Study of Nutritional Factors in Food Allergies and Food Intolerance...
ISSN 1018-5593
E U R O P E A N COMMISSION
Studies
Study of nutritional factors in food allergies and food intolerances
Agro-industrial Research Division
EUR 16893 EN
European Commission
Study of nutritional factors in food allergies and food intolerances In the framework of the agriculture and agro-industry including fisheries programme, adopted by the Council of Ministers of the European Communities Contractor
Prof. Claudio Ortolani Head of Department for Prevention, Diagnosis and Treatment of Allergic Disease, Niguarda Hospital, Milan, Italy. Responsible for the study
Prof. Elide Anna Pastorello Associate Professor of Allergy and Clinical Immunology, University of Milan-Policlinico Hospital, Milan, Italy. Collaborators
Dr Raffaella Ansaloni Dr Cristoforo Incorvaia Dr Marco Ispano Dr Valerio Pravettoni Dr Federica Rotondo Dr Joseph Scibilia Dr Giuseppe Vighi
AIR1-93-8012-IT Directorate-General XII Science, Research and Development
1997
EUR 16893 EN
Published by the EUROPEAN COMMISSION Directorate-General XII Science, Research and Development B-1049 Brussels
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Luxembourg: Office for Official Publications of the European Communities, 1997 ISBN 92-827-9554-3 © ECSC-EC-EAEC, Brussels · Luxembourg, 1997 Reproduction is authorized, except for commercial purposes, provided the source is acknowledged Printed in Italy
Abbreviations AD AGA ARF ASA BHA BSA BIHT CAMP CD CIE CUE CNS CRIE DBPCFC DNCB EAACI eHF EIA ELISA FDA FEV1 GALT G6PD HR kd IBS IEL MAO MHC MSG MW NSAID OAS OME OSA OVA PCB PGE pHF PMN RIA SDS-PAGE SPT TCR
Atopic dermatitis Antigliadin antibodies Adverse reactions to food Acetylsalicilic acid Butylated hydroxyanisole Bovine serum albumine Butylated hydroxytoluene Cyclic adenosine monophosphate Celiac disease Crossed Immunoelectrophoresis Crossed line Immunoelectrophoresis Central nervous system Crossed radio-immunoelectrophoresis Double-blind placebo-controlled food challenges Dinitro chlorobenzene European Academy of Allergology and Immunology Extensively hydrolyzed formulae Exercise induced anaphylaxis Enzyme linked immuno sorbent assay Food and Drugs Administration Forced expiratory volume at 1st second Gut associated lymphoid tissue Glucose-6-phospho-deidrogenase Histamine release (test) Kilo Dalton Irritable bowel syndrome Intra epithelial lymphocytes Monoamine oxidase Major histocompatibility complex Monosodium glutamate Molecular weight Non-steroidal anti-inflammatory drugs Oral allergy syndrome Otitis media with effusion Ovine serum albumine Ovalbumine Parachlorobenzene Prostaglandine Partly hydrolyzed formulae Polimorphonuclear cells Radio-immunoassay Sodium dodecyl sulfate-polyacrilamide gel electrophoresis Skin prick tests Τ cell receptor
INDEX SUMMARY
11
CLASSIFICATION AND TERMINOLOGY OF ADVERSE REACTIONS TO FOOD
15
1.1.
Toxic food reactions
16
1.2.
Non-toxic food reactions
16
1.2.1.
IgE-mediated reactions
16
1.2.2.
Non-lgE-mediated food allergy
16
GENERAL OUTLINE OF THE ROLE OF FOOD COVERING THE DIFFERENT HYPOTHESES
18
2.1.
Toxic reactions
18
2.2.
Non-toxic reactions
19
2.2.1.
Immunological reactions (food allergy)
19
2.2.1.1. IgE-mediated food allergy
19
2.2.1.2. Non-lgE-mediated food allergy
20
Non-immune mediated adverse reactions to foods
21
2.2.2.1. Enzymatic food intolerance
21
2.2.2.
2.2.2.2. Pharmacological food intolerance
21
2.2.2.3. Additive intolerance
22
SYMPTOMS OF FOOD ALLERGY AND FOOD INTOLERANCE
26
3.1.
Oral allergy syndrome (OAS)
26
3.2.
Extra oral symptoms
28
3.2.1.
Rhinoconjunctivitis
28
3.2.2.
Serous otitis media with effusion
28
3.2.3.
Asthma
29
3.2.4.
Urticaria and angioedema
29
3.
4.
3.2.5.
Atopie dermatitis (AD)
30
3.2.6.
Acute contact urticaria and angioedema
31
3.2.7.
Systemic anaphylaxis
31
3.2.8.
Exercise induced anaphylaxis (EIA)
33
3.2.9.
Gastrointestinal hypersensitivity reactions to food
33
3.2.9.1. Gastrointestinal anaphylaxis
34
3.2.9.2. Infantile colics
34
3.2.9.3. Allergic eosinophilic gastroenteropathy
34
3.2.9.4. Food-induced enterocolitis syndrome
35
3.2.9.5. Food-induced colitis
35
3.2.9.6. Food-induced malabsorption syndrome
35
3.2.9.7. Lactose intolerance
35
3.2.9.8. Dermatitis herpetiformis
36
3.2.9.9. Celiac disease (CD)
36
3.2.9.10. Heiner's syndrome or food-induced pulmonary hemosiderosis
37
PATHOGENESIS OF FOOD ALLERGY
46
4.1.
Introduction
46
4.2.
Oral tolerance
46
4.3.
Immaturity of the immune system
50
4.4.
Role of allergens
51
FOOD ALLERGENS
58
5.1.
Introduction
58
5.2.
Allergens
59
5.2.1.
Cow's milk
59
5.2.2.
Hen's egg
59
5.2.3.
Fish
61
5.2.4.
Shrimp
62
5.2.5.
Peanut
62
5.2.6.
Soybean
63
5.2.7.
Cereals
63
5.2.8.
Apple
64
5.2.9.
Celery
65
5.2.10 Prunoideae
65
PREVENTION OF FOOD ALLERGY
72
6.1.
Introduction
72
6.2.
Known risk factors for developing food allergy
72
6.3.
Possible interventions aimed at preventing food allergy
73
6.3.1.
Comparison between breast-feeding and cow's milk feeding
75
6.3.2.
Comparison between soya feeding and cow's milk feeding
75
6.3.3.
Comparison between hydrolyzed cow's milk formulae and other kinds of feeding
76
6.
6.4. Conclusions
76
INTERACTION WITH LIFESTYLE AND PROFESSION
83
7.1.
Interactions with lifestyle
83
7.2.
Interactions with profession
84
7.2.1.
Cereal flour
84
7.2.2.
Hen's egg
85
7.2.3.
Cow's milk
86
7.2.4.
Seafoods
86
7.2.5.
Legumes
86
7.2.6.
Coffee
87
7.2.7.
Garlic
87
7.2.8.
Onion
87
7.2.9.
Sesame seed
87
7.2.10. Others
87
Prophylactic measures
88
EPIDEMIOLOGY OF FOOD ALLERGY
93
8.1.
Introduction
93
8.2.
Epidemiology in adults
93
8.3.
Epidemiology in children
94
8.4.
Conclusions
95
CHANGING DIETARY HABITS
97
7.3.
8.
10. EFFECTS OF PROCESSING AND PREPARATION OF FOOD
10.1. Food allergens alteration by food processing and preparation
104
104
10.1.1.
Fruit and vegetables
105
10.1.2.
Cow's milk
105
10.1.3.
Fish
106
10.1.4.
Meat
107
10.1.5.
Hen's egg
107
10.1.6.
Shrimp
108
10.1.7.
Microparticulated proteins
108
10.1.8.
Peanut
109
10.1.9.
Soybean
110
10.1.10. Corn
110
10.1.11. Sunflower oil
110
10.1.12. Sesame seed oil
111
10.1.13. Lupin seed
111
10.1.14. Food contaminants
111
10.2. Food contaminants
114
10.3. Food additives
117
10.3.1.
Preservatives
119
10.3.1.1. Benzoates and parabens
119
10.3.2.
Antioxidants
120
10.3.3.
Sorbic acid
121
10.3.4.
Gallates
121
10.3.5.
Tocopherols
121
10.3.6.
Sulfiting agents
121
10.3.7.
Colourants
123
10.3.8.
Monosodium glutamate
125
10.3.9.
Other additives and spices
126
10.3.10. Controversy in food additive intolerance
126
10.3.11. Diagnosis of food additive intolerance
127
10.4. Hidden allergens
11. DIAGNOSIS OF FOOD ALLERGY
136
140
11.1. Introduction
140
11.2. Clinical history
140
11.3. Elimination diets
141
11.4. Skin tests
142
11.5. In vitro tests
144
11.6. Double-blind placebo-controlled food challenge (DBPCFC)
144
12. CONTROVERSY ON ADVERSE REACTIONS TO FOOD
150
12.1. Non-validated methods
150
12.1.1. Cytoxicity test
150
12.1.2. Subcutaneous and sublingual provocation and neutralization
151
12.1.3. DRÍA test
152
12.1.4. Electroacupuncture
152
12.1.5. Applied kinesiology
153
12.2. Inappropriate diagnostic tests
153
12.2.1. Serum IgG antibodies
153
12.2.2. Food immune complex assay
153
12.3. Clinical manifestations non-typical of food allergy 12.3.1. Headache
154
12.3.2. Children's hyperactivity
155
12.3.3. Schizophrenia
156
12.3.4. Other neurologic and psychic disorders
157
12.3.5. Arthritis
158
12.3.6. Vasculitis
158
12.3.7. Irritable bowel syndrome
159
12.3.8. Otitis media with effusion
159
12.3.9. Allergy to twentieth century
159
12.4. Conclusions
13. POSITIVE APPROACHES
160
166
13.1. Hypoallergenic formulas
166
13.2. Non-allergenic food
171
13.3. Specific immunotherapy in food allergy
180
14.
IMPORTANCE OF FOOD HYPERSENSITIVITY IN PUBLIC HEALTH, ECONOMIC EFFECTS, GROUPS AT RISK
183
14.1. The public health role
183
14.2. Groupsat risk
187
15. CONCLUDING REMARKS
10
154
194
SUMMARY The recent Position Paper of the European Academy and Clinical Immunology Subcommittee on Adverse Reaction to Food (ARF) divided the ARF into toxic and non-toxic. The latter are subdivided in immunomediated (in clinical practice represented quite exclusively by the IgE-mediated reactions) and non-immunemediated (enzymatic, pharmacologic and undefined intolerances). Toxic reaction to food affects all human beings exposed. The major sources of toxicity of foodstuffs are the toxic substances induced in food processing, contaminants and additives. IgE-mediated food allergy is the most frequent, the best known and the easiest to be diagnosed of the ARF. However the diagnosis of IgE-mediated food allergy must be made only when the relationship between the ingestion of a particular food and the symptoms is well established. An evident role in clinical food allergy of non-lgE-mediated food allergy (i.e. IgG responses to foods, immune complexes with food allergens, cell mediated immunity to food), at the moment has not yet been demonstrated, and this topic maintains only theoretical importance. Enzymatic food intolerances, except for lactase deficiency, are rare conditions, mainly due to inborn errors of metabolism. The pharmacological food intolerance includes: (1) the effects of vasoactive amine contained in some fruits; (2) the effects of mediator released by non-immunologic mechanism and (3) the intolerances to food additives. The symptoms of food allergy involve different organs. Oral allergy syndrome is frequent among patients with pollen allergy and it is provoked by sensitization to plant food allergens. This syndrome is frequently associated with birch or mugwort pollinosis. Rhinoconjunctivitis, asthma and otitis media with effusion are rarely due to food allergy. Acute orticaria/angioedema and atopic dermatitis frequently depend from food allergy. Many foods have been reported to provoke fatal food-induced anaphylaxis: i.e. milk, egg, peanut, seafood, nut, legumes, spices and fruits. Hidden foods have been demonstrated to be frequently responsible for anaphylactic fatalities. Exercise-induced anaphylaxis may be related to a food allergy. In these patients the ingestion of the culprit food without exercise does not provoke symptoms. Food allergy may provoke gastrointestinal reactions: gastrointestinal anaphylaxis is common in adults. In infancy, food intolerance may provoke some rare gastrointestinal syndromes, i.e. infantile colics, food-induced enterocolitis syndrome, food-induced colitis, food-induced malabsorption syndrome and food-induced hemosiderosis. Celiac disease and dermatitis herpetiformis are both gluten-related entero- and cutaneous-pathies in which a non-lgE mediated immune mechanism is probably involved. Allergic eosinophilic gastroenteropathy is a rare entity but only in some documented cases it is due to an IgE-mediated allergy. Lactose intolerance is a common disease due to acquired defect of intestinal lactase, more rarely the disease is dependent from an inborn lactase deficiency. 11
It is controversial whether clinical manifestations different from those listed above could be due to one food allergy. Medical knowledge and clinical studies provided by the literature do not justify the emphasis of some investigators and of the media in claiming the link between food allergy and unusual symptoms. Among atypical complaints migraine is the most suitable for a relationship with food intake. However the basic mechanism of the presumed foodadverse reaction is unknown and a true food allergy is unlikely. Among the immunologically mediated reactions to foods, IgEmediated food allergy is the most exhaustively investigated regarding the pathogenesis. An important role in development of food allergy is played by the break of oral tolerance, an immunologic mechanism mainly supported by Tsuppressor lymphocytes leading to a systemic hyporesponsiveness but local IgA hyperrespon siveness to antigens ingested in early infancy. Thus, immaturity of the immune system might account for the higher prevalence of food allergy in children than in adults. Also the characteris tics of some allergens, such as an enzymatic activity or the resistance to digestion, especially occurring with sequential allergens, may be important in determining food sensitization. In addition, recent studies showed that sensitization to crossreacting allergens present in food and inhalant source may underlie the development of food allergy. Compared with the vast number of aeroallergens as yet identified, only a few food allergens are known, mainly because of the difficulty to recruit sufficient patients with positive IgE test and DBPCFC and to perform the laboratory technique for detecting allergens. So far, food allergens have been identified in cow's milk (alactoalbumin, ßlactoglobulin, caseins), in hen egg (ovomu coid, ovalbumin, ovotransferrin in egg white, livetin in egg yolk), in fish (Gad c 1), in shrimp (Pen a 1, Pen a 2), in peanut (Ara h 1, Ara h 2), in soybean (Gly m 1), in cereals (a series of proteins with m.w. from 26 to 79 kd as yet not named), in apple (Mal d 1), in celery (Api g 1), in fruits belonging to prunoideae (an allergen of 13 kd proposed as Pru ρ 1). Because of the importance of psychological factors in food allergy, great differences are observed between the 'selfperception', accounting for 1520% of suspected allergy in the general popula tion and the real prevalence of food allergy as established by D BPCFC. Recent studies reported that the prevalence of true food allergy in adults was 1.41.8% in the United Kingdom, and about 1 % in the Netherlands. In children a prevalence as high as 8% was reported, with major importance for sensitization to cow's milk. As cow's milk allergy tends to outgrow with age, the findings on children and adults seem to be consistent. The diagnosis of food allergy should be based on clinical history and results of in vivo and in vitro tests, but a number of factors make their value questionable. In fact, clinical history is biased by the high 'selfperception' of food allergy, and skin tests and in vitro test have the drawback of unsatisfactory sensitivity and specificity due to the lack of standardized food allergen extracts. Thus, the 'gold standard' of diagnosis is the doubleblind placebocontrolled food challenge (DBPCFC), the only test assessing the patient's reactivity to a suspected food in conditions free from patient's and physician's subjective influences. Epidemiological data on food allergy are few and incomplete, and there are no figures on the changing prevalence of allergic reactions for each individual food. Particularly, there are no studies on how food allergy has changed with respect to the changes in dietary habits. However an increased risk for food allergy should be expected for several reason: (1) An increasing use of 12
domestic items within the household (e.g. freezer, microwave oven, frying devices, etc.); these items inevitably lead to the increased consumption of prepackaged food products, particularly frozen products and baked goods; (2) changes in life styles and work schedules facilitate the consumption of meals outside the household (e.g. fast-food restaurants, snack bars, etc.); (3) the increased distribution and availability of widespread food goods has reduced the boundaries of regional cooking habits and introduced new food products; (4) the food industry's expanding market of products that are processed and handled òn an industrial scale. Methods that are not shown to be effective and safe by proper clinical trials should be considered 'unproven methods' or 'non-validated methods'. Non-validated methods are not recommended in clinical practice, because the literature does not provide convincing data on the reliability of these methods and, in some cases, well-conducted studies do not show any difference between the investigated method and the placebo. The most commonly employed non-validated methods are discussed in Chapter 12. The only preventive measure able to interfere with development of food allergy is to postpone as much as possible the introduction into the child's diet of foods containing known allergens, such as cow's milk, egg, fish, and others. This is mainly done by prolonged breast-feeding; the preventive effect is improved by eliminating these foods from the mother's diet. Because of the difficulty to maintain such conditions it is not recommended to prolong breast-feeding over six months. As yet, there are not enough data to use hydrolyzed cow's milk formulas as a measure alternative to breast-feeding. Food allergic patients need to change their eating habits, to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of ARF. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. However food allergens, especially in an occupational setting, may induce allergic reactions even when inhaled or after skin contact. Foods most commonly involved in occupational food allergy are: cereal flour, egg, milk, seafoods and legumes. The most effective measure to prevent occupational diseases due to exposure to food allergens is primary prevention, that is prevention of exposure to food-related substances that can induce allergic reactions. A second step is secondary prevention, that is the detection of diseases at an early stage. The earlier the diagnosis is made, the more likely workers are to recover. Tertiary prevention consists in appropriate medical care of diseased workers. Due to that mentioned above, it is clear that any effort should be directed to primary and not to tertiary prevention. There are two main problems that arise from food processing and preparation: (1) food processing may alter content and/or properties of food allergens, both reducing and increasing the allergenicity of the starting material; (2) most processed, packaged and canned foods contain additives and other 'hidden' ingredients of both natural and synthetic origin. Common food allergens such as milk, egg, soya, and wheat are constituents of a wide variety of prepared foods, and in most cases labelling is incomplete and often misleading. This can have devesting consequences for a food-sensitive person. In fact almost all patients who died from food anaphylaxis had a history of allergic reactions to the food allergen responsible for the death, but they were unaware that the allergen was present in the food they ate. Therefore it is imperative that all processed foods sold
13
in the European Community be clearly labelled with the list of the ingredients and of the starting materials. Hypoallergenic formulas (HF) may be used to treat allergic symptoms induced by cow's milk in sensitized children or to prevent food allergies in infants at high risk for the development of allergic disease. The important role that HF may play in the treatment of cow's milk allergy has been defined. In vitro and in vivo studies show that extensive casein hydrolysates are the less allergenic formulas in cow's milk allergic children. An elemental formula (Neocat) seems to be a good alternative as well. However it should be underlined that these formulas are hypoallergenic and not non-allergenic, because some highly sensitive milk-allergic infant may react adversely to being fed such formulas. The role of HF in the prevention of allergic diseases is still controversial. Although some studies indicate a protective role of some H F in preventing allergic diseases in high-risk babies, further studies are needed to elucidate this point. In vitro and animal studies should select new formulas suitable for milk substitutes in cow's milk allergic children. Preclinical screening of these hydrolysates should demonstrate the absence of intact proteins and more than 99% of the peptides with molecular weight < 1.5 Kd, and non-anaphylaxis in animals challenged with the formula under investigation. Hydrolysates selected by preclinical studies should then be screened by DBPCFC and open consumption, showing to be tolerated in cow milk allergic infants, in which the diagnosis of allergy to milk has been documented by positive DBPCFC. The optimal treatment of food allergy is to avoid the culprit food, but this may be very difficult as masked foods are present in a number of preparations, exposing the allergic subject to unaware consumption. A series of fatal reactions derived from eating apparently unsuspected foods has been reported. In recent years, specific immunotherapy was considered as a treatment of food allergy and a first double-blind placebo-controlled study performed in patients allergic to peanut with a defatted peanut extract demonstrated, by a marked reduction of symptoms scores to DBPCFC and decrease of skin sensitivity to peanut extract in actively treated patients, that this treatment may be effective. A new idea of prevention in food allergy must take into account the production of hypo- or nonallergenic food. Current means used to induce hypoallergenicity are heating, enzymatic hydrolysis and selection of vegetable stocks which synthesises little or no major allergenic protein (e.g. wheat deficient in gliadins). This last goal could be obtained by the biogenetic engineering with the production of transgenic plants. Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the user receives accessible information on food products, and jointly to promote studies to set in motion the farthest-reaching positive approaches. 14
C L A S S I F I C A T I O N AND T E R M I N O L O G Y R E A C T I O N S TO F O O D
OF
ADVERSE
SYNOPSIS The recent Position Paper of the European Academy and Clinical Immunology Subcommittee on adverse reaction to food (ARF) divided the ARF into toxic and non toxic. The latter are subdivided in immunomediated (in clinical practice represented quite exclusively by the IgE mediated reactions) and non-immune mediated (enzymatic, pharmacologic and undefined intolerances).
