 Pesigan 281-2 Petrushewsky 413 Philpot 443 Pickells 746 Pigafetta 642 Pigoulewski 121 Pilsbry 203, 243 Pirajá da Silva 239, 243, 255, 814

832

A History of Human Helminthology

Pirie 522 Planck 53 Plato 32 Platter 398, 405, 471, 814 Plehn 704 Pliny 3, 30, 77, 356, 469, 694 Plutarch 694 Podjapolskaja 311 Poirier 128, 308 Poltera 728 Pons 250 Porter 204, 242 Posselt 344-5 Potiez 243 Pouchet 49, 52-3, 330-1 Powell 707 Poynton 605 Pratt 311 Priestley 599 Priston 282 Proffit 485 Prommas 59, 730-1 Prout 622, 663, 665 Pruner 500, 703, 814 Puig Solanes 675 Quénu 339 Quere 677 Radomyos 300 Raffier 711 Ragni 393 Railliet 54, 121, 129, 302, 422, 426-7, 431, 458, 500, 664 726, 729, 731, 742, 733, 735, 737, 739-40, 7423, 746-7, Rake 518 Raleigh 625 Ramsay G 710 Ramsay W 2 Ransom B 13, 393, 4778, 727,741, 746, 774, 815 Ransom W 372, 461,

484, 815 Rao 301, 605-6, 708, 712, 731 Rathouis 129 Ratz von 299 Rausch 345-6, 414 Recio 421 Reddy 709 Redi 33-5, 104, 108, 114, 320-1, 351, 469, 728, 771, 815 Redlich 404 Reichard 698 Reinhard 601 Reinus 642 Rendall 484 Renoult 209 Rep 502 Requine 3 Retzius 106 Reyher 407-8 Reyn von 746 Reynolds 710 Rhazes 694 Rhind 43, 480 Rhoads 519 Ricciardi 562 Richard-Lenoble 739 Richards 213 Richter 472 Ridley 675 Rieder 523, 776 Rim 151, 174, 306 Ringer 15, 159 Ripert 174 Rivas 652 Rivikka 86 Rivolta 306 Rizhikov 733 Ro 173 Robbins 462 Roberts J 683 Roberts W 602 Robles 58, 664, 668-9, 672-4, 681, 816 Roche 520 Rockefeller 529 Rodenburg 725

Rodenwaldt 129 Rodger 676 Rodhain 652, 666, 668, 672, 678, 681 Rodrigues 91, 309, 561 Roederer 456-7, 459, 461, 480, 772, 816 Rogers 651-2 Rook de 613 Rose 221 Rosen 58, 403-5, 723, 732 Rosenberg 402 Rosenblatt 605 Rosenstein 359, 773 Rosi 86 Ross 461, 476, 612-3 Roth 373, 653 Roubaud 704 Roupell 571 Roussel 709 Roux 150, 545, 550 Rovelli 54, 422-3, 549 Rudolphi 2, 8-9, 41, 82, 298, 300, 308, 325, 331, 363, 365, 387, 431-3, 456-7, 459, 461, 480, 728, 732, 742, 746, 772, 816 Ruffer 209 Ruiz Reyes 679 Rumler 362 Runeberg 407-8 Ruyschius 771 Ryuzi 151 Saboia 604 Saeki 425 Sagredo 459 Saha 745 Saito 144 Salzer 584, 586 Salzmann 423 Sambon 16, 236-8, 611, 647, 776, 816 Sambuc 149 Samson-Hammelstjerne 722

Person Index Sandares 59, 723 Sanders 282 Sandground 300, 310, 449, 549, 557-8, 664, 742-3, 747 Sandwith 304, 506, 508 Sangalli 506 Santiago-Stevenson 85, 626 Santos 282 Sasa 604 Sawada 88 Schapiro 87 Schaudinn 511 Schaum 726 Schenone 91 Schiller 345 Schinz 485 Schmidt 446 Schneider A 741 Schneider H 375 Schrank 301, 457, 746 Schraufstätter 89, 375 Schrecker 213 Schreiber 42, 86 Schubart 400 Schüffner 81, 443, 447, 524 Schulthess 504 Scott 743 Scott H 517 Scowden 559 Scribonius Largus 766 Seifert 547-8, 560 Seltzer 770 Sen 732 Senn 190 Serapion 4, 256 Sergent 737 Servantie 118 Seurat 604 Shaftesbut, Earl of 338 Shaldon 247 Shaw 215 Shillinger 87 Shimura 555 Shirai 114, 116 Sibthorpe 603 Siebold von 43-5, 47-8,

108-10, 128, 187-8, 234, 303, 327-31, 360, 365, 424, 442, 500, 577-8, 817 Siegenthaler 684 Silva 676, 678 Silva Araujo 55 Silva Lima da 598-9 Simon 665-6, 678 Simonds 108, 120 Singer 694 Singson 726 Sisinitsin - see Ssinitzin Skrjabin 299, 311, 726, 729 Smillie 517 Smith A 500, 652 Smith D 309 Smith M 745 Smith W 721 Soemmering 440, 448 Solander 769 Sommer 360 Sonsino 195, 198-9, 234, 287, 302, 422, 505, 514, 550, 601, 610, 817 Sooley 283 Sorel 707 Sorenson 445 Spallanzani 39, 817 Spiegel van der - see Spigelius Spigelius 32, 357, 398, 771 Spillman 483 Spooner 424 Spöring 399-400 Sprent 489 Spruit 462 Ssinitzin 115-6, 818 Stadelmann 741 Standen 449 Stanley 573 Steenstrup 13, 44-5, 109, 327, 361, 400, 818 Stein von 48, 328, 401