The document, entitled 'adverse reactions to food' prepared by the American Academy of Allergy and Immunology Committee on Adverse Reactions to Foods and the National Institute of Allergy and Infectious Diseases in 1984, suggested an up-to-date terminology in the field of adverse reactions to food, with the aim of establishing a definite common meaning of all terms generally used by the medical community for food allergy and intolerance1 ·2. Recently the European Academy of Allergy and Clinical Immunology (EAACI) Subcommittee on Adverse Reactions to Food presented a Position Paper with a new classification for adverse reactions to foods, based on pathomechanisms, that is the development of the American manual 3 (Figure 1.1).
TOXIC
IMMUNE MEDIATED (FOOD ALLERGY)
^ ^ ADVERSE REACTION TO FOOD
y/
^
igE
NON-lgE
NON TOXIC ENZYMATIC
\ NON-IMMUNE MEDIATED (FOOD INTOLERANCE)
PHARMACOLOGICAL
UNDEFINED
Figure
1.1.
According to this classification, adverse reactions to foods are divided into toxic and non toxic food reactions.
15
1.1.
Toxic
food
reactions
Toxic food reactions are due to some substances that contaminate foods or that are naturally present in them, e.g. poison in non-edible mushrooms. Toxicity affects all human beings exposed to high doses of a certain toxin with the same mechanism and is not connected to an individual susceptibility. Allergists must be aware of toxic food reactions on account of their prevalence among adverse reactions to foods, in order to make a correct differential diagnosis, particularly when these reactions may mimic in some way an allergic symptomatology (e.g. scombroid syndrome).
1.2.
Non-toxic
food
reactions
Non-toxic food reactions are due to an individual's susceptibility to certain foodstuffs and they are divided into immune-mediated and non-immune mediated reactions. Food allergy is the term commonly used for immune-mediated reactions, while food intolerance includes all non-immune mediated reactions. According to the immunological mechanism involved in the adverse reactions. Food allergy is defined IgE-mediated and non-lgE-mediated.
1.2.1. IgE-mediated
reactions
IgE-mediated reactions can be diagnosed in atopic patients when IgE antibodies specific to food, that significantly correlate with the symptoms and/or the provocative tests, are detected by in vivo and/or in vitro tests.
1.2.2.
Non-lgE-mediated
food allergy
Non-lgE-mediated food allergy includes: (a) immune reactions caused by, other than IgE, specific to food allergen/s; (b) food immune-complexes; (c) cell-mediated immunity specific to food. Also in this case, a correct diagnosis needs the demonstration of the existence of an immune mediated mechanism (other than IgE) against the suspected food by in vivo and/or in vitro tests and the clinical evidence of a correlation between the symptoms evoked by the ingestion of the suspected food and the immune reaction. Up to now no clear demonstrations exist in respect of food allergy mediated by (a) and (b). Food intolerance, that is non-immune-mediated food adverse reactions, is a term used when the causative role of a food in provoking complaints is irrefutable, as clearly shown by the history and/or the provocative tests, but there is no evidence of an immunological mechanism. Two mechanisms are likely to explain these reactions; they are enzymatic defects and pharmacological actions of drugs or other pharmacological active substances added to the food or naturally present in it. In this case the reactions are therefore subdivided into enzymatic and pharmacological reactions; while the non-immune mediated food adverse reactions due to an unknown mechanism are classified in the group of undefined reactions. Psychosomatic food-adverse reactions are not truly food dependent but are related to a primary mental disorder; therefore they are excluded in the EAACI classification. However, in clinical practice, most patients, who think they are allergic to some food, belong to this category 4 · 5 .
16
Unfortunately the individual beliefs of patients suffering from vague, recurrent symptoms, wrongly ascribed to some particular food, often find confirmation in many articles published in nonspecialized newspapers, that attribute a lot of symptoms to food allergy simply on the basis of non-validated hypothesis and anecdotal reports. Moreover many of these patients find their assumptions guaranteed by physicians who apply unorthodox non-validated diagnostic procedures. In order to avoid these mistakes, official international allergy associations have published diagnostic protocols to be followed to diagnose adverse reactions to food 3 · 6 .
REFERENCES 1
Anderson J.A., Sogn D.D., eds. 'Adverse reactions to foods'. AAAI and NIAID, NIH publication No 84-2442. 1984.
2
Anderson J.A. 'The establishment of common language concerning adverse reactions to foods and food additives'. J. Clin. Immunol. 78. pp. 140-144. 1986.
3
Bruijnzeel-Koomen C , Ortolani C , Aas K., Bindslev-Jensen C , Björksten B., Moneret-Vautrin D., Wuthrich B. 'Position Paper, Adverse reactions to foods'. Allergy, 50, pp. 623-635. 1995.
4
Pearson D.J., Rix K.J.B., Bentley S.J. 'Food allergy: how much in the mind?' Lancet, June 4, 1983. pp. 1259-1261.
5
Sloan A.E., Powers M.E. 'A perspective on popular perceptions of adverse reactions to food'. J. Allergy Clin. Immunol. 78. pp. 127-133. 1986.
6
Metcalfe D.D., Sampson H.A. Workshop on experimental methodology for clinical studies of adverse reactions to foods and food additives. J. Allergy Clin. Immunol. 86. pp. 421-442. 1990.
17
G E N E R A L O U T L I N E OF T H E R O L E THE DIFFERENT H Y P O T H E S E S
OF
FOOD
COVERING
SYNOPSIS Toxic reactions to food affects all human beings exposed. The major sources of toxicity of foodstuffs are the toxic substances induced in food processing, contaminants and additives. IgE-mediated food allergy is the most frequent, the best known and the easiest to be diagnosed of the ARF. However the diagnosis of IgE-mediated food allergy must be made only when the relationship between the ingestion of a particular food and the symptoms is well established. An evident role in clinical food allergy (i.e. IgG responses to foods, immune complexes with food allergens, cell mediated immunity to food) has not been demonstrated conclusively, and this topic is still the object of investigation. Enzymatic food intolerances, except for lactase deficiency, are rare conditions, mainly due to inborn errors of metabolism. The pharmacological food intolerance includes: (1) the effects of vasoactive amine contained in some fruits; (2) the effects of mediator released by non immunologic mechanism and (3) the intolerances to food additives.
2. 1
Toxic
reactions
Many toxic substances may occur in foodstuffs. However, the amounts of these toxic substances are generally too small to cause symptoms, and habitual dietary variety keeps down the intake of any single toxin; this could explain the low prevalence of toxic reactions. Toxic substances in foodstuffs are: 1.
Naturally occurring, both endogenous and exogenous;
2.
Induced in food processing;
3.
Contaminants;
4.
Additives.1
Some examples of naturally occurring toxins in animal and vegetal foods are shown in Table 2.1. Food toxicity mainly affects the CNS (headache, hallucination, incoherence and at times convulsions), liver and blood. Toxins induced in food processing, contaminants and additives are the major source of toxicity of foodstuffs today. Modern food technology enables us to produce, preserve and distribute large quantities of foods but there are frequent risks of breakdown in the food production and distribution chain, exposing many individuals to a high risk of food toxicity. The scombroid syndrome has become one of the major chemical food-borne illnesses reported in recent years. 2 · 3 18
Table
2.1
Naturally occurring toxins in food (by C. May,1 modified)
2.2.
TOXIN
FOOD
SYMPTOMS
Cyanide
Prunoideae fruits
Neuropathy, mental confusion
Glucosinolites
Cabbage
Goiter
Atropine
D. stramonium
Hallucination
Pressor amines
Banana
Headache, hypertension
Solanine
Potato (raw), Jerusalem cherry, unripe tomato, etc.
Headache, CNS depression, gastrointestinal
Aflatoxins
Contaminants of corn, nuts and meats, hypoallergenic milk
Reye's syndrome, gastrointestinal, hepatic
Colza toxins
Colza oil
Gastrointestinal, CNS, muscular
Histidin & scombrotoxins
Spoiled fish
Scombroid poisoning
Paralytic shellfish toxins
Shellfish
CNS (paralysis), cardiovascular, gastrointestinal, respiratory
Non-toxic
reactions
2.2.1.
Immunological
2.2.1.1.
IgE-mediated
reactions
food
(food
allergy)
allergy
Type I, IgE-mediated, reactions in food allergy are the most frequent, the best known and the easiest to be diagnosed. The presence of IgE antibodies to specific offending food support the existence of an IgE mechanism, although clearly the diagnosis of IgE-mediated allergy can be made only when the relationship between the ingestion of a particular food and the onset of symptoms is well established. Double-blind placebo-controlled food challenge (DBPCFC) is the gold standard to demonstrate this relationship in order to exclude psychological reactions, and physician's and patient's prejudice. The result of DBPCFC is considered the only objective evidence in food allergy. A variety of symptoms, likely to be secondary to an IgE-mediated response, are reported in controlled trials: 4 · 5 · 6 anaphylaxis (associated with exercise in some cases); cutaneous manifestations, like urticaria-angioedema, atopic dermatitis and contact dermatitis; upper and lower respiratory symptoms, like rhinitis (rare), larynx edema and asthma; gastrointestinal disorders, like oral allergy syndrome (OAS), infantile colics, nausea, vomiting, diarrhoea and abdominal pain and neurological symptoms. However, in connection with these last complaints, there is no definitive evidence of a relationship between food and hyperactivity, depression or migraine. 19
Various foods have been found to cause most frequently IgE-mediated food allergy in a series of DBPCFC7 in adults and children. The foods found responsible of IgE-mediated food allergy listed in order of prevalence are: egg, milk, peanut, nuts, fish and soya in children, and peanuts, nuts, fish and shellfish in adults. The prevalence of reactions to specific foods may depend on the eating habits or other peculiari ties of a given population. For example soybean allergy is more common in Japan and fish allergy is more prevalent in Scandinavian countries. Patients suffering from allergy to certain pollens more often react with OAS to certain fresh fruits and vegetables.8·9 These patients with pollen allergy present very intense mucosal sensitivity to foods, such that local symptoms are evident within 15 minutes of food contact. OAS is IgE-mediated. The symptoms are generally localized in the oral cavity and pharynx, though more severe local or systemic manifestations may also occur, often within few minutes after the oral contact with the responsible food, they are angioedema of the oral cavity and pharynx, urticaria, conjunctivitis, orbital angioedema, asthma, gastrointestinal symptoms and even anaphylactic shock. The main foods inducing this IgEmediated syndrome are apple, peach, cherry, nuts, celery, carrot, tomato and fennel. 8 · 9
2.2.1.2.
Non-lgE-mediated
food
allergy
Non-lgE-mediated food allergy provides the evidence that the adverse reaction is the conse quence of an immune response, other than IgE-mediated specific for a certain food; immunoglo bulins, belonging to a non-lgE class, food immune-complexes or cell-mediated immunity are directly involved in the mechanism provoking the symptoms. lgG4 to specific food antigens are frequently present in patients with adverse reactions to foods,10 but these antibodies are also often detected in normal subjects or in patients with inflammatory bowel disease, and their pathogenetic role has not been demonstrated. Their presence is likely to be the consequence of prolonged exposure to ubiquitous antigens resulting in an lgG4 restricted response.11 Circulating IgG and IgE immune-complexes containing food antigens may be found in patients with food allergy suffering from asthma and eczema, 10 · 12 but their pathophysiological role has been rarely unequivocally demonstrated. Furthermore there is no definitive evidence that either IgG or IgE food-immune complexes cause human disease. 10 · 12 There is ample indirect evidence that celiac disease (CD) may be provoked by a cell-mediated food allergy to gliadin, a prolamine contained in gluten. 13 · 14 Τ cells appear to be involved in the pathogenesis of this disease, 15 · 16 although, so far, there is no exhaustive proof that these immune phenomena are the direct original cause of the human disease. Recently an overrepresentation of one TCR variant of the lymphocytes present in the gut mucosa in CD was found, suggesting a role for these cells in the disease.17 Some experiments showed that the immunemediated intestinal damage is similar to that provoked in the intestinal mucosa by the graftversus-host reaction. 18 · 19 As yet the role of the increased IgAand IgG antigliadin antibodies in the immunopathogenesis of this disease is still unclear. 17 · 18 A clinical picture and histological alterations of the jejunal mucosa that mimic celiac disease are present in some infants with malabsorption syndromes; patchy villous atrophy with cellular infiltrate on jejunal biopsy is associated with the weaning period, and cow's-milk sensitivity is the most frequent cause of this syndrome.19 Sensitivity to soya, egg and wheat have also been 20
reported in this syndrome.20 Serum IgA and IgG antibodies specific to milk are elevated in cow's milk induced malabsorption.21 These abnormalities suggest both type-Ill (immunocomplexes) and type IV (cell-mediated) immunopathogenesis. The same mechanisms may be present in food-induced enterocolitis syndrome in infants.22 The jejunal biopsy shows flattened villi, edema and an increased number of lymphocytes, eosinophils and mast cells. The most prevalent responsible foods are cow's milk, soya protein or both together. These foods are also involved in food-induced colitis that differs from the above infantile syndromes in its mild clinical picture, generally characterized by the presence of gross or occult blood in the stools and a prominent eosinophilic infiltrate in the colonic mucosa.23 Heiner's syndrome, that is a food-induced pulmonary hemosiderosis, is very rare; it affects infants with non-lgE-mediated hypersensitivity to cow's milk; egg and pork have also been reported as the cause of this syndrome in some infants.24
2.2.2. Non-immune
mediated
2.2.2.1.
food
Enzymatic
adverse
reactions
to
foods
intolerance
Enzymatic food intolerance is present in patients affected by enzymatic defect that causes a clinically evident adverse reaction to certain foods or food additives. The most common conditions are: (1) disaccharidase deficiencies caused by a defect of lactase or sucrase; (2) galactosemia caused by a defect of galactose 1 phosphate uridyl transferase or uridine diphosphate-4 epimerase; (3) phenylketonuria due to phenylalanine hydroxylase deficiency; (4) alcohol intolerance consequent upon aldehyde dehydrogenase deficit; (5) favism due to a defect of glucose-6phospho dehydrogenase (G6PD). Except for lactase deficiency, these are very rare conditions or inborn errors of metabolism. However it is widely held that many undefined food intolerances may result from enzymatic defects. For example, a deficiency of diamine-oxidase has been postulated in patients with intolerance to histamine-containing foods,25 but clear evidence of a clinical syndrome due to this enzymatic defect has never been found.
2.2.2.2.
Pharmacological
food
intolerance
The main substances that may be responsible for pharmacological food intolerance are: (1) vasoactive amines like histamine, octopamine, phenylephine and other biogenic amines: tyramine, phenylethylamine (in chocolate), tryptamine (in tomatoes), 5-hydroxytryptamine (in banana and avocado), spermidine (in pork and cereal germs); (2) releasing factors present in foodstuffs causing indirect pharmacological reactions such as protamine, basic peptides, diamines and polyamines and peptones (histamine releaser foodstuffs);26 (3) food additives. Pharmacological food intolerance may depend on the direct effect of vasoactive amines naturally found in foods. Ingestion of large amounts of a food, containing one or more of these amines, will be followed by toxic symptoms. Some subjects, however, may have symptoms even after eating a very small amount of one of these substances. In particular, the threshold of susceptibility to
21
histamine may be lowered in some individuals, e.g. as stated above, subjects affected by diamine oxidase deficiency. Selected foods containing relatively large amounts of histamine or histidine or both can pose problems in these intolerant subjects.27 In scombroid poisoning factors potentiating histamine toxicity are involved and therefore this syndrome must be classified as a toxic food reaction.28 The largest amounts of histamine and tyramine are found in fermented foods, such as cheese, alcoholic beverages, tinned fish, fish autolysates (Nuoc-Mam), sauerkraut, tuna, dry pork and sausage. 29 · 30 · 31 · 32 Grapes, potatoes, and cabbage are rich in tyramine.33 Some studies indicate that tyramine may play a role in migraine and chronic urticaria, especially in patients treated with a MAO inhibitor.27 In addition certain foods are said to have histamine releasing properties.27·34 Examples include egg white, shellfish, strawberries, tomatoes, chocolate, citrus fruit, fish and pork. However there is no evidence of this effect in vivo. Studies generally quoted to support histamine release by these foods are non-controlled, very old and performed in laboratory animals. More appropriate studies are therefore necessary to validate this hypothesis. Pharmacological food intolerance might be evoked for the food intolerance present in patients with poor sulphoxidation ability. A poor sulphoxidation ability has frequently been documented in patients with ascertained food intolerance.35 The metabolism of foodstuffs containing sulphur, including thiophenes, sulphides and isothyocyanates might be impaired.
2.2.2.3.
Additive
intolerance
IgE-mediated additive allergy has been documented in some cases,36 but additive intolerance caused by non-toxic reactions does not seem to depend on immune-mediated mechanisms. Some observations suggest that additive intolerance may be consequent upon an enzymatic inhibition (e.g. sulphites and azo dyes).37 Other studies show non-specific mediator release in vivo induced by challenge with some additives (ASA, sulphites, etc.). 38 · 39 So far, however, the mechanisms of additive intolerance remains largely unknown, therefore it seems more appropriate to include the adverse reactions to additives in the group of undefined food intolerance.
REFERENCES
22
1
May C D . 'Immunologic versus toxic adverse reactions to foodstuffs'. Ann. Allergy 51 (II): pp. 267-268. 1983.
2
Taylor S.L., Stratton J.E., Nordlee J.A. 'Histamine poisoning (scombroid fish poisoning): An allergy-like intoxication'. Clin. Toxicol. 27: pp. 225-240. 1989.
3
Morrow J.D., Margolies G.R., Rowland J., Roberts L.J. 'Evidence that histamine is the causative toxin of scombroid-fish poisoning'. N. Engl. J. Med. 324: pp. 716-720. 1991.
4
Sampson H.A. 'Food allergy' (review). J. Allergy Clin. Immunol. 84: pp. 1062-1067. 1989.
5
Bock S.A. 'Prospective appraisal of complaints of adverse reactions to foods in children during the first three years of life'. Pediatr. 79: pp. 683-688. 1987.
6
Hill D.J., Firer M.A., Shelton M.J., Hosking C S . 'Manifestations of milk allergy in infancy: clinical and immunologic findings'. J. Pediatr. 109: pp. 270-276. 1986.
7
Bock S.A., Sampson H.A., Atkins R.M. et al. 'Double-blind placebo-controlled food challenge as an office procedure: a manual'. J. Allergy Clin. Immunol. 82: pp. 986-997. 1988.
8
Ortolani C , Ispano M., Pastorello E., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy 61 (II): pp. 47-52. 1988.
9
Pastorello E.A., Ortolani C , Incorvaia C , Bigi Α., Ispano M., Pravettoni V., Schilke M.L., Farioli L., Zanussi C 'IgE-mediated allergy from vegetable allergens'. Ann. Allergy 71: pp. 470-476. 1993.
10
Paganelli R., Quinti I., D'Offizi P., Papetti C , Carini C , Aiuti F. 'Immune complexes in food allergy: a critical reappraisal'. Ann. Allergy 59 (II): pp. 157-161. 1987.
11
Aalbersee R.C., Gaag Vander R., Leevwen Van J. 'Serologic aspects of IgG antibodies. I. Prolonged immunization results in an IgG-restricted response'. J. Immunol. 130: pp. 722-726. 1983.
12
Carini C. 'IgE-immune complexes in food allergy: significance, pathogenicity and clinical considerations'. Clin. Allergy 17: pp. 485-497. 1987.
13
Marsh M.N. 'Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten-sensitivity ('celiac sprue'). Gastroentero logy 102: pp. 283-304. 1992.
14
De Ritis G., Auricchio S., Jones H.W., Lew E., Bernardin J.E., Kasarda D.D. 'In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in coeliac disease'. Gastroentero logy 1994, pp. 41-49. 1988.
15
Marsh M.N. 'Studies of intestinal lymphoid tissue. XI. The immunopathology of cell-mediated reactions in gluten sensitivity and other enteropathies'. Scanning Microsc. 2, pp. 1663-1684. 1988.
16
Ferguson Α., Arranz E., O'Mahony S. 'Spectrum of expression of intestinal cellular immunity; proposal for a change in diagnostic criteria of celiac disease'. Ann. Allergy 71, pp. 29-32. 1993.
17
Arranz E., Ferguson A. 'Intestinal antibody pattern of celiac disease: occurrence in patients with normal jejunal biopsy histology'. Gastroenterology 104, pp. 1263-1272. 1993.
18
O'Mahony S., Arranz E., Barton J.R., Ferguson A. 'Dissociation between systemic and muco sal immune responses in coeliac disease'. Gut. 32, pp. 29-35. 1991. 23
19
Kuitunen P., Visakorpi J.K., Savilahti E., et ai. 'Malabsorption syndrome with cow's milk intolerance: clinical findings and course in 54 cases'. Arch. Dis. Child 50, pp. 351-356. 1975.
20
Goldman H., Proujansky R. 'Allergic proctitis and gastroenteritis in children'. Am. J. Surg. Path. 10, pp. 75-86. 1986.
21
Pearson J.R., Kingston D., Shiner M. 'Antibody production to milk proteins in the jejunal mucosa of children with cow's milk protein intolerance'. Pediatr. Res. 17, pp. 406-412. 1983.
22 Powell G.K. 'Milk and soya induced enterocolitis of infancy: clinical features and standardization of challenge'. J. Pediatr. 93, pp. 553-560. 1978.
24
23
Lake A.M., Whittington F., Hamilton S.R. 'Dietary protein-induced colitis in breast-fed infants'. J. Pediatr. 101, pp. 906-910. 1982.
24
Lee S.K., Kniker W.T., Cook CD., et al. 'Cow's milk-induced pulmonary disease in children'. Adv. in Pediatr. 25: pp. 39-57. 1978.
25
Wantke F., Götz M., Jarisch R. 'Histamine-free diet: treatment of choice for histamine-induced food intolerance and supporting treatment for chronical headaches'. Clin. Exp. allergy 23, pp. 982-985. 1993.
26
Schacter M. 'Histamine-release and the angfio-oedema type of reaction'. Histamine - Ciba Found Symp. pp. 167-169, London, Churchill. 1956.
27
Zeitz H.J. 'Pharmacologic properties of foods'. In Metcalfe D.D., Sampson H.A., Simon R.A. (eds.). 'Food allergy. Adverse reactions to foods and food additives': pp. 311-318, Blackwell Scientific Publications, Boston, 1991.
28
Taylor S.L. 'Histamine food poisoning: toxicology and clinical aspects'. CRC Crit. Rev. Toxicol. 17, pp. 91-128. 1986.
29
Monoret-Vautrin D.A. 'False food allergies: non-specific reaction to foodstuffs'. In Lessof MH (ed.): 'Clinical reactions to food', pp. 135-153, Chichester, Wiley. 1983.
30
Maga J.A. 'Amines in foods'. CRTC Crit. Rev. Food Sci. Nutr. 10, pp. 373-403. 1978.
31
lenistea C 'Bacterial production and destruction of histamine in foods, and food poisoning caused by histamine'. Nahrung 15, pp. 109-113. 1971.
32
Smith T.A. 'Amines in food'. Food Chem. 6, pp. 169-200. 1980.
33
Tarjan V., Janossy G. 'The role of biogenic amines in foods'. Nahrung 1978, pp. 22: 281-85.
34
Schacter M., Talesnik J. 'The release of histamine by egg-white in non-sensitized animal'. J. Phys. 118, pp. 258-263. 1952.
35
Scadding G.K., Ayesh R., Brostoff J., Mitchell S.C, Waring R.H., Smith R.L. 'Poor sulphoxida tion ability in patients with food sensitivity'. BMJ 297, pp. 105107. 1988.
36
Kägi M.K., Wüthrich B., Johansson S.G.O. 'CampariOrange anaphylaxis due to carmine allergy'. Lancet 344, pp. 6061. 1994.
37
Simon R.A. 'Sulfite sensitivity'. Ann. Allergy 56, pp. 281288. 1986.
38
Ortolani C , Mirane Α., Fontana Α., Folco G.L., Miadonna Α., Montalbetti Ν., Rinaldi M., Sala Α., Tedeschi Α., Valenti D . 'Study of mediators of anaphylaxis in nasal wash fluids after aspirin and sodium metabisulfite nasal provocation in intolerant rhinitic patients'. Ann. Allergy 59, pp. 106112. 1987.
39
Christie P.E., Tagari P., FordHutchinson A.W., Charlesson S., Chee P., Arm J.P., Lee T.H. 'Urinary LTE4 concentrations increase after aspirin challenge in aspirinsensitive asthmatic subjects'. Am. Rev. Respir. D is. 143, pp. 10251029. 1991.
25
3.
SYMPTOMS
OF
FOOD
ALLERGY
AND
FOOD
INTOLERANCE
SYNOPSIS The symptoms of food allergy involve different organs. Oral allergy syndrome is frequent among patients with birch or mugwort pollinosis and it is provoked by sensitization to plant food allergens. Rhinoconjunctivitis, asthma and otitis media with effusion are rarely due to food allergy. Acute orticaria/angioedema and atopic dermatitis frequently depend from food allergy. Many foods have been reported to provoke fatal food-induced anaphylaxis: i.e. milk, egg, peanut, seafood, nuts, legumes, spices and fruits. Hidden foods have been demonstrated to be frequently responsible for anaphylactic fatalities. Exercise induced anaphylaxis may be related to a food allergy. Gastrointestinal anaphylaxis is common in adults. In infancy food intolerance may provoke some rare gastrointestinal syndromes, i.e. infantile colics, food-induced enterocolitis syndrome, food-induced colitis, food-induced malabsorption syndrome and food-induced hemosiderosis. Celiac disease and dermatitis herpetiformis are both gluten related entero- and cutaneous-pathies in which a non-lgE-mediated immune mechanism is probably involved. Allergic eosinophilic gastroenteropathy is a rare entity but only in some documented cases is it due to an IgE-mediated allergy. Lactose intolerance is a common disease due to acquired defect of intestinal lactase, more rarely the disease depends from an inborn lactase deficiency.
Foods may induce the production of IgE towards specific protein antigens and release of mediators in allergic subjects after exposure to the sensitizing food. Food allergic symptoms involve different organs. Symptoms may appear in the organs that come in contact with the food (such as lips, mouth, pharynx) and/or in other target organs. We recognize therefore 'oral' and 'extra oral' symptoms. Food allergy symptoms may also be subdivided according to the type of contact mode with the food: i.e. symptoms due to food ingestion, contact or inhalation.
3.1
Oral
allergy
syndrome
(OAS)
OAS is a food allergy syndrome due to the contact of the oral mucosal with allergenic foods, particularly plant allergens. The term OAS was used first by Amlot et al. 1 to identify immediate symptoms in the lip, mouth, pharynx and larynx in subjects sensitized to food allergens. The symptoms may be present in organs other than the oral cavity. All foods may provoke this syndrome, however it is very common with fresh fruits and vegetables. This syndrome may be associated with pollinosis, particularly birch or mugwort pollen allergy. The first report of this association dates to 1942,2 but thereafter several clinical studies were conducted in Scandinavia, 3 · 4 · 5 and in other European and American countries.6 Nearly 60-70% of allergic patients with OAS suffer from allergic pollen rhinoconjunctivitis.7 The contact between food and oral mucosa provokes itching and swelling of the lip, tongue, uvula, and larynx. Systemic reactions of different severity such as urticaria, rhinitis, asthma, laryngeal edema or anaphylactic shock may also occur. 26
The oral symptoms appear within a few minutes after having eaten the offending food. In some cases the symptoms may appear in organs other than the mouth or generalized; and may develop 30 to 60 minutes after contact with the offending food. This suggests that OAS may be defined as a variable syndrome in which immediate oral symptoms may be associated with delayed manifestation of symptoms in other organs. The laryngeal edema may present as constriction of throat, cough, dysphonia, wheezing and tirage. The foods that more frequently cause OAS are apple, nuts, fruit, peach, fennel, cherry and celery. Some animal foods such as milk, egg and fish also may occasionally provoke OAS. Some patients have symptoms in response to more than one food, and a food may provoke different symptoms. Moreover some patients have symptoms only upon contact with fresh foods whereas they tolerate the same food when cooked. In food-allergic patients it is possible to detect associations between hypersensitivity to different foods. Some of these associations occur very commonly. Therefore we can identify some definite 'clusters' of hypersensitivity. Some cross-reactivities respect the taxonomie classification, others do not. The clusters of food more frequently provoking OAS are: (1) peach, plum, apricot, cherry; (2) celery, carrot, fennel, parsley; (3) apple, apricot, cherry, pear; (4) hazelnut, pear; (5) peanut, almond, hazelnut; (6) watermelon, melon, tomato. Allergy to prunoideae may not be associated to a pollen allergy; food allergy to watermelon, melon and tomato cluster may be associated with grass pollen allergy; all the other clusters are correlated with birch pollen allergy. Several recent studies have investigated the immunological basis of these association. Andersen and Dreyfuss8 demonstrated a cross-reactivity between ragweed pollen and extracts of melon and banana; Hannuksela and Lahti, 3 Eriksson and Formgren4 and Dreborg and Foucard5 found an association between birch pollen allergy and apple, nuts, peach, cherry pear, plum, carrot and potato allergy. Pauli and Bessot9 showed that a celery extract could inhibit RAST for birch and mugwort Staeger and Wuthrich 10 confirmed the presence of common allergens between celery and birch and between celery, spices and mugwort. De Martino et al. 11 found an association between grass pollen allergy and tomato allergy. Ortolani et al. 7 found an association between grass pollinosis and tomato, melon and watermelon allergy. OAS is frequently associated with respiratory allergy from grass, birch and mugwort pollen. The importance of the pollinosis in relation to the subsequent development of food allergy was further demonstrated by the observation that in a study group the prevalence of birch pollinosis was four 27
times higher than in a control group (patients with pollinosis regardless of whether they were or were not affected by OAS). In conclusion OAS is a polymorphic disease related to IgE-mediated allergy in which local symptoms of the mouth may be associated with organ and systemic manifestations. 3.2.
Extra
oral
symptoms
3.2.1.
Rhinoconjunctivitis
Ocular and nasal symptoms may be isolated or associated to OAS. DBPCFC have demonstrated the appearance of ocular itching, lacrimation, conjunctival hyperemia, nasal itching, rhinorrhea, sneezing, obstruction, cough, wheezing and bronchospasm; these symptoms occur within five minutes to two hours after food intake. The frequency of respiratory symptoms due to IgE-mediated food allergy is higher in children. The temporal relation between food intake and the appearance of symptoms, and the ability to reproduce symptoms by DBPCFC, clearly attest to the food etiology. Eriksson12 reported that 46% of food allergic patients have conjunctivitis and rhinitis. Ortolani et al. 7 observed rhinitis in 10% of these patients, 3.5% conjunctivitis and 7% asthma. There are no data regarding the prevalence of food allergy as a cause of chronic sinusitis even if the repeated exposure to food antigen, which is typical of the allergic disease, may be important for the chronicity of sinusitis. 3.2.2.
Serous
otitis
media
with
effusion
The relation between serous otitis media with effusion and food allergy remains controversial. Some studies13 show an increased prevalence of otitis media in allergic children, but the true prevalence is unknown. Bernstein14 points out the association between serous otitis media and IgE-mediated allergy only in 35-40% of patients; the symptoms may be associated to allergy to bacteria, viruses, or to a mucociliary clearance defect. Milk, wheat, egg, peanut and soya may be etiologic factors in otitis media in children. 15 · 16 · 17 . 18 · 19 In a recent investigation Nsouli et al. 20 noticed that in 81/104 pediatric patients there is a statistical correlation between food allergy and recurrent serous otitis; 70/81 had clinical and instrumental improvement after a period of elimination diet, 66/70 reported otitis after an open challenge with the suspected food. These data may be confirmed with double-blind challenges. In agreement with the above authors, foods may provoke serous otitis media with several mechanisms; food causes nasal congestion and obstruction with nasopharyngeal pressure increase and then reflux of pharyngeal secretion; the food induced nasal obstruction gives rise to a different nasopharyngeal pressure, with eustachian tube dysfunction (otodynia, tinnitus hearing loss, vertigo); foods could cause edema of eustachian tube due to weakness of tensor veli palatini muscle, and finally the middle ear could be the shock target organ of food allergy. In conclusion the possibility of an IgE-mediated allergy should be considered in all pediatric patients with recurrent otitis media. 28
3.2.3.