833 Stejksal von 775 Stekhoven 555 Stevenson 649 Stewart F 444, 475-8, 818 Stewart I 747 Stiles 163, 176, 303, 308, 312, 421, 424, 428, 430, 470, 500, 516-8, 528-9, 550, 643, 728, 738, 741, 744, 746, 819 Stock 213 Stoll 87, 412, 512 Stone 722 Stossich 740 Stransky 281 Straub 525 Stricker 443 Ströbel 585 Strom 299 Strong 670, 673, 676 Stuckey 743 Stunkard 59, 287, 421 Suga 162 Suganumu 624 Sui - see Koino Suyeyasu 276 Suzuki 56, 268, 270-2, 274, 285, 743 Swammerdam 33, 35-6, 819 Swartzwelder 87, 90, 460, 483, 561 Swayne 484 Sweet 706, 713, 733 Swellengrebel 443, 447 Swift 721 Symmers 246-8, 819 Szidot 411 Taillandier 560 Takata 490 Takemoto 276-7 Talaat 89 Taliaferro 485, 624, 776 Talyzin 487 Tanabe 299, 310 Tang 427

834

A History of Human Helminthology

Tansurat 731 Tarassov 407, 413 Tardieux 150 Tayler-Jones 428 Taylor 286 Teissier 553 Tennent 698 Termakov 464 Tesch 283, 300 Thayer 551 Theophrastus 77, 356 Théoridès 91 Thiel van 725 Thienpont 91 Thira 555, 558 Thomas A 53, 110-3, 115, 119-21, 820 Thomas H 92 Thomas J 332, 324 Thompson 201, 204, 661, 775 Thoonis 87 Thorensen 340 Thorpe 674 Tiedemann 575 Todokoro 284 Tomita 562 Topley 526 Toroella 678, 682 Torres Estrada 678 Tötterman 409 Travassos 297, 725-6 Trent 618 Trewn 708 Tsamis 216 Tsao 178 Tsujuki 169 Tsykalas 216 Tubangui 59, 275, 300-1 Tukalewski 463 Tullis 485 Tulp 357 Turkhud 56, 704-5, 709, 820 Turner 615 Tyson 35, 80, 321-2, 357-9, 364, 369, 469, 471, 771, 820

Uchimara 425 Ulrich 461, 484 Unterberger 473 Upatham 308 Vaillant 426 Vallisnerius 38, 386 Vanda de la 711 Vandepitte 310 Vandyke Carter 614 Veglia 288 Veiga de 695 Velden van den 775 Velschius 694-5, 710, 771 Verloren 400 Verrier 49, 330-1 Vervoort 486 Vialleton 197, 199 Vic-Dupont 288 Vilela 561 Viljoen 377 Villanovanus 31, 356, 820 Villeneuve de - see Villanovanus Virchow 50-1, 344, 57981, 589, 820 Virik 310 Vix 441 Voelker 177-8 Voge 288 Vogel 59, 177-8, 281, 298, 305, 307, 345, 483 Vogt 11 Wagener 50, 109 Wagler 327, 370, 456, 459, 772 Wakeshima 168 Waldeck 584 Walker B 275 Walker J 130, 135-6 Walther 583 Walton 485 Wang 151, 172 Wanson 670, 681

Ward 118, 129, 176-7 309, 642, 732 Warren E 203-4 Warren K 249 Wassell 431 Watkins-Pitchford 203 Watson 311 Watson-Wemyss 149 Wawruch 388, 733 Webb 629-30 Webbe 221 Wedl 484 Weinberg 118, 337, 373, 774 Weingarten 629 Weinland 110, 128, 190, 423-4 Welch 92 Weller 445 Wepfer 105, 323, 432, 821 Werner 363, 744 Westerman 162-3 Weston 92 Whalen 726 Wharton 362 Wherry 643 White A 449 White G 722 White R 449 Whitmarsh 622 Wielinga 725 Wilder 744-5, 821 Wiley 215 Willach 740 Williams C 515 Williams F 212 Williams O 744 Willius 114 Wilms 54, 549, 552

Person Index Wilson 615 Wiltschur 408 Winogradoff 306 Winter 629 Witenberg 311 Wolff 197 Wolffhüggel 433 Wolfs 289 Wolphius 398 Wood 582 Woodland 425 Woodruff 653, 677 Wordsworth 368 Wormald 571, 573 Wright 86, 445 Wrisberg 456 Wu 170 Wucherer 81, 500, 5023, 513, 523, 526, 598-

600, 623, 821 Wundt 442 Wurtz 707 Wykoff 59, 308, 771 Yamada 172, 428 Yamagiwa 169, 172, 264 Yamaguti 730 Yarwood 310 Yeh 737 Yokogawa M 168, 173, 176 Yokogawa S 56-7, 16670, 173, 275, 303-6, 510, 555, 729, 822 Yorke 737 Yoshida 119, 166, 169, 275, 428-9, 477-9, 554

835 Yoshimoto 281 Yoshino 369-70 Young 740 Zancarol 207, 235, 245 Zeder 6-7, 325, 363, 432, 457, 726, 744, 746 Zenker 50, 442-4, 447, 579, 581, 583-4, 5867, 725, 822 Zimmerman 422 Zschukke 675 Zuelzer 744 Zune 735 Zurn 432

SUBJEC T INDEX

- - disease 209, 520 Abiogenesis 29 Abramis 307 Acanthocephala 2, 8 Acanthocheilonema perstans 16, 737 Acanthocheilonema streptocerca 738 Acantogobius 304 Acerina 402 Achatina 723 Achillurbania nouveli 297, 311 Achillurbania recondita 297 Acis 423 Acriflavine 216 Acupuncture 772 Aedes 605, 613 Afroplanorbis 243 Agamofilaria streptocerca 738 Agchylostoma duodenale 500 Agchylostomum ceylanicum 502 Alaria 297 Albendazole 91 Alocima - see Bithynia Alternation of generations 43-5, 109, 327 Alyselminthus crassiceps 432 Amphimerus pseudofelineus 309 Amphistomum hominis 302 Anacardium, oil of - see cashew nut oil Anaemia, iron deficiency 512-20 Anaemia, pernicious 407-10 Anatrichosoma cutanea 721 Anchylostoma duodenale 13 Anchylostomum duodenale 501 Ancylostoma braziliense 502, 721-2 Ancylostoma caninum 510-1, 722 Ancylostoma ceylanicum 502 Ancylostoma duodenale anaemia 512-22 clinical features 520-2 diagnosis 522-3

discovery 499-501 epidemiology 527-8 landmarks 540-1 life cycle 502-10 nomenclature 500-1 pathology 510-20 prevention 528-31 synopsis 499 treatment 523-7 Ancylostoma malayanum 723 Ancylostomiasis 499-541 Ancylostomum duodenale 501 Angiostrongylus cantonensis 723-4 Angiostrongylus costaricensis 724-5 Anguillula intestinalis 13, 545-6 Anguillula stercorale 544 Anguillula stercoralis 13, 544-6 Anisakiasis 725 Anisakis marina 725 Anisakis simplex 725 Anisus 301 Ankylostoma duodenale 12, 501 Annelida 2 Anopheles 612-3 Anthelmintics see also individual anthelmintics traditional 75-82 1800-99 82 1900-24 82-4 1925-49 84-8 1950-74 88-92 1975+ 92 Anthiomaline - see antimonials Antimonials 83, 214-6, 282, 711 Ants 298, 427 Aphanius 304 Arecha catechu 80, 374 Arion ater 111 Armigerus 244 Arsenicals 84, 213, 711 Artemisia 77

836

Subject Index Artyfechinostomum mehrai 309 Artyfechinostomum sufratyfex 309 Ascariasis 469-97 Ascaridia columbae 473 Ascaris canis 744 Ascaris lumbricoides clinical features 480-4 diagnosis 484-5 discovery 469-71 epidemiology 487-8 landmarks 497 life cycle 471-4 nomenclature 470, 473-4 pathology 474-80 prevention 488-9 synopsis 469 treatment 485-7 Ascaris maculosa 473 Ascaris marginata 473 Ascaris megalocephala 473 Ascaris mystax 473, 746 Ascaris suum 489-90 Ascaris trichiura 457 Ascaris vermicularis 4, 440, 470 Ascaris vermicularis cauda subulata 5 Aspidium, oleoresin of - see male fern Australorbis 244 Avian schistosomes 286-7 Baermann technique 428 Baginulus 724 Bandwürmer 7 Barbus 307 Beetles 423 Belascaris cati 746 Belascaris mystax 744, 746 Bephenium 88, 487, 526 Bertia studeri 421 Bertiella mucronata 421 Bertiella polyordna 421 Bertiella satyri 421 Bertiella studeri 421 Betanaphthol 83, 136, 486, 524 Betel nut - see Areca Bible 30, 209, 588, 694 Bilharzia crassa 197 Bilharzia haematobia 12, 189-91 Bilharzia magna 189

837 Bilharzia polonica 202, 286 Biogenesis 53 Biomphalaria see Heliosoma, Planorbis Bismuth 83 Bithiniol 88, 119, 173 Bithynia 146-7, 307 Blackflies 667-670 Blanfordia 275-6 Blasenwürmer 7 Blicca 307 Bosmina 403 Bothriocephalus latus 9-10, 390 Bothriocephalus liguloides 428 Bothriocephalus mansoni 428 Bothriocephalus tropicus 388 Bradybaena 302 Brugia malayi discovery 604-5 Brugia pahangi 528 Brugia patei 605 Brugia timori 605 Bulimus 146 Bulinus - see Bullinus Bullinus 202-3, 241, 287-8 Bythinella 178, 308 Cambarus 177 Cambendazole 91, 561 Camphora 82 Cancer 776 Capillaria aerophila 725-5 Capillaria hepatica 726 Capillaria philippinensis 726-7 Carbon tetrachloride 83-4, 132, 134, 136, 486, 524 Carcinus 311 Cardiocondyle 427 Cashew nut oil 84 Cephalocotylea 11 Ceratocephyllus 423, 425 Cercaria 42, 107, 109-10, 286-8 Cestoda 2, 9 Cestoidea 9 Cheilospirura 727 Cheiracanthus siamensis 731 Chenopodium, oil of 81, 462, 486, 524 Chloroform 524

838

A History of Human Helminthology

Chloroquine 85, 173 Chloxyl - see Hetol Chrysanthemum 78, 374 Clarias 731 Classification 1-28 Clonorchiasis 141-57 Clonorchis endemicus 143 Clonorchis sinensis clinical features 149-50 diagnosis 151-1 discovery 141-3 epidemiology 152-3 landmarks 157 life cycle 143-7 nomenclature 142 pathology 147-9 prevention 153 synopsis 141 treatment 151 Coenurosis 431-2 Coenurus cerebralis 329-30, 332-3, 432 Coenurus glomerulatus 431 Coenurus tenuicollis 324, 329, 389 Conocephalus 302 Contracaecum osculatum 727 Corpse worms 769 Crabs 165-6, 174, 177-8, 311 Crayfish 174 Crustaceans 403-5, 428-9, 702-6, 711-3, 731 Ctenocephalides see Pulex Cucullanus 704 Cucurbita pepo 80, 374 Culex 604, 607, 609-11, 613, 626 Culicoides 735-8 Cyclocheilichthys 308 Cyclodontostomum purvisi 727 Cyclops 403-4, 428, 702-6, 711-3, 731 Cyprinus 307 Cystica 9 Cysticercosis 355-83 Cysticercus 363 Cysticercus bovis 390, 393 Cysticercus cellulosae clinical features 371-2 discovery 322, 362-3 life cycle 364-9 nomenclature 8, 363 see also Taenia solium