Asthma
Patients spontaneously associate cutaneous symptoms to food allergy, whereas respiratory symptoms, particularly asthma, are rarely considered as associated to food allergy.24 Physicians must suspect food allergy when asthma appears in youth, when it is associated to atopic dermatitis with high levels of total IgE, and when asthma does not respond to treatment. Food allergic asthma is provoked in childhood by milk, egg, wheat and peanut. 21 · 22 The disease appears in 4 to 6% of patients, whereas in asthmatic adults the prevalence of food allergic asthma is only 1-4%.23·25 Food additives may cause asthma, perennial rhinitis and urticaria-angioedema in sensitized subjects. Tartrazine, sodium metabisulphite and sodium benzoate are the most important additives responsible for intolerance.26 Respiratory symptoms may also be caused by inhalation of food allergens, particularly after industrial exposure in sensitized workers. In addition to the classic baker's asthma27 resulting from occupational airborne exposure to flour (wheat, but also alpha amylase), various agents may cause occupational asthma: hen egg, 28 milk, vegetable dusts (green coffee, soya, castor bean), spices, and crustaceans. Some of these patients eat the foods which cause respiratory symptoms without problems. Allergic reactions to foods through inhalation of food particles have also been reported in housewives who were exposed to the steam from cooking legumes, chicken, peas, lentils, potatoes, or fish. In these cases most patients became sensitized in childhood via the gastrointestinal route and generalized symptoms usually occur after ingestion. The 'bird-egg syndrome' consists of respiratory symptoms following exposure to serum proteins from birds and then with allergy symptoms after egg ingestion. This phenomenon is caused by cross reactivity between bird proteins and egg yolk.29 The inverse situation was also described as 'egg-bird syndrome': (sensitization by the ingestion of egg proteins and reactions following inhalation exposure to birds and egg).30 In these cases, skin-prick tests (SPT) and serum IgE determination, are also essential to demonstrate an IgE-mediated mechanism.
3 . 2 . 4 . Urticaria
and
angioedema
Urticaria is a well-demarcated skin reaction clinically characterized by erythematous palpable lesions called wheals: these are evanescent areas of edema of the dermis that resolve within hours. Angioedema is characterized by a deeper swelling of the subcutaneous or submucosal tissues, often with normal-appearing skin, accompanied by a tingling or burning sensation rather than pruritus.31 If symptoms recur for less than six weeks the urticaria-angioedema is defined as acute, if the lesions persist or recur for more than six weeks, it is defined as chronic. Acute symptoms are generally provoked by food intake or contact. The most important foods are egg, milk, peanut, fish, cereals, crustacean and vegetables. Symptoms of OAS may precede the cutaneous symptoms.32 Chronic urticaria is rarely due to food allergy and an IgE-mediated allergy has been demonstrated only in a small percentage of patients with chronic recurrent urticaria (mainly due to cereals and legumes). Symptoms can appear an hour or more after a meal. The association between food intake and urticaria may not be made when symptoms are caused chronically by foods consumed on a daily basis. Moreover, the patient's response to the food may vary according to how the food is prepared: for example, some fruits may cause symptoms when raw and not when cooked. 29
3.2.5. Atopie
dermatitis
(AD)
AD is a chronic inflammatory skin disorder that occurs in 10% of the pediatric population;33 it is characterized by pruritus, patterned distribution and a chronic relapsing course. The pathogenesis of AD remains unknown. Recent studies on bone marrow transplantation suggest that the basic defect in AD resides in a bone marrow derived cell. 34 It has been reported that patients with Wiskott Aldrich syndrome, who have eczema and elevated serum IgE that are comparable to AD, were noted to show clearing of their cutaneous symptoms and normalization of serum IgE titer after successful bone marrow transplantation.35 Individuals receiving bone marrow from atopic donors developed atopic symptoms after transplantation. Histological studies of skin lesions demonstrated cellular infiltration that is suggestive of a type IV cell-mediated hypersensitivity reaction. However, the exact relationship between AD and IgE-mediated sensitivity remains unclear. Approximately 2/3 of the children with AD have a positive family history for atopic disease; 50-80% of these children have or will develop allergic rhinoconjunctivitis and/or asthma. 36 · 37 In 80% of the patients with AD serum IgE concentrations are elevated and skin tests and serum-specific IgE are positive for a large number of allergens. Many inhalant allergens cause eczematous cutaneous skin lesions: pollens, 38 · 39 · 40 · 41 animals42 and mould. 43 The first studies concerning the first comprehensive description of AD and relationship between house dust mite allergens and AD were published by Rost44 and Besnier;45 thereafter, Piatt Mills et al. 46 confirmed the importance of mites in AD. The above observations considered both the clinical improvement after mite allergen control measures and the appearance of cutaneous symptoms after mite allergen exposure. The histological analysis of the eczematous lesions in AD demonstrate a prominent T-lymphocytes cellular infiltration. Investigators 47 · 48 · 49 · 50 · 51 have carried out patch tests (evaluated after 48 to 72 hours) in AD subjects to demonstrate that such allergens may also cause delayed reactions and eczematous lesions. Several studies52 suggest that the application of mite allergens on the skin of subjects with AD may cause binding to allergen-specific IgE situated on Langherans' cells, thereby delaying the reaction to the patch tests. The recruitment of eosinophils may occur by the release of chemotactic factors by mast cells and Langheran's cells. 53 Over 50 years ago Brunner, Waltzer and Wilson 54 · 55 demonstrated that many food antigens cross the gastrointestinal barrier and come into conctact with cutaneous mast cells within minutes to hours after food intake.56 Thereafter a large number of studies were aimed at clarifying the pathogenesis of food allergy in AD. Afterwards an attempt was made to establish the presumed prevalence of food allergy in AD. According to some authors nearly 1/3 of the patients evaluated in the dermatology and/or allergology clinic complained of the exacerbation of cutaneous symptoms after food intake. The frequency of food allergy in children with AD has been reported to be 5-20%. Other studies have reported a frequency of 60% independently of serum-lgE values.57 The latter study investigated the role of oral challenges in AD. The population described by Sampson was made up of young patients with AD and respiratory symptoms (47% had rhinitis and asthma, 28% only rhinitis, and 4% only asthma); nearly all had reported an extensive history of cutaneous symptoms. The choice of food allergens used in the challenges was based upon the results of the diagnostic tests and/or a positive history of food allergy. The symptoms began within 15 to 120 minutes after the challenge, and were characterized by morbilliform rash and urticaria which resolved after 1 to 3 hours. After this period of time the only lesions observed were those caused by scratching 30
(plasma histamine was monitored during the challenge to demonstrate that the symptoms were secondary to IgE mediated mast cell activation). Skin reactions were seen in 70% of the patients challenged; only 30% of the patients had an isolated cutaneous response.37 Studies performed on other patient groups revealed gastrointestinal symptoms in 55% of the cases and upper respiratory complaints in 39%. The high frequency of gastrointestinal symptoms has lead many authors to search for a defect in intestinal permeability by the lactulose/rhamnose test. 58 · 59 These authors have demonstrated an increase of lactulose uptake and excretion, suggestive of malabsorption, only in those patients with food hypersensitivity. Egg, peanut, and milk are the foods that more frequently account for positive challenge in AD patients (70% of the cases).57 The latter three foods along with soya, fish, and wheat account for 90% of the food allergic reactions seen in patients with food allergy. Of these children, 38% did not have an allergic reaction to food, 28.5% reacted to one food, 20% to two foods, 9.5% to three foods, and 4 % to four foods or more. This study demonstrated that eliminating the allergen from the diet for a period of one to two years allowed for the development of tolerance to the food eliciting the symptoms. There was a correlation between the development of tolerance and the type of food: less than 25% of the cases of hypersensitivity to egg, peanut, and milk, were lost during the dietary period, while one third of wheat sensitivity cases and one half of soya sensitivity cases were outgrown after one to two years of elimination diet. 57
3 . 2 . 6 . Acute
contact
urticaria
and
angioedema
This syndrome appears 10 to 30 minutes after skin exposure to some foods.60 It can be provoked by an IgE-mediated mechanism and disappears within 24 hours. Contact urticaria may appear at the point of skin contact or in other cutaneous regions. In these patients the contact with the offending food may at times cause systemic effects in other target organs (e.g. rhinitis, conjunctivitis, asthma, anaphylactic shock). The term 'contact-urticaria syndrome' coined by Maibach61 indicates the above systemic reactions that appear in hypersensitized subjects after exposure and cutaneous absorption of the allergen. The symptoms consist of itching, tingling, erythema, and wheal formation; the erythematous reaction can be localized or systemic. The foods most commonly involved are egg, milk, wheat, peanut, vegetable, and fish. Most of these individuals handle food products through occupational exposure for extended periods of time before complaining of symptoms. The name 'protein contact dermatitis' was suggested by Hjorth and Roed-Petersen62 to describe patients with chronic eczema who complained of exacerbations within 30 minutes after exposure of the affected skin to certain food protein such as those found in fish, wheat, milk, vegetable, and spices.63 The symptoms consist of itching, erythema, urticarial swelling of the fingers or extensor surface of the hand.
3 . 2 . 7 . Systemic
anaphylaxis
Systemic anaphylaxis is a dreadful allergic reaction that usually occurs 1 to 30 minutes after food exposure, but may also take place up to two hours after the meal. Systemic anaphylaxis can be the initial manifestation of food allergy, or it may develop in subjects with previously documented reactions io a known food.
31
The term 'anaphylaxis'64 is used to describe a generalized and severe reaction that follows the release of various mediators that are able to provoke cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms. Anaphylaxis can be fatal when severe symptoms rapidly progress and proper assistance is delayed. Many foods have been reported to cause anaphylaxis: milk, egg, peanut, seafood, nut, legumes, spices, and some exotic fruits. There is no reliable data on the prevalence and incidence of fatal and near fatal anaphylactic reactions. Yunginger et al. described seven cases of fatal food-induced systemic anaphylaxis that occurred immediately after intake (fish, peanut). 65 · 66 These reactions did not occur at home and patients were unaware that the food they had eaten contained the responsible allergen. All had experienced a previous, less severe anaphylactic reactions to the same food. Sampson et al. described six fatal cases due to the ingestion of either peanut, nut, or egg. 67 Five patients initially had oral and abdominal symptoms, later they developed various combinations of cutaneous, respiratory, gastrointestinal, and cardiovascular signs and symptoms. Dutau et al. 68 described four cases of food-induced anaphylaxis: the offending food was milk in two cases, egg in one case, and snail in the other. Previously, the same author had pointed out the occurrence of severe symptoms after peanut intake in 7.5-25% of pediatric patients.69 Sampson et al. 70 has reported that 50% of the children with peanut-induced anaphylaxis have symptoms so severe that oral challenges with peanut are not possible. A retrospective analysis of American and European studies on anaphylaxis shows that peanut is responsible in 50% of the cases. Milk71 · 72 and egg 73 are also known to cause severe reactions especially in pediatric patients; these reactions sometimes can follow unknown inhalation of food allergens. Ansaloni et al. 74 reported 24 patients who had severe systemic reactions to food, of these patients nine had had anaphylactic shock and 13 laryngeal edema that were supported by medical records. The foods eliciting the severe symptoms were milk (three cases) and hazelnut (three cases); peach, cherry, kiwi, egg, fish, food crustácea (two cases for each food); apple, wheat, maize, mustard, pear, fennel, legumes (one case for each food). Symptoms appeared within 1 to 60 minutes after food intake. In this study laryngeal edema was the most frequently reported severe reaction, and milk and hazelnut were the foods most frequently responsible. The anaphylactic reactions due to milk are generally provoked by casein. Due to the increasing use of vegetarian foods, sesame seeds induced anaphylaxis75·76 has recently been described. Spices that are included in sauces and other foods, such as mustard 77 · 78 · 79 · 80 and coriander, can also provoke anaphylactic symptoms. It is important to consider a diagnostic protocol in order to reach a diagnosis of food induced anaphylaxis or other food induced life threatening reactions. The following are the main points of the diagnostic work-up:
32
•
verify the life-threatening event (anaphylactic shock, laryngeal edema, or severe asthma that requires emergency treatment) and substantiate it with medical documentations;
•
exclude other causes of anaphylaxis (insect sting, concurrent diseases, etc.);
•
determine the likelihood that the food eaten is the cause of the life threatening reaction;
•
positive skin tests and/or RAST to the suspected food(s) can confirm the IgE mediated mechanism.
3.2.8. Exercise-induced
anaphylaxis
(EIA)
EIA has been recognized as a distinct form of physical allergy characterized by flushing or urticaria associated with symptoms of the upper respiratory tract and/or gastrointestinal tract that in some cases can precede cardiovascular failure. 81-82 The intake of an offending food can elicit severe anaphylactic reactions when followed by exercise, whereas the ingestion of the food alone or exercise alone do not provoke symptoms. At times the offending food alone does not cause anaphylaxis but symptoms of anaphylaxis are elicited only when the food is combined with exercise. The pathogenesis of this syndrome remains unknown but it probably involves the degranulation of mast cell and an abnormal response of the autonomic nervous system. There are rare reports of this disease: Maulitz et al. 8 3 report one reaction of exercise-induced anaphylaxis to shellfish; Kidd and Cohen81 report three cases after celery intake. In these patients symptoms appeared within 2 to 15 minutes after initiating exercise. In one patient it was clearly shown that exercise without prior food ingestion or exercise occurring two hours after an offending meal did not produce an anaphylactic reaction. Other cases have reported a delay in the onset of symptoms: usually apparent 1-4 hours after physical exercise. The diagnosis should become evident if DBPCFC is followed by exercise. In conclusion exercise-induced anaphylaxis is the result of an IgE-mediated reaction to a sensitizing food, occurring when physical exercise is performed after the ingestion of that food in a previously sensitized individual.
3.2.9. Gastrointestinal
hypersensitivity
reactions
to
food
Some diseases of the gastrointestinal tract can be caused by allergic reactions to food allergens. The gastrointestinal system converts the ingested foods into simple elements which are easily absorbed. During the digestive process immunological (GALT) and physiological mechanisms act to hinder the passage of foreign antigens through the gastrointestinal mucosal barrier. Foodspecific IgA antibodies that are secreted by the lymphatic structure into the lumen, aid in hindering the absorption of food antigens. In fact proteins or their fragments that cross the mucosal barrier are then inactivated in the systemic circulation mainly by Kuppfer cells of the liver and phagocytic cell of the retículo endothelial system. Disorders of intestinal barrier can allow macromolecules easily to reach the systemic circulation, triggering clinical reactions locally or at sites distant from the site of absorption.84 Some allergic reactions of the gastrointestinal tract can be caused by more than one immunological mechanism. Nonetheless, most reactions are IgE-mediated: i.e. oral allergy syndrome; gastrointestinal anaphylaxis (malaise, abdominal pain, vomiting, and/or diarrhoea) and infantile colic. Other adverse reactions to food depend on a non-lgE-mediated immunological mechanism: i.e. food-induced enterocolitis syndrome, allergic eosinophilic gastroenteropathy; food-induced colitis, malabsorption syndromes, intolerance to lactose; dermatitis herpetiformis; celiac disease and food-induced pulmonary hemosiderosis. 33
3.2.9.1.
Gastrointestinal
anaphylaxis
This disease is an IgE-mediated gastrointestinal hypersensitivity that accompanies allergic manifestations in other target organs.37 This results in a variety of symptoms that generally develop within minutes to two hours after food intake, mainly nausea, abdominal pain, vomiting, and/or diarrhoea. In children with atopic dermatitis and food allergy,59 the frequent ingestion of food allergens may induce partial desensitization of gastrointestinal mast-cells resulting in less pronounced symptoms (poor appetite, periodic abdominal pain). In these patients the abnormal gut permeability has been shown to be related to histological alterations of the gastrointestinal tract.
3.2.9.2.
Infantile
colics
This is a syndrome characterized by a unrestrainable crying and intractability that develop during the first 3-4 months of life. 85 A possible cause of the pain could be the hypersensitivity to cow's milk.86 In fact, psychosocial and dietary factors have been implicated in the etiology of this syndrome. However, recent double-blind crossover trials in bottle-fed and breast-fed infants suggest that IgE mediated hypersensitivity may be a pathogenic factor in some infants.87 This mechanism accounts for only 10-15% of all colicky infants, the etiopathology of the remaining cases remain unclear.88
3.2.9.3.
Allergic
eosinophilic
gastroenteropathy
This disorder is characterized by peripheral eosinophilia, eosinophilic infiltration of gastric and intestinal mucosa, and exacerbation of symptoms.89 A large number of gastropathies fall under the heading of 'eosinophilic gastroenteropathy', but an IgE-mediated food allergy has been recognized only in the disorder with the characteristics described by Waldman.90 Their patients simultaneously showed other atopic diseases. The eosinophilic infiltrate involves various gastric and intestinal layers. Eosinophilic invasion of the muscular layer lead to thickening and rigidity of the stomach and intestinal walls, along with eosinophilic infiltration of the serosal cells. Symptoms are post-prandial nausea and vomiting, abdominal pain, diarrhoea (occasionally steatorrhoea), weight loss in adults or failure to thrive in young infants. These patients have a form of the disease that is mainly localized to the mucosa; an IgE-mediated reaction to food has been identified as the cause of this disorder. This form of allergic eosinophilic gastroenteropathy can be accompanied by elevated IgE antibodies in duodenal and jejunal tissue, elevated serum IgE titres, positive prick tests to inhalant and foods allergens, peripheral blood eosinophilia, iron deficiency anemia, and hypoalbuminemia. Edema secondary to hypoalbuminemia may occur in infants with protein-losing enteropathy with minimal gastrointestinal symptoms. A small number of patients have an improvement of symptoms after an elimination diet. Symptoms may resolve after eliminating the responsible food from the diet for a period of 6 to 12 weeks. 34
3.2.9.4.