Cysticercus crispus 328 Cysticercus ex taenia mediocanellata 390 Cysticercus fasciolaris 321, 323-4, 3279, 333, 433 Cysticercus finna 7 Cysticercus longicollis 432 Cysticercus pisiformis 320, 329-30, 333, 365-6 Cysticercus tenuicollis 320-1, 324, 330 Davainea formosana 427 Davainea madagascariensis 426-7 Demerera filaria 734 Diaptomus 403-4, 412 Dibothriocephalus latus 399 Dibothrium latum 11, 399 Dichlorophene 88, 136 Dicrocoelium dendriticum 297-0 Dicrocoelium hospes 299 Diethylcarbamazine 85, 487, 626, 6534, 679-80 Dioctophyma renale 728 Dioplongonoporus fukuokaensis 422 Dipetalonema arbuta 728 Dipetalonema ozzardi 735 Dipetalonema sprenti 728 Dipetalonema streptocerca 738 Diphetarsone 462 Diphyllobothriasis 397-419 Diphyllobothrium cordatum 428 Diphyllobothrium dalliae 414 Diphyllobothrium decipiens 430 Diphyllobothrium dendriticum 414 Diphyllobothrium erinacei 430-1 Diphyllobothrium houghtoni 430 Diphyllobothrium lanceolatum 414 Diphyllobothrium latum clinical features 405-10 diagnosis 410 differentiation 397-9 epidemiology 411-3 landmarks 419 life cycle 399-405 nomenclature 399 pernicious anaemia 407-10 prevention 413 synopsis 397 treatment 410-1

Subject Index Diphyllobothrium mansoni 429 Diphyllobothrium mansonoides 430 Diphyllobothrium okumari 430 Diphyllobothrium pacificum 414 Diphyllobothrium ranarum 430 Diphyllobothrium reptans 430 Diphyllobothrium ursi 414 Diplocanthus 424 Diplogonoporus grandis 422 Diploscapter coronata 729 Dipterex - see metrifonate Dipylidium caninum 331, 364, 422-3 Dipylidium cucumerinum 422 Dirofilaria conjunctivae 729 Dirofilaria immitis 612, 729 Dirofilaria repens 729 Dirofilaria tenuis 729 Dirofilaria ursi 730 Distoma - 106, see also Distomum Distoma - see also Distomum Distoma buski 14, 160 Distoma compactum 162 Distoma conjunctum 309 Distoma cygnoides 109 Distoma endemicum 152 Distoma haematobium 12, 188-9 Distoma hepaticum 7 Distoma hepatis endemicum sive innocuum 142 Distoma hepatis endemicum sive perniciosum 142 Distoma heterophyes 14, 303 Distoma japonicum 14 Distoma nodulosum 111 Distoma pancreaticum 302 Distoma pulmonale 162 Distoma pulmonalis 162 Distoma rathouisi 129 Distoma ringeri 14, 160 Distoma rude 162 Distoma sinense 14 Distoma spathulatum 142 Distoma trigonocephalum 111 Distoma viverrini 308 Distoma westermanni 163 Distomum capense 190 Distomum crassum 13, 128 Distomum hians 108

839 Dithiazanine 88-9, 462, 561 Dobium erinacei-europaei 431 Dochmius ankylostomum 501 Dochmius trigonocephalus 502, 507 Dracontiasis - see dracunculiasis Dracunculiasis 693-720 Dracunculus loa 12, 643 Dracunculus medinensis clinical features 707-9 diagnosis 709 discovery 693-8 epidemiology 711-3 incubation period 706-7 landmarks 720 life cycle 698-706 nomenclature 697-8 prevention 713-4 synopsis 693 treatment 709-11 Dryoptera filix mas - see male fern Ducks 41 Earworms 768 Ebers papyrus - see Papyrus Ebers Echinochasma perfoliatus 299 Echinococcosis 319-53 Echinococcus altricipariens 12, 326, 332 Echinococcus alveolaris 433-4 Echinococcus granulosus clinical features 335-6 diagnosis 337-8 discovery 319-26 epidemiology 340-1 landmarks 353 life cycle 326-33 nomenclature 325 pathology 333-5 prevention 342-3 synopsis 319 treatment 338-40 Echinococcus hominis 325-5 Echinococcus hydatidosa 326 Echinococcus multilocularis 343-6 Echinococcus polymorphus 325 Echinococcus scolicipariens 12, 326 Echinococcus simiae 325 Echinococcus simplex 326 Echinococcus veterinorum 325-6, 331 Echinococcus vogeli 346-7

840

A History of Human Helminthology

Echinoparyphium paraulum 299 Echinoparyphium recurvatum 299 Echinostoma hortense 300 Echinostoma ilocanum 300 Echinostoma jassyense 301 Echinostoma lindoense 300 Echinostoma malayanum 309 Echoing worms 769 Eliocharis 132 Emboitement 33, 38 Emetine 173, 216, 281 Enterobiasis 439-54 Enterobius vermicularis clinical features 444-5 diagnosis 445-6 discovery 439-40 epidemiology 446-7 landmarks 454 life cycle 440-3 nomenclature 440 pathology 443-4 prevention 447-9 synopsis 439 treatment 447-9 Entozoa 2 Epigenesis 32 Equivocal generation 29 Eriocheir 165-6 Esox 401, 412 Eucalyptus, oil of 524 Euparyphium melis 301 Eurytrema pancreaticum 302 Eustoma rotundatum 725 Eustrongyloides 730 Eustrongylus gigas 728 Eyeworms 768 Fasciola gigantica 121 Fasciola hepatica clinical features 116-8 diagnosis 118 discovery 103-6 epidemiology 119-20 landmarks 126 life cycle 106-14 prevention 121 synopsis 103 treatment 118-9 Fasciola hominis 6

Fasciola melis 301 Fasciola revoluta 301 Fascioletta ilocanum 300 Fascioliasis 107-26 Fasciolopsiasis 127-40 Fasciolopsis buski clinical features 133-5 diagnosis 135-6 discovery 127-9 epidemiology 136-7 landmarks 140 life cycle 130-2 nomenclature 129 pathology 133-8 prevention 137 synopsis 127 treatment 136 Fasciolopsis fülleborni 129 Fasciolopsis goddardi 129 Fasciolopsis spinifera 129 Fermentation 52 Ferrisea 205 Ficus 81 Filaria bancrofti 15, 602 Filaria demarquayi 734-6 Filaria dermathemica 662 Filaria diurna 15, 644 Filaria immitis 729 Filaria labialis 732 Filaria lacrymalis 10, 643 Filaria loa 14, 643 Filaria malayi 604 Filaria medinensis 6 Filaria nocturna 614, 644 Filaria oculi 643 Filaria oculi humani 10, 643 Filaria ozzardi 15 Filaria palpebralis 743 Filaria papillosa haematobia canis domestica 729 Filaria perstans 15, 644 Filaria philippinensis 604-5 Filaria sanguinis hominis 13, 601, 603 Filaria sanguinis hominis diurna 644 Filaria sanguinis hominis major 644 Filaria sanguinis hominis minor 644, 736 Filaria sanguinis hominis nocturna 644 Filaria sanguinis hominis perstans

Subject Index 644, 736 Filaria subconjunctivalis 643 Filaria volvulus 15 Filaria volvulxus 662-3 Filariasis 597-640 Filix mas - see Male fern Fish 41, 144-5, 299, 304-8, 400-2, 731 Fleas 423, 425 Fluke 104 Formica 208 Frogs 299, 301-2, 429 Furia infernalis 769-70 Fusaria dispar 7, 457 Fusaria lumbricoides 7 Fusaria mystax 744, 746 Fusaria vermicularis 7 Galumna 421 Galvinism 710 Gambusia 304 Gastrodiscoides hominis 302 Geese 44, 108 Gentian violet 85-6, 499, 561 Gigantobilharzia 287 Glossobius 731 Glottis 361 Gnathostoma hispidum 732 Gnathostoma pulchrum 732, 776-7 Gnathostoma siamense 731 Gnathostoma spinigerum 730-2 Gnathostomiasis 7302 Goeffroea surinamensis cortex 82 Gordius medinensis 4 Grasshoppers 302 Gregarina 161-2 Ground-itch 509 Guinea worm - see Dracunculus medinensis Guinea worm infection - 693-720 Gynaecophorus haematobia 189-90 Gyraulus 300 Haemonchus contortus 732 Haemostrongylus ratti 723 Hagenia abyssinica 78, 374 Hakenwürmer 7 Halysis lata 7 Halysis solium 7 Hampala 308

841 Haplorchis pumilio 303 Haplorchis tachui 303 Haplorchis yokogawai 303 Helicella 298 Helicorbis 302 Heliosoma 243 Helminal 486 Helminth, derivation of term 2-3 Helminthocorton 82 Hepaticola hepatica 726 Heterakis maculosa 473 Heterobilharzia 287 Heterodera radicicola 449-50 Heterogenesis 52 Heterogony 505-6 Heterophyes aegyptiaca 303 Heterophyes brevicaeca 311 Heterophyes heterophyes 303-4 Heterophyes katsuradai 304 Heterophyes nocens 303 Heterophyes yokogawai 305 Hetol 89, 307 Hexachlorophene 89 Hexylresorcinol 86, 136, 462, 486, 525 Himasthla muehlensi 305 Hippeutis - see Planorbis Höllenwurm 769-70 Hookworm - see Ancylostoma, Necator Hookworm disease 499-541 Hycanthone 86, 217 Hydatid - see Echinococcus Hydatigera granulosus 325 Hydatigera taeniaeformis 433 Hymenolepis diminuta 423-4 Hymenolepis fraterna 425 Hymenolepis longior 425 Hymenolepis nana 424-6 Hypoderaeum conoidea 305 Hypoloberca 177 Idus 307 Illustrations of worms, early 771-2 Imaginary worms 765-70 Immunity 37, 774-6 Indoplanorbis 301, 309 Inermicapsifer madagascariensis 426 Infection 26 Infestation 26