Food-induced
enterocolitis
syndrome
This disorder is seen in children within the third month of life; it is characterized by vomiting, diarrhoea, and malabsorption. Symptoms are provoked by hypersensitivity to cow-milk and soya proteins.91 The damaged intestinal mucosa and accompanying malabsorption may also be caused by intolerance to chicken, rice, fish, and egg. Stools may contain occult blood, eosinophils, neutrophils, and may also test positive for sugar malabsorption. Skin-prick tests for food are generally negative. Jejunal biopsy also shows mild atrophy of the mucosa that is similar to that seen in celiac disease. Vomiting and diarrhoea may occur within minutes to hours after a foodchallenge test. However, opinions regarding the pathogenesis of this syndrome remain discordant. Although many authors consider this enteropathy as non-lgE mediated, an increase in IgE antibodies has been demostrated after challenge with the suspected foods. 92 - 93 Studies performed on intestinal biopsies showed evidence of an increase in plasma cells producing IgM and IgA. 94 · 95 Recent investigations report the IgE-mediated activation of intestinal mast-cells. A milk-free diet induces a quick resolution of symptoms and many children tolerate milk by their first year of life, also in the presence of moderate abnormalities of the jejunal mucosa.
3.2.9.5.
Food-induced
colitis
This is a disorder that develops in the first few months of life; symptoms are caused by hypersensitivity to milk and soya proteins. 96 · 97 The most important complaint is bloody diarrhoea; histologic lesions are seen in the large bowel and primarily consist of mucosal edema and eosinophilic infiltration of the epithelium and lamina propria. In these children, symptoms improve after eliminating cow's milk or soya from their diet or the mother's diet if the infant is being breast-fed. These children tolerate milk by the age of two.
3.2.9.6.
Food-induced
malabsorption
syndrome
This disorder is present in the first several months of life and is characterized by diarrhoea, poor weight gain, and carbohydrate malabsorption.98 These patients are generally intolerant to either cow's milk proteins, soya, egg, or wheat. Jejunal biopsy is typically defined by patchy villous atrophy and cellular infiltration. Moreover these patients show elevated serum IgA and IgG antibodies specific for cow's milk proteins.
3.2.9.7.
Lactose
intolerance
Intestinal lactase is an enzyme able to hydrolyze lactose and glycosilceramide found in human milk. 99,100
Isolated deficiency of this enzyme is rare and is usually manifested at birth. On the other hand, the acquired deficiency is frequently seen in adults, often after disease of the small bowel. The concentration of lactase in the intestinal brush-border cells tends to decrease in the long run. The prevalence of acquired lactase deficiency is elevated in Orientals, Negroes, and American 35
Indians (90%);101 in subjects of Northern Europeans the prevalence is only about 5%. In Italy the prevalence of lactase deficiency has been reported to be 4, 52, 55, 102 and 78%, according to the different studies performed on healthy adults. Secondary lactase deficiency is present in some inflammatory bowel disorders, untreated celiac disease, bowel reactions in chronic alcoholism, and after anti-neoplastic chemotherapy. Identification of these patients is possible with the use of indirect methods: measuring glycemia after lactose load and H2 concentration assay in expiratory air after lactase ingestion (H 2 breath test).103 The latter test is very sensitive for quantifying the lactose that is not absorbed. Management of the lactose intolerant patient is based on educating the patient on what foods reduce symptoms rather than instructing the patient to exclude those foods that contain lactose. It has been verified that lactase is an induceable enzyme and that patients with lactase deficiency can induce acquired tolerance to lactose by drinking large quantities of milk, thereby selecting the development of a bacterial flora that metabolizes lactose in the presence of an acidic environment.104
3.2.9.8.
Dermatitis
herpetiformis
This disease is a papular-vesicular skin disease often associated with gluten sensitive enteropathy (85% of patients). Dermatitis herpetiformis, as celiac disease, has an increased association with specific cellular surface antigens: 80-90% of these patients have the HLA B8 and DRW3 haplotype.10·69 The histology of the skin lesions is characterized by infiltration of PMN in the dermoepidermal junction. The derma of 85-90% of the patients with dermatitis herpetiformis reveals granular deposits of IgA with J-chains. This suggests that the IgA antibodies most probably originate from the mucosal surface of the small bowel. Linear IgA deposist without J-chains can be found in 5% of the patients, suggesting non-mucosal origin of these immune globulins. 107 ' 108 Intestinal biopsy in patients with granular IgA deposits indicates injury that is similar to celiac disease.109 On the contrary, patients with linear IgA deposits do not show the typical intestinal defects. Elimination of gluten from the diet leads to resolution of skin symptoms and normalization of intestinal intercellular structures over several months; and this permits the tapering of sulfones.
3.2.9.9.
Celiac
disease
(CD)
CD is a gluten sensitive enteropathy caused by an abnormal intestinal immune response to gluten. 110 · 111 It appears in individuals with genetic susceptibility and the haplotype HLA B8 DW3. interaction between gluten and the immune system not only involves intestinal mucosa but also the skin, oral mucosa, kidney, and joints. In the intestinal mucosa T-cell mediated immunity accompanies the histological and functional alteration: flat mucosa or normal crypts and villi with an intraepithelial lymphocytic infiltration of the villi. A clear correspondence between histological alteration and symptoms is not always present: therefore celiac disease has been defined as active, silent, latent, and potential celiac disease. 36
Villous atrophy, crypt hyperplasia, gastrointestinal symptoms, and malabsorption characterize the active form. In silent disease there is a scarcity of symptoms and the mucosa is flat. In latent celiac disease the intestinal mucosa is normal when on a free diet, but these patients can or will develop a flattened mucosa that normalizes after a gluten-free diet. The immunopathogenesis is not evident but recent studies suggest a cell-mediated mechanism. Pathological lesions of the small intestine consist of neutrophilic and eosinophilic infiltration of the mucosa with edema and increased vascular permeability. Subsequently the mucosa is infiltrated by mononuclear cells, plasma cells, and lymphocytes. In chronic celiac disease one sees a reduced flat intestinal mucosa with villous athrophy, plasma cells, and lymphocytic infiltration of the lamina propria. The increased antibody response (antigliadin antibodies or food-antigen antibodies) is a consequence of anti-inflammatory activity. It is unlikely that antigliadin antibodies (AGA) play an important role in the mucosal damage, although an activated complement system is evident in these patients. Some authors consider celiac disease to be an autoimmune disease caused by gluten ingestion, the target organ being the protein of the lamina propria after identification of Ab antireticuline, Abantiendomysium, Ab-antijejunum. 112 · 113 · 114 ' 115 The active form of celiac disease occurs in the first two years of life and is characterized by chronic diarrhoea, weight loss, vomiting, and anorexia. If extensive mucosal damage is present the patients may suffer from steatorrhoea, peripheral edema, pallor due to food loss caused by vitamin-K deficiency, and tetany due to calcium and magnesium deficiency. Recent instrumental investigations have shown new forms of the disease. These forms are frequent during late infancy and in adults with extraintestinal symptoms: iron deficency anemia (resistant to iron replacement therapy), retardation of puberty and low stature. The association between celiac disease and joint disease and the evidence of elevated transaminase levels and chronic hepatitis has also been reported. Moreover, an association has been indicated between celiac disease and epilepsy in patients with bilateral occipital calcifications. Dentinoenamel hypoplasia and recurrent aphtous ulcers can be symptoms of celiac disease. Granular IgA accumulations have been found in celiac patients. Treatment for celiac disease consists of a gluten-free diet. Clinical improvement, particularly in children, can be seen within days of dietary treatment and morphologic abnormalities are reversed in a matter of weeks. A life-long gluten-free diet is recommended for celiac disease patients regardless of symptoms.
3.2.9.10.
Heiner's syndrome or food-induced pulmonary hemosiderosis
This is a syndrome characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates caused by hemosiderosis, iron deficiency anemia due to gastrointestinal blood loss, failure to thrive, vomiting, cough, and dysplasia. Hemosiderin-laden macrophages may be found in the gastric fluid or on biopsy specimens of the lung; multiple serum precipitins to cow's milk may also be seen in the peripheral blood. 116 · 117 This rare syndrome is often associated with a non-lgE-mediated hypersensitivity to cow's milk but reactivity to egg and pork has also been reported: the immunological mechanisms are not known. 37
Rare studies report deposits of IgG, IgA, and C'3 in lung biopsy specimens. Antigen antibody complexes and lymphocyte mediated hypersensitivity responses to milk are postulated in the immunopathogenesis of this disorder. This hypothesis is based on the presence of elevated serum levels of milk specific IgG antibodies. The elimination of milk or other foods responsible resolves symptoms.
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Reitamo S., Visa K., Kahonen K., Kayhko K., Stubb S., Salo O.P. 'Eczematous reactions in atopic patients caused by epicutaneous testing with inhalant allergens'. British Journal of Dermatology 114, pp. 303309. 1986.
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De Groot A.C. and Young E. 'The role of contact allergy to aeroallergens in atopic dermatite'. Contact D ermatitis 21, pp. 209214. 1989.
51
Seidenari S., Manzini Β.M., D anese P. and Giannetti A. 'Positive patch test to whole mite culture and purified mite extracts in patients with atopic dermatitis, asthma and rhinitis'. Ann. of Allergy 69, pp. 201206. 1992.
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BruynzeelKoomen C , Van Wichen D .F., Toonstra J., Berrens L., Bruynzeel P.L.B. 'The presence of IgE. molecules on epidermal Langherans cells in patients with atopic dermatitis'. Arch. Dermatol. Res. 278, pp. 199205. 1986.
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Bruynzeel Koomen C , Van Wichen D .F., Spry C.J.F., Venge P. and Bruynzeel P.L.B. Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis'. British J. Dermatol. 118, pp. 229238. 1988.
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Flick J.A., Sampson H.A., Perman J.A. 'Intestinal permeability to carbohydrates in children with atopic dermatitis and food hypersensitivity'. Pediatr. Res. 23, p. 303 A. 1988.
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Lahti Α., Maibach H.I. 'Contact skin allergy: urticaria'. Clinical Science 61, pp. 14631469. 1987.
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45
4.
PATHOGENESIS
OF
FOOD
ALLERGY
SYNOPSIS Among the immunologically-mediated reactions to foods, IgE-mediated food allergy is the most exhaustively investigated regarding the pathogenesis. An important role in development of food allergy is played by the break of oral tolerance, an immunologic mechanism mainly supported by T-suppressor lymphocytes leading to a systemic hyporesponsiveness but local IgA hyperresponsiveness to antigens ingested in early infancy. Thus, hyperresponsiveness to antigens and immaturity of the immune system might account for the higher prevalence of food allergy in children than in adults. Also the characteristics of some allergens, such as an enzymatic activity or the resistance to digestion, especially occurring with sequential allergens, may be important in determining food sensitization. In addition, recent studies showed that sensitization to crossreacting allergens present in food and inhalant sources may underlie the development of food allergy.
4.1
Introduction Adverse reactions to foods can be classified in two main groups, the immunologically-mediated and the not-immunologically-mediated reactions, the latter comprising: (1) adverse reactions due to intolerance to carbohydrates, intestinal lactase deficiency being the most common cause of adverse reactions to foods; (2) toxic reactions to food contamination by pathogenic microbes or their toxins; (3) pharmacological reactions due to substances naturally occurring in foods such as caffeine and tyramine, or added in food preparation such as nitrites, or developing during storage such as histamine. Immunologically-mediated reactions comprise: (1) IgE-mediated reactions, the only ones that have been exhaustively evaluated from all clinical and pathogenetic aspects, since the results of double-blind placebo-controlled food challenge (DBPCFC) show they are the only reactions really reproducible in controlled conditions. IgE-mediated reactions cause symptoms such as urticaria, atopic dermatitis and asthma, but also anaphylactic shock and gastrointestinal symptoms such as vomiting and diarrhoea; (2) cell-mediated reactions, including gluten enteropathy and probably the child-at-breast enteropathies, whose typical histological aspects include atrophic villus and hyperplastic crypta, elicited by foods such as soya, fish and milk. IgE-mediated reactions are properly defined as allergic and are part of the large group of atopic diseases, involving both the exposure to certain antigens and a particular genetic disposition. However, a third factor is also likely to play a pivotal role in the case of IgE-mediated sensitization to foods, known as oral tolerance.1
4.2.
Oral
tolerance
The existence of oral tolerance has been known for a long time, but its mechanisms are only partially recognized. By this phenomenon the exposure to an antigen by the enteral route induces a specific systemic immunologic hyporesponsiveness, limited to IgE-mediated and cell-mediated 46
immunity, to subsequent exposures to the same antigen also by other routes, such as the parenteral one. Oral tolerance can be easily induced, especially with soluble antigens, but does not occur with replicant antigens and therefore oral tolerance cannot be induced to viral antigens. Oral tolerance has been demonstrated by a series of experimental models. For example some chemical aptens able to elicit contact dermatitis if administered in the experiment animal by the gastroenteric route significantly inhibited the contact sensitization compared to the control animals.2 First studies were performed by DNCB and demonstrated an inhibition of cell-mediated reactivity.3 Regarding food antigens, the most reproducible model is the oral tolerance to ovalbumin in mice, which can be induced by a single administration and can last up to two months. In a study a single administration of ovalbumin at different amounts induced a wellmeasurable suppression of cell-mediated reactivity.4 This obviously gave rise to various theoretical speculations about the most convenient rhythms of feeding in man and on the importance of the so-called 'priming' effect.5 This is a well reproducible and measurable phenomenon, the mechanisms of which are incompletely known, regulating the immune response to antigenically intact absorbed proteins. However absorption of intact proteins occurs only rarely, since some mechanisms globally defined as mucosal barrier are aimed at interfering with the intake of macromolecules. The gut is constantly exposed to large amounts of soluble and particulate antigens, mostly derived from foods. To avoid massive absorption followed by non-selective immunization, particular mechanisms have developed in the intestine, some non-immunologic forming a barrier to the passage of macromolecules, and others immunologic regulating the immune response if this barrier is broken. 6
The intestinal barrier consists of mucus, gastric acid, duodeno-pancreatic enzymes. Gastric digestion by acid secretion and pepsinic hydrolysis provides a first degradation of food proteins, then completed by proteolytic enzymes determining a digestion in to simple peptides to be absorbed by the bowel. Therefore, the small bowel is reached only by a few intact proteins, the absorption of which is further prevented by the presence of the intestinal mucus. This is continuously produced by the mucus-secreting cells scattered in the intestinal epithelium and forms a viscous barrier trapping all the proteins with a molecular weight higher than 17 kd. However its major efficacy relies in being constituted by large glycoproteins with a prateie core and a carbohydratic contour. The latter account for about 80% of the molecular weight and have monosaccharidic terminal residues such as fucose and sialic acid. Many antigens, even of foods, adhere by such carbohydratic residue to enter in the enterocytes and thus the mucus acts by competition, blocking the food proteins as well as the cell walls of many microbes. The mucus, once trapped all refused substances, flows by peristaltic mechanisms. Another non-immunologic mechanism is represented by the selective permeability of the microvillum membrane of the enterocytes, which largely depends on age and maturation of the subject.
Also an immunologic mechanism consisting in the immunoexclusion by secretory IgA antibodies can concur to the intestinal barrier. They are prevalently represented by the lgA2 subclass, probably because of its greater resistance to enzymatic degradation compared to lgA1 subclass. If secretory IgA certainly block some antigens, especially bacterial,7 their role with food protein is yet unclear. So far a correlation between deficiency of secretory IgA and food allergy has not been reported, however this mechanism is under continuous investigation because of the theoretical importance of the block by IgA to antigen intake. This block occurs at three levels, namely in the lumen where IgA are secreted, in the epithelium and in the lamina propria. Despite this, a small 47
quota of macromolecules, corresponding to about 2%, physiologically reach the intestine, on one hand giving rise to further production of secretory IgA and on the other the development of oral tolerance, which is an anergic mechanism but involves many regulatory mechanisms.