842

A History of Human Helminthology

Infusoria 39 Intestina 4 Iron deficiency anaemia 512-20 Isalopotamon 177 Iulus 473 Ivermectin 92, 561, 680 Jericho 209 Kahun papyrus 209 Kamala 80, 374 Katayama disease 279 Katayama - 273 Kosso - see Kousso Kousso 78-9 La dauve 114 Lagochilascaris minor 733 Latex of higueron - see Leche de higueron Leche de higueron 81-2, 462, 523 Leptodera 544 Leuciscus 307, 473 Leucobia 144 Levamisole 91, 487 Lice 422 Ligula mansoni 428 Limnea 110-3 - see also Lymnaea Limneus 110-3 - see also Lymnaea Lithoglyphosis 288, see Tricula Loaches 300 Loa loa clinical features 649-51 diagnosis 651-2 discovery 641-6 epidemiology 654 landmarks 660 life cycle 647-9 nomenclature 643 periodicity 643-7 prevention 655 synopsis 641 treatment 652-4 Loiasis 641-60 Lota 401, 412 Loxotrema ovatum 305 Lucanthone 86, 216, 282 Lumbricus 3-4, 322, 324 Lymnaea 107, 286, 301, 305 - see also Limneus, Limnea

Maggots, generation of 33-5 Magic 773 Male fern 76-7, 213, 301, 373, 375, 524 Mallotus philippinensis 80, 374 Mammomonogamus laryngeus 733 Mansonella ozzardi Mansonella perstans 736-8 Mansonella streptocerca 738 Mansonia 613 Massage 772 Mastigodes hominis 7 Mebendazole 91, 340, 449, 462, 487, 526, 727 Melania 145-6, 164, 166, 306 Menichopholan - see Niclofolan Meningonema peruzzii 738 Mepacrine 86-7, 375, 426 Mesocestoides lineatus 426 Mesocestoides variabilis 926-7 Metagonimus 174 Metagonimus yokogawai 305 Metastrongylus elongatus 739 Metrifonate 89, 217, 253 Metronidazole 119, 711 Microfilaria bolivarensis 739 Microfilaria rodhaini 739 Microfilaria semiclarum 739 Micronema deletrix 739-40 Microscope 36 Miracils - see hycanthone, lucanthone Misgurnus 300 Mites 421 Molluscicides 221 Monkey 189, 197 Monostomum flavum 108 Monostomum mutabile 108-9 Moon 773 Mordwurm 769-70 Morerastrongylus costaricensis 724 Mosquitoes 606-613 Moxibustion 772-3 Mugil 304 Multiceps longihamatus 433 Multiceps multiceps 432 Multiceps serialis 432 Music 370, 773 Mytilus 305 Myzelmintha 11

Subject Index Nanophyes salmincola 311 Nanophyetus salmincola 311 Nanophyetus schickhobalovi 311 Nasal worms 768 Nasturtium officinale 120 Necator americanus discovery 501 nomenclature 501 see also Ancylostoma duodenale Necator suillis 740 Nematoda 1, 8 Nematomorpha 2 Niclofolan 174 Niclosamide 89, 375, 411, 426 Niridazole 89-90, 217, 253, 282, 711 Nomenclature, rules of zoological 16 -24 Nomenclature 1-28, see also individual worms Notropis 144 Odontobutis 306 Oesophagostomum apiostomum 740 Oesophagostomum bifurca 740 Oesophagostomum brumpti 740 Oesophagostomum stehpanosum 740 Oleum animali Dippelis 82 Oleum cajeputi 82 Oleum chaberti 82 Oleum terebinthicae 82 Olive oil 448 Onchocerca dermathemica 662 Onchocerca gutturosa 684 Onchocerca volvulus clinical features 670-7 diagnosis 677-8 discovery 661-4 epidemiology 681-2 landmarks 691 life cycle 667-70 nomenclature 664 pathology 665-7, 670-7 prevention 682-4 synopsis 661 treatment 679-80 Onchocerciasis 661-91 Oncomelania - see Blanfordia, Katayama Opisthorchis felineus 306-7

843 Opisthorchis guayaquilensis 309 Opisthorchis noverca 308-9 Opisthorchis sinensis 142 Opisthorchis tenuicollis 308 Opisthorchis viverrini 308 Orientobilharzia 287 Ornithobilharzia 287 Ostertagia circumcincta 741 Ostertagia ostertagi 741 Oxamniquine 90, 253 Oxantel 90 Oxytrema 311 Oxyuris "incognita" 449 Oxyuris vermicularis 10, 440 Papyrus Ebers 75-6, 209, 355, 439, 469, 520, 693 Parafossarulus - see Bithynia Paragonimiasis 159-85 Paragonimus africanus 177 Paragonimus ecuadoriensis 177 Paragonimus heterotremus 177 Paragonimus hueitungensis 177 Paragonimus kellicotti 176-7 Paragonimus mexicanus 178 Paragonimus miyazakii 178 Paragonimus peruvianis 178 Paragonimus szechuanis 178 Paragonimus tuanshahensis 177 Paragonimus westermani clinical features 171-2 diagnosis 172 differentiation 177 discovery 159-63 epidemiology 174-5 landmarks 185 life cycle 164-9 nomenclature 163 pathology 169-70 prevention 175-6 synopsis 159 treatment 172-4 Parascaris equorum 473 Parasitism 24-5 Parasitophobia 770 Paromomycin 90 Parthenogenesis 549 Paryphostomum sufratyfex 309 Pelodera strongyloides 741

844

A History of Human Helminthology

Perca 402 Periodicity 613-5 Pernicious anaemia 407-10 Phenothiazine 87, 449 Philophthalmus 309 Phocanema 743 Physaloptera caucasica 741 Physaloptera mordens 741 Physopsis 203-4 Piperazine 87, 439, 486-7 Pirenella 304 Plagiorchis 309 Plagiorchis congolensis 310 Plagiorchis javensis 310 Plagiorchis muris 310 Plagiorchis philippinensis 310 Planaria latiuscula 103 Planorbarius 204 Planorbina 244 Planorbis 132, 137, 202-4, 241, 341-4, 289, 300-1 Platyhelminthes 1 Plectoglossis 305-6 Plerocercoides prolifer 430 Polycephalus echinococcus 7, 325 Polycephalus hominis 7, 325 Polysarcus 163 Pomatiopis 177 Pomegranate 76, 374 Potadoma 177 Potamon 165-8 Praziquantel 92, 119, 136, 151, 217, 282, 307, 375, 411, 426 Preformation 33 Priority, law of 18, 22-4 Proglottis 361 Prontosil - see Sulphonamides Pseudasbora 144, 146 Pseudoparasites 770 Pseudorhabditis stercoralis 547 Pulex 422-3, 425 Pulmonema cantonensis 723 Pumpkin seeds 80, 374 Punica granatum 76, 374 Punta 308 Purgatives 82, 485-6 Pygidiopsis summa 310-1 Pyrantel 90, 449, 487, 526 Pyrgophyla 202

Pyrvinium - see Viprynium Quinacrine - see Mepacrine Raillietina celebensis 427 Raillietina demerariensis 427 Raillietina madagascariensis 426 Rats 724 Rattus 724 Redia 108 Rhabditis 502, 544, 546, 742 Rhabdonema intestinale 14 Rhabdonema strongyloides 548 Rictularia 742 Rockefeller Foundation 222, 517, 529 -30 Royal yellow worms 107-8 Rules of zoological nomenclature 16 -24 Rundwürmer 7 Salmo 306, 412 Salpae 109 Salvarsan - see Arsenicals Santonin - see Semen-contra-vermes Saugwürmer 7 Scannus 423 Scheloribates 421 Schistosoma bovis 202, 287 Schistosoma cattoi 267 Schistosoma haematobium clinical features 208-11 dams and 219 diagnosis 211-2 discovery 187-9, 191 epidemiology 218-9 landmarks 231 nomenclature 189-91 pathology 205-8 prevention 220-2 synopsis 187 treatment 212-8 Schistosoma incognitum 287 Schistosoma intercalatum 287 Schistosoma japonicum clinical features 279-81 diagnosis 281 discovery 263-8 epidemiology 283-4

Subject Index landmarks 295 life cycle 268-76 pathology 276-9 prevention 284-6 synopsis 263 treatment 281-2 Schistosoma mansoni clinical features 249-51 diagnosis 251-3 discovery 233-40 epidemiology 254 landmarks 262 life cycel 240-4 nomenclature 236 pathology 244-9 prevention 220-2 synopsis 187 treatment 217-8 Schistosoma margrebowiei 288 Schistosoma matthei 288 Schistosoma mekongi 288 Schistosoma rodhaini 289 Schistosome dermatitis 286-7 Schistosomes, avian 286-7 Schistosomiasis haematobia 187-231 Schistosomiasis japonica Schistosomiasis mansoni 233-62 Sclerostoma caninum 722 Sclerostoma duodenale 12, 501 Scolex 362 Segmentina 130-2, 137 - see also Planorbis Semen-contra-vermes 77, 486 Semisulcospira - see Melania, Thiara Sesarma 166 Sheep rot 116-7, 119-20 Simulium 668-70 Siropotamon 177 Slugs 724 Snails - see individual genera Snails 49, 106-14, 130-2, 143-7, 164-9, 198-205, 240-4, 270-6, 298, 300-2, 304-5, 307, 309, 311, 723 Snakes 429, 730 Sparganosis 428-30 Sparganum erinacei-europaei 431 Sparganum mansoni 428 Sparganum proliferum 430 Spelotrema brevicaeca 311

845 Spirocerca lupi 742 Spirometra 430 Spirometra erinacei 431 Spirometra houghtoni 430-1 Spirometra neoplastica 776-7 Spirometrosis 430-1 Spontaneous generation 29-53 Stannum 82 Stellanctchasmus falcatus 312 Stephanolecithus parvus 168 Stibocaptate - see Antimonials Stibophen - see Antimonials Stilbazium 90 Stizolobium 82 Stizostedeon 412 Stomachida lumbricoides 470 Strobilos 361-2 Strongyloides intestinalis 15 Strongyloides stercoralis clinical features 557-9 diagnosis 559-60 discovery 543-50 epidemiology 562 landmarks 569-70 life cycle 551 nomenclature 546 pathology 550-1, 553-7 prevention 562 synopsis 543 treatment 560-1 Strongyloidiasis 543-70 Strongylus colubriformis 746 Strongylus contortus 732 Strongylus convulutus 741 Strongylus elongatus 739 Strongylus fülleborni 562 Strongylus fülleborni-like 562 Strongylus gigas 728 Strongylus intestinalis 546 Strongylus lupi 742 Strongylus ostertagi 741 Strongylus probulurus 746 Strongylus quadridentatus 501 Strongylus subtilis 747 Sudanautes 177 Sulphonamides 173 Suramin 87, 679 Syngamus kingi 733 Syngamus laryngeus 733