Regulation of the immune response is based on the activity of anatomical structures such as Peyer's patches, M (microfold) cells, and other components of the immune system in the intestinal mucosa grouped under the umbrella term GALT (gut associated lymphoid tissue).8
Intestinal lymphatic tissue is one of the most abundant in the human organism and its basic elements are Peyer's patches and a specialized epithelium represented by M cells in the ileum. Peyer's patches are certainly an unique element in lymphatic system and can be defined as sites of induction of IgA response. They are complexly structured and include three main areas: socalled dome zones, in which are contained macrophagic dendritic cells and scattered Τ and Β lymphocytes, and two other well organized zones. These are the parafollicular zone where the Τ lymphocytes (T areas) are found and the follicular zone with two germinative centers where the Β lymphocytes (B areas) are the type of lymphocytes in the parafollicular zones which has been investigated in a number of studies and it has been possible to define, at least partly, the phenotype functions of these cells. Being Peyer's patches sites preferentially inductive of IgA response, they are provided of all the immunocompetent cells helping this response. Thus, in parafollicular zones Τ lymphocytes are essentially of CD4 phenotype with helper function, with only a small quote of CD8 lymphocytes.9 CD4 cells are lymphocytes regulating isotypic switch of Β cells from BlgM to BlgA. Peyer's patches are a site with a large concentration of BlgA, i.e. already capable of IgA production, however these are only 40% of resident Β cells, being 60% represented by cells that await the signal for switching.10
Also other types of lymphocytes are present. Recent studies reported the presence of subtype TH2 of CD4 cells, as demonstrated by the model of immunization with heterologous red cells in mice showing that, once the switch has occurred, lymphocytes producing cytokines such as IL-4, IL-5 and IL-6 (characteristic of the TH2 pattern) were found. 11 In particular, IL-5 is involved in further development and differentiation of Β lymphocytes in plasma cells producing IgA.12
In Peyer's patches, an antigen-specific as well as an antigen-non-specific suppression may occur. The latter is demonstrated by the increase of oral response to certain antigens, the decrease of suppressor Τ cell response after oral challenge, and by the lack of oral unresponsiveness in animals genetically unresponsive to lipopolysaccharide.1
Once the sensitization to the antigen has occurred a specific Β IgA (with its TCD4) leaves through the efferent lymphatics, arrives to mesentheric lymph nodes, passes in the thoracic duct and reaches the bloodstream, then homing in the lamina propria of the different secretory sites, where the effector IgA response is effective. Therefore, most Β IgA cells return to the intestinal lamina propria (which is the induction site), where they develop to plasma cells and produce the dimeric IgA which adhere by their secretory or J component and are transported to the luminal surface. However, Β IgA cells may also reach different sites located in the respiratory, urogenital and mammary tissues, being influenced by endothelial factors such as addressins.13 48
This gives rise to the concept of a common mucosal system,14 which makes it reasonable that a sensitization that occurred in the GALT can account for antigen-specific IgA in all secretory apparata. Considering the epithelium above Peyer's patches, M cells are caliciform cells lacking lysosomial organelles, thus allowing an unaffected passage of antigens, which reach intact macrophages, dendritic cells, and the dome zone of Peyer's patches, where they are processed and elicit the immune response. However M cells are only a minority in the intestinal epithelium, where the most common cell is the enterocyte. This cell absorbs the antigens and certainly plays an important role in the regulation of the immune response to food antigens because (1) it carries secretory IgA and joins them to J component (2) it has a rich lysosomial apparatus and expresses class II MHC antigens (3) it is in continuous contact with intraepithelial lymphocytes (IEL), to which deep investigation have been devoted from many years.15 These lymphocytes are an homogeneous group of Τ cells with CD3 + CD8 + phenotype, thus showing a suppressor/cytotoxic function, which represent 70-90% of human IEL 16 ; those cells recently were attributed the function of suppressing the immune response at a systemic level. 17 In rats and humans, antigen presentation by epithelial cells expressing class II MCH antigens is likely to induce a selective stimulation of CD8+ suppressor cells with subsequent block of the immune response to that antigen. 18 ' 19 It is reasonable to suppose that these activated CD8+ cells are IEL. From a theoretical point of view, as enterocytes present the antigen in conjunction with class II MHC molecules a preferential stimulation of CD4+ cells, i.e. helper lymphocytes, should occur, but on the contrary a suppressor stimulation takes place. This fact has not yet been explained, however recent studies reported that antigens produced by immature IEL can stimulate Τ suppression.20 Moreover, enterocytes express anomalous class II antigens and may produce tolerogenic substances.9 It is possible that the type of antigen presentation by the enterocyte may condition the activation of CD8+ lymphocytes, which once migrated in the spleen should induce anergy. The phenomenon of oral tolerance is currently under thorough investigation because it has been found that it can be used in treatment of immunologic diseases. For example in experimental allergic encephalopathy of the mouse, equivalent to multiple sclerosis in man, administering basic myelin by feeding made it possible to stop the demyelination lesions.21 Moreover, oral immuniza tion with allogeneic splenocytes was able to inhibit accelerated rejection of cardiac graft.22 Therefore oral tolerance seems to be a very important immunologic mechanism mainly supported by T-suppressor lymphocytes, as demonstrated by its inhibition by T-suppressor depletion made with cyclophosphamide.23 It occurs quickly following a single assumption and depends on the animal's age, doses and times of administration, developing according to a sequence in which the antigen uptake by M cells in intestinal Peyer's patches is followed by local production of secretory IgA antibodies accompanied by suppression of the systemic response by T-suppressor lympho cytes. This gives rise to a systemic hyporesponsiveness of IgM, IgG and IgE but local hyperresponsiveness of antigen-specific secretory IgA, which then helps block further antigen absorp tion. Though it has not been proved that IEL are solely responsible for oral tolerance, considering their phenotype and the contiguity with epithelial cells and mucosal lymphatic system, they are probably the cells most involved. 49
These observations suggest that any break in this sequence of events, even partial or shortlasting, can cause the loss of oral tolerance, resulting in sensitization to foods.
4.3
Immaturity
of
the
immune
system
The dependency of oral tolerance on the animal's age suggests the importance of maturation of the immune system in this mechanism. It has been found that a too early feeding with solid foods in respect to the animal's age can determine an activation of IEL antigens, resulting in the abolition of tolerance also to soluble antigens.24 Thus, in humans an inadequacy of the mechan isms underlying oral tolerance might account for the higher prevalence of food allergy among children, especially in the very first years when factors regulating the intestinal barrier are not yet fully developed.25 The final maturation of the specialized structures of the intestinal barrier would thus explain the spontaneous resolution of food allergy in the first three years of life, which occurs, as demonstrated by Bock, very commonly.26 By contrast, a food allergy arising after this age is unlikely to resolve spontaneously. It is thus conceivable that in infancy the lack of fine regulation of IgA synthesis and of full maturation of enterocyte microvillus membrane may condition a high passage of food antigens and, as a consequence, a sensitization to foods caused by a breakdown of tolerance. The overall immaturity of the immune system in the first months of life might explain the high prevalence in early infancy of atopic eczema, a disorder often related to food allergy. True immunodeficiency diseases involve eczema and dysregulation of IgE and IgA antibodies. Among these are some diseases due to the presence of dysfunctional Β cells, such as Wiskott-Aldrich syndrome and hyper-lgE syndrome in which both eczema and high levels of IgE are likely to be related to an impaired function of the Τ suppressor cells. 27 Thus in a child with no true immunodeficiency a transient slowing or arrest of the maturation of these cells might cause eczema symptoms and/or an increase of IgE (even specific) which will disappear when the immune system matures. Recent studies underlined the importance of intestinal mast cells. In the gut there is a vast number of both mucosal and connectival mast cells, though in humans this distinction is not as clear-cut as in rats since the two types may have similar characteristics according to the conditions of the environment.28 In the regulation of IgE sinthesis two signals are required: the presence of IL-4 and the T-B interaction, which may be cognate (i.e. with interposition of the antigen) but also non-cognate.29 Recently the mechanism of non-cognate interaction was identi fied as the ligand CD 40 on the Τ cell and this ligand was found also on mast cells and basophils, thus these cells can determine, in cooperation with Β cells, the production of IgE with no Tcells.30 This has to be carefully considered to explain why sensitization is particularly important in sites with the most abundance of mast cells, such as the intestinal and respiratory mucosa. However food allergy does not always occur in the first three years of life. In patients with allergic symptoms after this age it is difficult to lay the blame on factors such as impairment of the gastroenteric barrier or of immunecompetent cells, and other mechanisms are more likely to be involved, such as the exposure to certain food allergens. 50
4.4.
Role
of
allergens
Pathogenetic mechanisms linked to food allergens, or even to allergens from other sources, are still largely unknown, but on the basis of recent data some hypotheses can be proposed. It is likely that in adults with a mature intestinal immune system, only some characteristics of the allergens might favour the sensitization. The pivotal characteristic that makes an antigen aller genic is still unidentified, however general characteristics of allergens include the glycoprotein nature, a molecular weight ranging from 5 to 50 kd (but reaching also 8090 kd) and a variable resistance to heat and digestion. The latter is related to the antigenic determinants, many of which have particular functional properties, sometimes linked to an enzymatic nature. For example, the soybean tryptic inhibitor31 and the major allergens of dermatophagoides mites 32 are enzymes and the enzymatic activity may account for an easier sensitization. Of particular importance in providing the allergenicity of an antigen are some reaction sites with Τ and Β lymphocytes as well as with IgE antibodies. There are continuous allergenic sites represented by an epitopes formed by a unbroken segment of polypeptide chain, that is a series of aminoacids, which are defined as sequential allergens. This kind of allergens is almost indestructible, being very small and hardly affected by proteolytic activity. By contrast discontinuous allergenic sites are formed by epitopes obtained by justa/position of aminoacids caused by folding of the peptidic chain and their activity is linked to tertiary proteic structure. They are defined as conformational allergens and are more easily denatured by chemical procedures or digestion. Among sequential allergens the most investigated is allergen M from codfish (Gad c 1 from the taxonomie name Gadus callarí as according to current allergen nomenclature), which is a low molecular weight protein, of 12.3 kd, formed by a sequence of 113 aminoacids. The IgE reactive epitope is formed by two tetrapeptides separated by an inert aminoacidic sequence33 and this structure accounts for the sequential nature and makes the allergen in toto resistant to heat and proteolysis. Another sequential allergen is ovalbumin, one of the major allergens of chicken's egg, in which a reactive epitope formed by a sequence of 10 aminoacids was identified34. A very important allergenic source, especially in USA, is peanut (Arachis hypogea). All the proteins contained in the hydrosoluble globulinic fraction are allergens and Ara h 1 and Ara h 2 were recognized as major allergens. 35 · 36 So far, no sequential allergen has been identified, however the peculiar allergenicity of peanut is indicated by the particular natural history of peanut allergy, showing, differently from other food allergies, no tendency to be outgrown with time. 37 Among conformational allergens it is known that the allergens contained in the albuminic fraction of wheat flour are responsible for sensitization by the inhalant route, causing the socalled baker's asthma, but are unable to resist to digestion and thus allergic subjects can eat bread with no reaction.38 Upon different conditions, a sensitization route other than the gastroenteric one could be important in determining food allergy. Some patients may be sensitized by inhalation, inducing IgE production toward foods sharing allergens or epitopes with inhalant sources such as pollens, mites or animal hair and dander. This seems true for the most common food allergy in adults, the oral allergy syndrome, which especially involves vegetable foods.39 This syndrome is very frequently associated with pollinosis and allergy to certain vegetable foods is related to allergy to 51
certain pollens, as reported since 194240 and confirmed in a number of studies.41 Well-known associations between foods and pollens are: apple and birch; 42 celery and birch and mugwort;43 melon and banana and ragweed;44 tomato and peanut and grass;45 kiwi and grass and birch. 46 Recent studies investigated the pathogenetic basis of these clinical associations and in some cases it has been possible to identify the allergen determining IgE cross-reactivity. For example the major allergen of birch (Betula verrucosa) Bet ν 1, with a molecular weight of 17 kd, was found as the allergen causing clinical reaction to apple in subjects allergic to birch pollen. 42 Bet ν 1 and its iso-allergen in apple demonstrated an homology of about 75% at nucleic acid level, thus making it reasonable to suppose that, considering the diffusion of birch pollinosis, most subjects allergic to apple are sensitized to the 17 kd allergen by the inhalant route. Allergy to kiwi fruit also seems conditioned by sensitization to allergens cross-reactive with grass and birch pollens, as demonstrated by the inhibition of immunoblotting, which causes a complete disappearance of some allergens demonstrating an almost identical structure.46 Patients with allergy to vegetable foods and pollens always report that pollinosis began before, often many years before, the oral allergy syndrome, thus indicating the route of sensitization as the inhalant one. Another model of cross-sensitization is allergy to avian proteins occurring in bird breeders, or in whatever subjects exposed to birds, conditioning hypersensitivity to egg. 47 Also in this case, which has been defined as 'bird-egg syndrome', the homology between the two allergenic sources was demonstrated in the laboratory by a very high inhibition of RAST, and in particular the cross-reactive allergen was identified in egg yolk α-livetin, homologous to chicken serum albumin.48 Similarly to oral allergy syndrome and pollinosis, sensitization to avian proteins precedes allergy to egg, confirming the importance of the inhalant route. In some cases ubiquitous antigens are involved, these are defined as panallergens, that is allergens extremely diffuse in both the vegetable and animal kingdoms. This is true for profilin, a well-known protein with a molecular weight of about 14 kd, determining in animals actine polymerization and involved in macrosomial reaction of spermatic cells. This kind of sensitization occurs in birch and mugwort pollinosis, both conditioning hypersensiti vity to celery due to profilin.49 In birch, profilin has been identified as the major allergen Bet ν 2, 50 but its presence has been recognized in a number of vegetable foods, and in some cases monoclonal antibodies have demonstrated the identity of the two profilins.51 Being reported a homology of 34% also with human profilin, it cannot be excluded that in some cases the IgE reactivity to this allergen may be maintained by an autosensitization.51 Other ubiquitous proteins accounting for sensitization by different routes are lectins. These constitute a heterogeneous group of glycoproteins which have the characteristic to specifically bind with very high avidity to a single monosaccharide.52 Lectins are extremely diffuse in the vegetable kingdom but were identified also in animals.53 Due to their high affinity for carbohydrate residues, lectins were suspected to induce degranulation of basophils by IgE-binding,54 but in in vitro studies RAST-inhibition with specific sugars failed to demonstrate such a mechanism.55 Thus sensitization to lectins is likely to occur by other mechanisms, such as intracellular 52
penetration by their ability to adhere to free monosaccharidic residuals. Because of this ability lectins are commonly used in immunologic research as mitogens. Recent evidence has been added to our knowledge of the ubiquitous allergens tropomyosin, a protein involved in actine activation during muscle contraction, which has been identified as a cross-reactive allergen in shrimp, mites, and several insects.56 It is conceivable that in a number of patients allergic to mites, sensitization to tropomyosin, representing for shrimp its major allergen Pen a 1, 5 7 may trigger the development of food allergy to shrimp.
REFERENCES 1
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2
Strobel S. 'Oral tolerance'. In Auricchio S., Ferguson Α., Troncone R. (eds.): 'Mucosal immun ity and the gut epithelium. Interactions in health and disease'. Dyn. Nutr. Res. Basel, Karger, 1995, vol 4, pp. 65-75.
3
Lowney E.D. 'Tolerance of a contact sensitizer in man'. Lancet 1968, 1, p. 1377.
4
Bruce M.G., Ferguson A. 'Oral tolerance to ovalbumin in mice: Studies of chemically modified and "biologically filtered" antigen'. Immunology 1986, 57, pp. 627-630.
5
Strobel S., Ferguson A. 'Immune responses to fed protein antigens in mice. III. Systemic tolerance or priming is related to age at which antigen is first encountered'. Pediatr. Res. 1984, 18, pp. 588-594.
6
Walker W.A. 'Role of mucosal barrier in antigen handling by the gut'. In Brostoff J., Challacombe S.J. (Eds.): 'Food allergy and intolerance'. Bailliere Tindall, London, 1987, pp. 209-222.
7
Brandtzaeg P., Nilssen D.E., Rognum T.O., Thrane P.S. Ontogeny of the mucosal immune system and IgA deficiency'. Mucosal immunology. I. Basic principles. Gastroenterol Clin. North Am. 1991,20, pp. 397-439.
8
Kagnoff M.F. 'Immunology of the intestinal tract'. Gastroenterology 1993, 105, pp. 1275-1280.
9
Kaiserlian D. 'The intestinal epithelial cell: a nonconventional type of antigen-presenting cell'. In Auricchio S., Ferguson Α., Troncone R. (eds.): 'Mucosal immunity and the gut epithelium. Interactions in health and disease'. Dyn. Nutr. Res. Basel, Karger, 1995, vol. 4. pp. 32-39.
10
Straber W., James S.P. 'The mucosal immune system'. In Stites D.P., Terr A.I., Parslow T.G. (eds.): 'Basic and clinical immunology'. Lange, East Norwalk, 1994. pp. 541-551.
11
Guy-Grand D., Vassalli P. 'Gut intraepithelial Τ lymphocytes'. Curr. Opin. Immunol., 1993, 5, pp. 247-252. 53
54
12
Harriman G.R. 'The role of IL-5 in IgA Β cell differentation'. J. Immunol. 1988, 140, pp. 30333039.
13
Picker L.J., Treer J.R., Ferguson-Darnell B., Collins P., Buck D., Terstappen L.W.M. 'Control of lymphocyte homing in man: I. Differential regulation of the peripheral lymph node homing receptor L-selection on T-cells during the virgin to memory transition'. J. Immunol. 1993, 150, pp. 1105-1121.
14
Bienenstock J., Mc Dermott M., Befus AD. 'A common mucosal system'. In Ogra PL, Dayton D (eds.): Immunology of breast milk. Raven Press, New York, 1979, pp. 135-151.
15
Ferguson A. 'Progress report. Intraepithelial lymphocytes of the small intestine'. Gut 1977, 18, pp. 921-37.
16
Dobbins W.O. 'Human intestinal intraepithelial lymphocytes'. Gut 1986, 27, pp. 972-85.
17
Barrett T.A., Gajewski T.F., Danielpour D., Chang E.B., Beagley K.W., Bluestone J.A. 'Differen tial functions of intestinal intraepithelial lymphocytes subsets'. J. Immunol. 1992, 149, pp. 1124-1130.
18
Bland P.W., Warren L. 'Antigen presentation by epithelial cells of the rat small intestine. II. Selective production of suppressor Τ cells'. Immunology 1986, 58, pp. 9-14.
19
Mayer L., Shlein R.C. 'Evidence for function of la molecules on gut epithelial cells in man'. J. Exp. Med. 1987, 166, pp. 1471-83.
20
James S.P. 'Mucosal T-cell function'. Gastroenterol Clin. North Am. 1991, 20, pp. 597-612.
21
Whitacre C.C., Gienapp I.E., Orosz CG., Bitar D.M. 'Oral tolerance in experimental autoim mune encephalomyelitis. III. Evidence for clonal anergy'. J. Immunol. 1991, 147, pp. 21552163.
22
Hancock W.W., Sayegh M.H., Zhang Z.J., Kwok CA., Weiner H.L., Carpenter C.B. 'Oral immunization with allogeneic spenocytes inhibits development of accelerated but not acute rejection of cardiac grafts: Analysis of intragraft effector mechanisms'. Transplant Proc. 1992, 24, pp. 250-251.
23
Mowat A.M., Strobel S., Drummond Η.E. 'Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide'. Immunology 1982, 45, pp. 105-13.