846

A History of Human Helminthology

Syngenesis 33 Systema Naturae 1, 5, 18, 362-3, 386, 440, 469 Tabanids 647-9 Taenia à épine 398 Taenia alveolaris 344 Taenia brauni 431-2 Taenia canina 14, 422 Taenia cateniformis 331 Taenia cellulosae 6 Taenia crassiceps 329, 432-3 Taenia crassicollis 328-30, 332, 433 Taenia cucumerina 331, 364, 422 Taenia cucurbitina grandis saginata 5, 386-7 Taenia cucurbitina plana pellucida 5, 386-7 Taenia demerariensis 427 Taenia dentata 388 Taenia echinococcus 12, 331-3 Taenia egyptiaca 424 Taenia elliptica 12 Taenia ex cysticerco tenuicollo 365-6 Taenia flavopunctata 12 Taenia hydatigena 320, 324, 365 Taenia hydatigena granulosa 325 Taenia inerme 388 Taenia infantis 457 Taenia intestinorum 398 Taenia lata 4 Taenia longihamatus 433 Taenia madagascariensis 427 Taenia mediocanellata 12, 388 Taenia multiceps 332, 431-2 Taenia murina 424 Taenia nana 12, 331 Taenia osculis marginalibus oppositus 422 Taenia pellucida 388 Taenia pisiformis 329 Taenia prima Plateri 398 Taenia saginata clinical features 392 diagnosis 392 discovery 385-9 epidemiology 393 landmarks 396 life cycle 389-91

nomenclature 3-4, 388-9 prevention 393 synopsis 385 treatment 392 Taenia sans épine 386, 398 Taenia secunda Plateri 398 Taenia serialis 431-2 Taenia serrata 330, 365-6 Taenia solium clinical features 369-72 diagnosis 372-3 discovery 355-63 epidemiology 376 landmarks 383 life cycle 364-9 nomenclature 3-4, 6, 356-7, 361-2 prevention 376-7 synopsis 355 treatment 373-5 Taeniarhynchus saginata 389 Taeniasis saginata 385-396 Taeniasis solium 355-83 Taenia taeniaeformis 324, 328, 433 Taenia vesicularis, cerebrina, multiceps 432 Taenia visceralis 6 Taenia visceralis socialis granulosus 5, 325-6 Taenia vulgaris 6 Tanaceti vulgaris semina 82 Taphius 244 Tartar emetic - see Antimonials Tenebrio 328, 423, 425 Ternidens deminutus 742-3 Terranova 743 Tetrachlorethylene 87, 136, 525 Tetramisole 91, 487 Tetrapetalonema perstans 737 Tetrapetalonema streptocerca 738 Thecosema 189 Thelazia californiensis 744 Thelazia callipaeda 743 Theology 38 Thiabendazole 91, 449, 487, 526, 561, 586, 727 Thiara 145-6 - see also Melania Thomas, curse of 616 Thominx aerophila 725 Thymobenzene 213

Subject Index Tilapia 304 Tin 78, 374 Tinca 307 Toothworms 765-8 Toxocara canis 473, 744 Toxocara cati 473, 746 Toxocariasis 744-6 Transmission of worms 29-74 early times 29-33 1650-1699 33-7 1700-1749 37-9 1750-1799 39-41 1800-1824 41-3 1825-1849 43-6 1850-1874 46-53 1875-1899 53-5 1900-1924 55-8 1925+ 68-9 landmarks 70-3 see also Individual worms Trapa 132 Treatment, unorthodox 772-3 Treatment, worms as 774 Trematoda 1, 8-9 Trichina affinis 10, 457 Trichina spiralis 10, 573 Trichinella spiralis clinical features 582-4 diagnosis 584-5 discovery 571-80 epidemiology 586-8 landmarks 596 life cycle 578-80 nomenclature 573 pathology 580-2 prevention 588-91 synopsis 571 treatment 585-6 Trichinosis 571-96 Trichobilharzia 286 Trichocephalos 5 Trichocephalus affinis 458 Trichocephalus crenatus 458 Trichocephalus depressiusculus 458-9 Trichocephalus dispar 11, 457, 579 Trichocephalus hominis 6 Trichocephalus trichiurus 15 Trichodectes 422 Trichosoma aerophilum 725

847 Trichosoma cutaneum 721 Trichostrongyliasis 746-7 Trichostronyglus axei 746 Trichostrongylus brevis 746 Trichostrongylus colubriformis 746 Trichostrongylus orientalis 746 Trichostrongylus skrjabini 746 Trichostrongylus vitrinus 746 Trichuriasis 455-68 Trichuris suis 463 Trichuris trichiura clinical features 459-61 diagnosis 461-2 discovery 455-7 epidemiology 463 landmarks 468 life cycle 457-8 nomenclature 456-7 pathology 458-9 prevention 463 synopsis 455 treatment 462 Trichuris vulgaris 457 Trichuris vulpis 463-4 Tricula 177-8, 288 Troglotrema salmincola 311 Tropical eosinophilia 629-30 Tropicorbis 243 Turpentine 374, 448, 462, 486 Tylenchus 737 Tympanotonus 304 Umbilical worms 768-9 Uncinaria americana 15Uncinaria duodenale 501 Uncinaria duodenalis 501 Uncinaria stenocephala 501-2, 747 Unio 193 Univocal generation 36 Unorthodox treatment 772-3

848

A History of Human Helminthology

Urine worms 768 Vermes 1 Verminus 777 Vermis 1, 4 Viprynium 92, 449 Vitamin B12 409-10 Water caltrop 132, 136-7 Water chestnut 132, 136-7 Watercress 120 Watsonius watsoni 311-2 Worm, derivation of term 1 Wormseed oil - see Oil of Chenopodium Wuchereria bancrofti clinical features 615-23 diagnosis 623-4 discovery 597-605

epidemiology 626-7 landmarks 640 life cycle 606-13 nomenclature 604 pathology 618-23 periodicity 613-5 prevention 627-8 synopsis 597 treatment 624-6 Wuchereria malayi 605 Wuchereria pahangi 605 Xenopsylla 423, 425 Zebrina 298 Zoological nomenclature 16-24 Zoophyta 4