24
Hanson D.G., Vaz N.M., Maia L.C.S. 'Inhibition of specific immune responses by feeding protein antigens. III. Evidence against maintenance of tolerance to ovalbumin by orally induced antibodies'. J. Immunol. 1979, 123, pp. 2337-43.
25
Taylor B., Norman A.P., Orgel M.A. 'Transient IgA deficiency and pathogenesis of infantile atopy'. Lancet 1973, 2, pp. 111-13 .
26
Bock S.A. 'The natural history of severe reactions to foods in young children'. J. Allergy Clin. Immunol. 1985, 107, pp. 676-80.
27
Vercelli D., Jabara H.H., Arai K., Geha R.S. 'Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the Τ cell receptor/CD23 complex and MHC class II antigens'. J. Exp. Med. 1989, 169, pp. 1295-1307.
28
Gauchat J.F., Henchoz S., Mazzel G., Aubry J.P., Brunner T., Blasey H., Life P., Talabot D., Flores-Romo L., Thompson J., Kishi K., Butterfield J., Dahinden C , Bonnefoy J.Y. 'Induction of human IgE synthesis in Β cells by mast cells and basophils'. Nature 1993, 365, pp. 3409-3413.
29
Parronchi P., Tiri Α., Macchia D. 'Non-cognate contact-dependent Β cell activation can promote IL-4 dependent in vitro human IgE synthesis. J. Immunol. 1990, 144 pp. 2102-2108.
30
Noelle R.J., Ledbetter J.A., Aruffo A. CD40 and its ligand: an essential figand-receptor pair for thymus-dependent B-cell activation. Immunol. Today, 1992, 13, pp. 431-437.
31
Moroz L.A., Yang W.H. 'Kunitz soybean tripsyn inhibitor: A specific allergen in food anaphy laxis'. N. Engl. J. Med. 1980, 302, pp. 1126-1128.
32
Yasueda H., Mita H., Akiyama K. 'Allergens from dermatophagoides mites with chymotryptic activity'. Clin. Exp. Allergy 1993, 23, pp. 384-390.
33
Elsayed S., Somes S., Apold J. 'The immunological reactivity of the three homologous repetitive tetrapeptides in the region 41-64 of allergen M from cod'. Scand. J. Immunol. 1982, 16, pp. 77-82.
34
Elsayed S., Holen E., Haugstad M.B. 'Antigenic and allergenic determinants of ovalbumin. II. The reactivity of the NH2 terminal decapeptide'. Scand. J. Immunol. 1988, 27, 587-591.
35
Burks A.W., Williams L.W., Helm R.M. 'Identification of a major peanut allergen, Ara h I, in patients with atopic dermatitis and positive peanut challenge'. J. Allergy. Clin. Immunol. 1991, 88, pp. 172-179.
36
Burks A.W., Williams L.W., Connaughton C. 'Identification and characterization of a second major peanut allergen, Ara h II, with use of sera of patients with atopic dermatitis and positive peanut challenge'. J. Allergy Clin. Immunol. 1992, 90, pp. 962-969.
37
Bock S.A., Atkins F.M. 'The natural history of peanut allergy'. J. Allergy Clin. Immunol. 1989, 83, pp. 900-904.
38
Sutton R., Hill D.J., Baldo B.A. 'Immunoglobulin E antibodies to ingested cereal flour compon ents: studies with sera from subjects with asthma and eczema'. Clin. Allergy, 1982, 12, pp. 6374.
39
Ortolani C , Ispano M., Pastorello E.A., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy, 1988, 61, pp. 47-52. 55
56
40
Tuft L., Blumstein G.I. Studies in food allergy. II. Sensitization to fresh fruits: clinical and experimental observations'. J. Allergy, 1942, 13, pp. 574-582.
41
Ortolani C , Pastorello E.A., Farioli L., Ispano M., Pravettoni V., Berti C , Incorvaia C , Zanussi C. 'IgE-mediated allergy from vegetable allergens'. Ann. Allergy, 1993, 71, pp. 470-76.
42
Ebner C , Birkner T., Valenta R., Rumpold H., Breitenbach M., Scheiner O., Kraft D. 'Common epitopes of birch pollen and apples'. Studies by Western and Northern blot. J. Allergy Clin. Immunol. 1991, 88, pp. 588-94.
43
Pauli G., Bessot J.C, Dietermann-Molard A. 'Celery sensitivity: clinical and immunological correlations with pollen allergy'. Clin. Allergy, 1985, 15, pp. 273-279.
44
Anderson B.L., Dreyfuss E., Logan S. 'Melon and banana sensitivity coincident with ragweed pollinosis'. J. Allergy, 1970, 45, pp. 310-319.
45
De Martino M., Novembre E., Cozza G., De Marco Α., Bonazza G., Vierucci A. 'Sensitivity to tomato and peanut allergens in children monosensitized to grass pollen'. Allergy, 1988, 43, pp. 206-213.
46
Pastorello E.A., Ortolani C , Pravettoni V., Farioli L., Ispano M., Asman I., Bengtsson Α., Incorvaia C. 'Identification of the allergenic components of kiwi fruit and evaluation of their cross-reactivity with timothy and birch pollens'. Submitted.
47
Hoffman D.R., Guenther D.M. Occupational allergy to avian protein presenting as allergy to ingestion of egg yolk'. J. Allergy Clin. Immunol., 1988, 81, pp. 484-88.
48
Szepfalusi Z., Ebner C , Pandjaitian R., Orlicek F., Scheiner O., Boltz-Nitulescu G., Kraft D., Ebner H. 'Egg yolk α-livetin (chicken serum albumin) is a cross-reactive allergen in the bird-egg syndrome. J. Allergy Clin. Immunol., 1994, 93, pp. 932-942.
49
Valuer P., Dechamp C , Valenta R., Vial O., Deviller J. 'Purification and characterization of an allergen from celery immunochemically related to an allergen present in several other plant species. Identification as a profilin'. Clin. Exp. Allergy, 1992, 22, pp. 774-782.
50
Valenta R., Duchene M., Ebner C , Pettemburger K., Scheiner O., Kraft D. 'Profilins constitute a novel family of functional plant pan-allergens'. J. Exp. Med., 1992, 2, pp. 377-385.
51
Valenta R., Duchene M., Pettemburger K., Sillaber P., Valent P., Bettelheim P., Breitenbach M., Rumpold H., Kraft D., Scheiner O. 'Identification of profilin as a novel pollen allergen; IgE autoreactivity in sensitized individuals'. Science, 1991, 253, pp. 557-60.
52
Summer J.B., Howell S.F. 'Identification of hemagglutinin of jack bean concanavalin'. A. J. Bacteriol., 1936, 32, pp. 227-237.
53
Freed D.L.J. 'Dietary lectins and disease'. In Brostoff J., Challacombe S.J. (eds.): Food allergy and intolerance, Bailliere Tindall, London, 1987, pp. 375-400.
54
Siraganian R.P., Siraganian P.A. 'Mechanism of action of concanavalin A on human basophils'. J. Immunol., 1975, 114, pp. 886-893.
55
Barnett D., Howden M.E.H. 'Lectins and the radioallegosorbenttest'. J. Allergy. Clin. Immunol., 1987,80, pp. 558-561.
56
Witteman A.M., Akkerdaas J.A., van Leeuwen J., van der Zee J.S., Aalberse R.C 'Identification of a cross-reactive allergen (presumably tropomyosin) in shrimp, mite and insects'. Int. Arch. Allergy Appi. Immunol., 1994, 105, pp. 56-61.
57
Shanti K.N., Martin B.M., Nagpal S., Metcalfe D.D., Subba Rao P.V. 'Identification of tropomyosin as the major shrimp allergen and characterization of its IgE-binding epitopes'. J. Immunol., 1993, 151, pp. 5354-5363.
57
FOOD
A L L E R G E NS
SYNOPSIS Compared with the vast number of aeroallergens as yet identified, only a few food allergens are known, mainly because of the difficulty to recruit sufficient patients with positive IgE test and DBPCFC and to perform the laboratory technique for detecting allergens. So far, food allergens have been identified in cow's milk (alactoalbumin, ßlactoglobulin, caseins), in hen's egg (ovomucoid, ovalbumin, ovotransferrin in egg white, αlivetin in egg yolk), in fish (Gad c 1), in shrimp (Pen a 1, Pen a 2), in peanut (Ara h 1, Ara h 2), in soybean (Gly m 1), in cereals (a series of proteins with m.w. from 26 to 79 kd as yet not named), in apple (Mal d 1, Mal d 2), in celery (Api g 1), in fruits belonging to Prunoideae (an allergen of 13 kd proposed as Pru ρ 1).
5.Í
Introduction
Allergens are polypeptide molecules of molecular weight (MW) ranging from 5 to 100 kd, able to elicit a specific IgE response. D ifferently from inhalant allergens, that have been thoroughly investigated, and the major, intermediate, and minor allergens1 have been identified, the process of identification of food allergens is ongoing and only a limited number of foods has been evaluated. This is mainly due to the difficulty, given the relative rarity of food allergy as compared to inhalant allergy, in recruiting a reasonable population size of subjects with specific IgE tests and doubleblind placebocontrolled food challenge (DBPCFC) positive for a given food, in order to perform the laboratory techniques necessary to detect the allergens and to determine their clinical importance.2
So far, this has been possible for some of the foods most frequently responsible for food allergy such as cow's milk, hen's egg, fish, shrimp, peanut, wheat, soybean, and for some vegetable foods frequently involved in oral allergy syndrome (OAS), such as apple, celery, and Prunoideae fruits.
In recent years considerable efforts have been made to identify the major allergens of legumes, cereals, fruits and vegetables. This has been possible for some of the above mainly by using SDSPAGE and immunoblotting on the sera of patients with OAS, the most common form of food allergy in adults, especially prevalent in subjects with pollinosis. A number of observations indicate that the majority of allergens in fruits and vegetables are crossreactive with homologous allergens in pollens, and that some allergens are particularly frequent. This is true for profilin, a substance involved in fertilization of plants, and for the allergens related to the major allergen of birch, Bet ν 1, which can be considered panallergens in the vegetable kingdom. On the other hand, allergens not crossreacting with pollens are surely involved in clinical symptoms, as demonstrated for fruits of the Prunoideae subfamily. 58
5.2.
Allergens
5 . 2 . 1 . Cow's
milk
Since the 1960s it has been found that cow's milk contains about 20 proteins able to elicit the specific IgE synthesis.3 These proteins can be divided into caseins, representing about 80% of the protein fraction of milk, and whey proteins, representing about 20%. The casein fraction is comprised of five distinct proteins, namely αcasein (MW 27 kd), ascasein (23 kd), ßcasein (24 kd), Kcasein (19 kd), and γcasein (21 kd). The whey proteins comprise ßlactoglobulin (36 kd), of which three genetic variants with different electrophoretic mobility, but with no immunological differences, have been reported,4 alactoalbumin (14.4 kd), bovine serum albumin (69 kd), peptone (420 kd), as well as bovin immunoglobulins, lactoferrin, tranferrin, and lipase. Carbohydrates contained in cow's milk have no allergenic activity, but it has been reported that the allergenicity of cow's milk proteins can be enhanced by a nonenzymatic reaction with lactose, resulting in the coupling of the sugar to the protein, as demonstrated by a greater skin reactivity to ßlactoglobulin treated with lactose onehundredfold higher than seen with untreated ßlactoglo bulin in milk allergic patients.5 Caseins are heatstable if boiled, whereas ßlactoglobulin is partially denatured and the other whey proteins are almost completely denatured.6 ßlactoglobulin was stable to digestion in a gastric model in vitro, the whole protein resisted 60 minutes to digestion, casein whole protein was stable two minutes, while its fragments 15 minutes.7 The availability of the various cow's milk proteins allowed to evaluate their allergenic importance by testing patients with demonstrated allergy to cow's milk. Out of 45 children who underwent challenges with the individual milk protein, 28 (62%) had a positive response to ßlactoglobulin, 27 (60%) to casein, 24 (53%) to alactalbumin, and 23 (51%) to bovine serum albumin. 8 In vitro investigation by crossedradioimmunoelectrophoresis (CRIE) found that alactalbumin, ß lactoglobulin, bovine serum albumin and bovine gamma globulin act as major allergens as assessed by the IgEbinding of most sera of milk allergic patients.9 In addition, studies by SDS PAGE/immunoblotting have detected in milks of various animals proteins that crossreact, as demonstrated by IgEbinding of sera of sensitized individuals with this component in milk from cows, goats, and sheep.10
5 . 2 . 2 . Hen's
egg
Most protein components determining allergic sensitization are contained in egg white, which comprises more than 20 proteins. Major allergens are ovalbumin, ovomucoid (Gal d 1), and ovotransferrin (Gal d 3), previously known as conalbumin,11 as demonstrated by CRIE 12 and SDSPAGE immunoblotting.13 Ovalbumin, named Gal d 2, according to the current allergen nomenclature14 based on the accepted taxonomie denomination of the animal or vegetal species representing the allergen
59
source (which in this case is Gallus domesticus), has a molecular weight of 45 kd and comprises more than 50% of egg's white proteins. Its complete aminoacid sequence has been described,15 and a terminal decapeptide able to specifically bind with the IgE in sera of egg-allergic patients and to inhibit further binding with whole ovalbumin in RAST-inhibition experiments, was identified. 16 The allergenic activity of ovalbumin was found to be resistant to both thermal and trypsin denaturation, as shown by negligible RAST-inhibition following these treatments, whereas pepsin hydrolysis caused an inhibition of 50%, demonstrating significant alteration of the antigenic structure.17 Gal d 2 was stable 60 minutes to digestion in a gastric model in vitro, the Gal d 1 whole protein resisted eight minutes and the Gal d 3 whole protein was instable to gastric digestion, while its fragments were stable after 15 minutes.17 The cleavage of ovalbumin with cyanogen bromide resulted in four fractions, all binding specific IgE in the sera obtained from egg-sensitive individuals.17 A recent study was aimed at defining the allergenic epitopes of ovalbumin by using two preparations either physically and chemically denatured or containing ovalbumin fragments obtained by enzymatic digestion.18 Analysis of the sera of patients with egg allergy by SDS-PAGE followed by an ELISA technique showed that the primary structure of ovalbumin was retained after both types of denaturation, whereas the conformational structure was modified only by physical denaturation by heat, as demonstrated by differences in fine specifities of IgE compared to IgG and IgA against ovalbumin. Another study investigated the epitope mapping of ovalbumin using synthetic peptides comprising a segment of 70 aminoacid residues located at the N-terminal.19 It was observed that the allergenicity, tested by inhibition of ovalbumin binding by specific IgE from allergic patients, was distributed in the 11-70 region, being the 11-19 peptide able to inhibit IgE-binding despite a weak antigenicity. The 11-70 region seemed to contain conformational rather than continuous allergens.
Ovomucoid (Gal d 1) has a molecular weight of 28 kd, comprises about 10% of egg's white proteins, is heat stable20 and not denaturated by chemical procedures.21 Because of these characteristics, ovomucoid seems particularly involved also in the allergic reactions that occur when cooked eggs are eaten. A recent study investigated a group of 18 children with egg allergy in relation to the in vivo and in vitro response to ovalbumin and ovomucoid.22 Wheals elicited by skin test with ovomucoid were significantly greater than those elicited by ovalbumin, and ovomucoid-specific IgE concentrations in serum were significantly higher than ovalbumin-specific IgE concentrations. In addition, in two groups of patients respectively with persistent egg allergy and with development of tolerance to egg, specific IgE to ovomucoid were significantly higher in the former, whereas no difference was found in specific IgE to ovalbumin. These findings led the authors to suggest that, contrary to what is commonly thought, ovomucoid is the immunodominant protein fraction in egg white.
Ovotransferrin or conalbumin (Gal d 3) has a molecular weight of 78 kd, theoretically precluding penetration in the intestinal mucosa, however its ability to react with specific IgE was demonstrated in vitro by CRIE and in vivo by skin tests performed in 15 patients clinically sensitive to egg. 23
Lysozyme (Gal d 4) has a molecular weight of 15 kd and comprises about 3% of egg white proteins. This allergen cannot be considered a major allergen, since lysozyme-specific IgE have been found only rarely.24 60
Very recently, ovalbumin, ovomucoid, ovotransferrin, and lysozyme were purified and character ized by raising specific antibodies in immunized rabbits and performing immunoblots with sera from patients with a positive D BPCFC 25 Purification of the four proteins allowed the observation that apparent positivity of IgE tests to ovotransferrin, and especially to lysozyme, are caused in most cases by the presence of contaminating proteins in crude preparations. In fact, only one serum showed a positive IgE reaction to purified lysozyme. Interestingly, ovomucoid was detected in at least two homologous variants, ranging from 32 to 46 kd in molecular weight, varying in N glycosilation of the third domain. Egg yolk contains three main protein fractions, namely globulins, livetins, and lowdensity lipoprotein, which were found to bind IgE in sera from patients allergic to egg. 24 The authors of this study could not exclude that the binding was due to presence of contaminants, however at least livetin was successively demonstrated as an allergen. In fact, αlivetin was identified as the allergen crossreacting with chicken serum albumin in subjects with allergic reaction to egg and respiratory allergy to bird feathers defining the socalled birdegg syndrome.26 Another study from the Netherlands performed SD SPAGE/immunoblotting and confirmed the presence, in the sera of adult patients with respiratory allergy to birds, of an allergen cross reacting with egg yolk, but found that sera from exclusively foodallergic children mainly reacted with a component of 35 kd, which is likely to represent another allergen of egg yolk. 27 The different pattern of IgE binding makes it reasonable to suppose that in adult patients sensitization to αlivetin occurs through the respiratory route by inhalation of avian proteins.
5.2.3.
Fish
The most extensively characterized allergen of fish is represented by a parvalbumin (i.e. a sarcoplasmic protein from muscle tissue of fish not present in mammals) contained in the myogen fraction of the meat of codfish, initially described as allergen M 28 and actually named Gad c 1 (from the taxonomie name Gadus callarías) following the current allergen nomenclature. This 12.3 kd allergen is formed by 113 aminoacids and is particularly resistent to heat and proteolysis, maintaining its allergenic properties after cooking and enzymatic digestion.29 It has been also possible to define its threedimensional structure, which has three domains,30 as well as to identify the IgEreactive epitope, which constitutes a sequential linear antigen, being formed by a repetitive group of a few aminoacids, unlikely to be altered. A recent study demonstrated by SD SPAGE/immunoblotting that protein components cross reactive with Gad c 1 are present in a number of common fish species.31 However other allergenic proteins, though as yet not isolated, different from Gad c 1, are likely to be involved in allergic reactions. This is suggested by the findings of a study of RASTinhibition performed with sera from 20 children with a positive history for fish allergy and positive skin tests for 17 fish species, showing a high crossreactivity between the antigens from cod, bass, dentex and eel, but a lower one with sole and tuna; only two children had a IgEreactivity for dogfish. 32 In addition, the inability of lyophilized fish to provoke symptoms during challenge in patients otherwise reactive to unmanipulated fish, strongly suggests the involvement of unstable allergens, which have yet to be identified.33
61
5.2.4.
Shrimp
Allergens of shrimp have been thoroughy investigated, and by CRIE at least seven allergenic components were detected, comprised in three main fractions, respectively located at pi of 4.5-5, 5-5.5, and 5.5-6.34 A more recent study conducted by SDS-PAGE/immunoblotting with material obtained from boiling shrimps (including the water in which they were boiled) and sera from 13 patients allergic to shrimp found nine IgE-binding components.35 A successive study on the same sera found that 92% of them bound to a component of 36 kd, which thus acted as an important major allergen and was named Pen a 1 from the taxonomie name Penaeus aztecus.36 This allergen is a protein with an aminoacid composition rich in glutamic and aspartic acid, representing about 20% of the shrimp's extract and inhibiting 75% of RAST to shrimp.36 Pen a 1 is similar to a protein of 34 kd previously isolated from the species of shrimp Penaeus indicus and preliminarily named Sa (i.e. shrimp allergen)-ll.37 In that study, another allergen of 8.2 kd, named Sa-I, was found, but inhibition studies showed a 54% sharing of allergenic epitopes, suggesting the possibility that Sa-I might be simply a fragment of Sa-ll. Evidence for allergens common to other crustácea, such as lobster, crawfish, and crab, was provided by positivity of IgE-tests for these crustácea in patients allergic to shrimp but with no exposure to other crustácea and by RAST-inhibition experiments.38 Monoclonal antibodies to Pen a 1 were found to react against a 36 kd protein present in crustácea as well as in other seafood such as oyster, squid, and scallop.36 Finally, the 36 kd shrimp allergen, that is, Pen a 1, was identified as tropomyosin, a protein involved in activation of actin during muscle contraction present in all vertebrates, as revealed by equal molecular mass, isoelectric point, and high homology in amino acid sequences.39 Tropomyosin was then found to be a cross-reactive allergen in a number of arthropods including mites and insects,40 but not to cross-react with tropomyosin molecules from vertebrates of phylogenetically distinct species.39 A study investigated the possible species-specific shrimp allergens by evaluating in 31 patients allergic to shrimp the IgE reactivity to white shrimp (Penaeus setifecus) and brown shrimp (Penaeus aztecus). Specific IgE in serum were found in most patients to both shrimp, whereas in two subjects there were IgE only to brown shrimp and in one only to white shrimp.41 RASTinhibition in two individuals revealed qualitatively different allergens in the different species, supporting the existence, even rarely, of species-specific shrimp allergens, which have yet to be identified.
5.2.5.
Peanut
Allergens of peanut are essentially contained in water-soluble fraction, constituted by globulins which in turn are divided in two fractions, arachin and conarachin, according to their precipitation in ammonium sulphate.42 By CRIE, 16 allergenic fractions have been detected, with molecular weight ranging from 15 to 66 kd. 43 A study conducted on nine patients with a positive DBPCFC to peanut identified as major allergen a 63.5 kd protein, thus named, from the taxonomie name Arachis hypogaea, Ara h i . 4 4 This protein showed characteristics similar to a glycoprotein of about 65 kd previously described as an important peanut allergen.45 Very recently, the cDNA coding for Ara h 1 was cloned and sequenced, and it was found that this allergen has multiple IgEbinding domains.46 Other studies identified a second major allergen, Ara h 2, as a component of 62
17 kd, 47 and peanut agglutinin, with a molecular weight of 31 kd, as an intermediate allergen, being recognized by 50% of sera from patients with a positive challenge to peanut.48 As reported in a study of RAST-inhibition, peanut contains one or more allergens cross-reacting with tomato as well as with grass pollen. 49 The clinical significance of this cross-reactivity has yet to be determined, whereas it has been demonstrated that the cross-allergenicity observed by skin tests and RAST among peanut and other members of the legume family, such as various beans, soybean, and pea, is not clinically important, as assessed by a positive response to DBPCFC to more than one legume in only 5% of 69 patients with apparent multiple sensitization.50
5.2.6.
Soybean
This member of the legume family contains water-soluble proteins, which are albumins, and saltsoluble proteins, which are globulins, the latter constituting about 90% of soybean proteins.51 Ultracentrifugation further separates four fraction respectively with a sedimentation rate of 2S (whey fraction), 7S (a-conglycinin), 11S (glycinin), and 15S (aggregated glycinin). Glycinin has a molecular weight of 320 kd and includes six subunits, each containing one acidic and one basic polypeptide; these polypeptides are heterogeneous and have molecular weights from 34 to 45 kd for the acidic polypeptide and from 19 to 22 kd for the basic one. 52 ß-conglycinin has a molecular weight of about 180 kd and is composed of three subunits, with a respective molecular weight of 76, 72, and 53 kd. 53 The first study on the allergenicity of the fractions 2S, 7S, and 11S was conducted by RAST and RAST-inhibition with sera from patients with suspected allergy to soybean, and found that the three fractions were cross-reactive as to IgE-binding, but the 2S showed the highest inhibiting potency.54 The IgE-binding was reduced by heat treatment for the 7S and 11S fractions, but not for the 2S one. Thus, this fraction, i.e. the whey fraction, which is known to include components such as the Kunitz trypsin inhibitor and cytochrome c, seemed to be the most allergenic. In particular, the trypsin inhibitor, of molecular weight of about 20 kd, was reported in the same year as responsible of anaphylaxis in one patient.55 However, a study conducted with sera from nine patients with atopic dermatitis and positive DBPCFC to soybean, investigating the IgE-binding to a crude soya extract and to the 2S, 7S, and 11S fractions found no difference in allergenicity of the different fractions.56 In addition, trypsin inhibition was recently demonstrated to represent only a minor allergen of soybean, showing an IgE-binding in only 20% of sera from patients positive to DBPCFC to soybean.48 A study in patients with allergic reactions to ingestion of soybean establishing its major, intermediate, and minor allergens, and thus attributing their allergen nomenclature, is as yet unavailable, whereas in patients suffering from asthma to inhalation of soybean, the major allergen has been identified as a component of 14 kd and named Gly m 1 from the taxonomie name of Glycine maxima.57 This component, contained in the hull of soybean, is likely to represent an allergen not inducing food allergy, though this hypothesis has not been definitely demonstrated. Another study performed on asthmatic patients reported a protein of 21 kd, a molecular weight similar to that of trypsin inhibitior, as an allergen cross-reacting between soya and wheat flour.58
5.2.7.
Cereals
It has been long known, on the basis of their solubility, that cereals contain four different protein fractions.59 Albumins and globulins are soluble in neutral solutions, glutenins In acid solutions, 63
and prolamines in ethanol. The first studies on allergens of cereals were conducted on sera from patients with respiratory allergy to flour, the so-called baker's asthma, and found that IgE-binding occurred mainly to proteins of molecular weight ranging from 12 to 20 kd present in neutral solution. 60 · 61 More recent investigations found other major allergens as components of the neutral fraction of 47 kd 6 2 and 66 kd. 63 A study comparing the IgE-binding in patients with asthma to that in patients with eczema due to the ingestion of wheat flour, found that allergenic fractions of cereals seemed represented by albumins when regarding asthma, and by globulins and glutenins regarding skin symptoms.64 Recently, SDS-PAGE/immunoblotting with sera from 35 patients with atopic dermatitis and positive skin tests and RAST for one or more cereals (wheat, rye, barley, and oats) revealed that the most frequent IgE-staining occurred with proteins of 26, 28-30, 40-50, 69, and 79 kd. 65 A similar IgE-binding, suggesting cross-allergenicity, was observed with wheat, rye and barley, but not with oats, which appeared to cross-react only weakly. An extensive cross-reactivity between wheat, rye, and barley, as assessed by RAST-inhibition experiments, was observed using sera of patients with wheat-induced asthma.58 Major allergens of wheat were proteins with molecular weight of 12, 21, 26, 33, and 69 kd, whereas in rye they were proteins of 12 and 21 kd and in barley they were proteins of 10, 52, and 69 kd. These findings were partly confirmed in a study of sequence analysis of wheat allergens separated by two-dimensional electrophoresis, which found a major IgE-binding in the area of 14-18, 27, and 37 kd. 66 Recently, the major wheat allergen of 15 kd was identified as α-amylase inhibitor, belonging to the family of a-amylase/trypsin inhibitors acting on mammalian and insect α-amylases.67 This allergen seems mainly involved in baker's asthma,68 but it has been also reported as responsible for food allergy.69
5.2.8.
Apple
Using CLIE, antigens of apple were found to have structural similarities with antigens of birch and grass pollen.70 Apple allergens in the range of 17-18 kd were detected by immunoblotting in 81 patients allergic to birch. In particular, a 17 kd allergen was found highly homologous, by sharing of common epitopes, with the major allergen of birch Bet ν 1. 7 1 These allergens seem to belong to the group of 'pathogenesis-related proteins' involved in resistance to diseases of plants.72 By microsequencing, it was found that the apple allergen cross-reacting with Bet ν 1 has identical but also different antigenic determinants compared to Bet ν 1, such as the three consecutive proline residues in position 14-16.73 This might account for variation in sensitization patterns in indivi duals sensitized or not to birch pollen.
Recently the major allergen of apple, Mal d 1 (allergen 1 from Malus domestica), has been purified and its characteristics were studied: 74
64
1.
Bet ν 1 has all allergenic epitopes of Mal d 1, but Mal d 1 is only a weak inhibitor of IgE reactivity with Bet ν 1 ;
2.
Mal d 1 represents the main allergenic activity of apple;
3.
Mal d 1 is extremely labile due to interactions with phenols present in the fruit.
The complete DNA sequence of Mal d 1 has been obtained: it is a 158 residue protein with M. W. of 17.5 kda. 75 " 76 In SDSPAGE Mal d 1 has an apparent higher molecular weight. The amino acid sequence of Mal d 1 is 63% identical to Bet ν 1.
5.2.9.
Celery
A study used SD SPAGE to separate the protein components of celery, which were detected in the range from 15 to 90 kd. The 15 kd allergen was analyzed by twodimensional electrophoresis, which showed the presence of isoallergenic forms, and purified. By using a specific rabbit polyclonal antibody recognizing a recombinant birch profilin, this allergen was identified as profilin. Profilin is present in mugwort, which cross reacts via profilin with celery.77 A second major allergen of celery is Api g 1, (allergen 1 from Apium graveolens) an allergen related to Bet ν 1 and belonging to a group of 'pathogenesis related proteins'. By preincubation with recombinant Bet ν 1 it was possible to reduce IgE binding to homologous proteins in celery.78 Api g 1 has recently been cloned and sequenced showing a high immunological and structural relationship to Bet ν 1 and Bet ν 1 related allergens.76
5.2.10.
Prunoideae
SDSPAGE/immunoblotting in 23 patients with OAS from peach and skinprick tests, RAST and oral challenge positive for peach and other fruits of Prunoideae such as apricot, plum and cherry, detected at least 10 allergenic components, of molecular weight ranging from 13 to 70 kda, three of them acting as major allergens. The 13 kd component, detectable by IgEbinding in 90% of allergic patients, was found to be the most relevant major allergen of peach, thus deserving the denomination of Pru ρ 1 (major allergen 1 of Prunus persicus), shared by other Prunoideae but not by grass and birch pollens, otherwise widely crossreacting with Prunoideae as regards the other allergens.79
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PREVENTION
OF
FOOD
ALLERGY
SYNOPSIS The only preventive measure able to interfere with development of food allergy is to postpone as much as possible the introduction into the child's diet of foods containing known allergens, such as cow's milk, egg, fish, and others. This is mainly done by prolonged breast-feeding; the preventive effect is improved by eliminating these foods from the mother's diet. Because of the difficulty to maintain such conditions it is not recommended to prolong breast-feeding over six months. As yet, there are not enough data to use hydrolyzed cow's milk formulae as a measure alternative to breast-feeding
6.7.
Introduction A disease can be successfully prevented when the factors underlying its occurrence are fully understood. This is not the case of food allergy, the pathogenesis of which is largely unknown. However, the important increase in recent years of the prevalence, especially in children, of diseases related to food allergy such as atopic dermatitis or asthma1 has made it worthwhile to perform a series of studies on the prevention of food allergy based on the knowledge of the factors involved in the development of this clinical condition.
6.2.
Known
risk
factors
for
developing
food
allergy
The major risk factors connected with the development of food allergy are represented by a reliable parental history of atopic diseases and by an early exposure to sensitizing antigens contained in particular foods. As regards the first point, a series of studies investigated both retrospectively and prospectively the frequency of atopic diseases in children with a uniparental or biparental history of atopy. It has been found that a uniparental history of atopy is associated with a risk ranging from 20 to 38% when evaluated retrospectively2"5 and from 13.5 to 58% when evaluated prospectively.6"11 In these studies, as well as in other studies,12"13 it has been reported that a biparental history of atopy increases the risk up to 100%. In newborns with a parental history of atopy, the decision to establish preventive measures can also be based on some immunological parameters, the most important of which is generally thought to be the detection of IgE antibodies in cord blood or in blood during the first week of life. This parameter has been initially described as a good predictor of future allergic diseases, 14 · 15 however recent studies demonstrated that its predictive accuracy is less than satisfactory.16·17 In particular, the sensitivity of this test, ranging from 14 to 74%, was found to be not significantly better than that of a family history of atopy.17 Detection of high levels of total IgE in children up to 14 years selected by a negative family history of atopy, resulted a good predictive factor, as in one study 75% of children with high IgE levels had atopic disorders, during the follow-up compared to 6% of those with low IgE levels.18 However, more recent studies investigating the diagnostic accuracy of this parameter in populations of children with positive or negative family history of atopy reported unsatisfactory sensitivity and specificity.19"20 Regarding the value of specific IgE 72
to foods in infancy as a risk factor for food allergy a study claimed that positivity of skin tests to egg was associated to subsequent food allergy also to other foods and to respiratory disorders as well. 21 Nevertheless, in another study, positivity of both skin test and RAST to ovalbumin and ß lactoglobulin showed a specificity close to 100% but a very low sensitivity.17 Because of the overall unsatisfactory predictive value of total or specific IgE measurements, which led Kjellman to conclude that they are not suitable for allergy risk screening on an individual basis,22 other parameters have been considered as possible predictors of food allergy. They consist of: (1) assessment of the number of CD 4+ and CD8+ lymphocyte subpopulations and their ratio, which are of pivotal importance in the regulation of IgE synthesis;23 this parameter resulted in acceptable specificity but poor positive predictive value; 17 (2) platelet counts, as platelets seem involved at various levels in atopic disorders;24 in one study, conducted on a small number of newborns, all subjects developing atopy within the following 18 months had low platelet counts in cord blood; however, an overlapping of values with newborns not developing atopy was observed;25 (3) histamine release by cord blood basophils, which was not found to be independently helpful; 26 (4) content in linolenic acid of cord blood lecithin, which was found higher in children with atopic dermatitis than in healthy controls;27 levels of phosphodiesterase in leukocytes, which are inversely correlated with intracellular levels of cAMP, a basic mechanism underlying regulation of lymphocytes, and possibly IgE production; high levels of phosphodiester ase were found in newborns with family history of atopy and children with atopic dermatitis.28 A recent study investigated several of these parameters, as well as that of IgE and of skin tests with histamine and allergens, and found that neither single parameter nor any combination of them provided acceptable predictive capacity to be used for routine screening of allergy risk at birth. 29
6.3.
Possible
interventions
aimed
at
preventing
food
allergy
Due to the obvious importance of allergen exposure in determining food allergy, the infant at risk should avoid coming in contact with food known to be allergenic. In particular, cow's milk contains foreign proteins, such as ßlactoglobulin, αlactalbumin, and casein, which elicit in all human subjects an antibody response including IgG, IgA, IgM, and IgG isotypes,11 these proteins are also important allergens and thus trigger the IgE response. The optimal preventive measure is thought to be prolonged breastfeeding, which however induces a weaker response not only of IgE but also of the other immunoglobulin classes; this does not result in a less efficient defence from infections.30 In order to avoid an early exposure to food allergens, the mother should not eat foodstuffs known to contain allergens able to pass in human milk, whereas dietary restriction during pregnancy is unnecessary: it is broadly accepted that intrauterine sensitization does not occur.31 Various allergens of cow's milk and hen's egg have been detected in human breast milk,11 though it has never been clearly demonstrated that they cause allergic sensitization. In particular a study investigated the secretion of ßlactoglobulin in milk of mothers of infants with cow's milk allergy and found different patterns of secretion, some with an increase, others with a decrease and others with no detectable ßlactoglobulin, after an oral cow's milk load. 32 The factor underlying these different patterns was unknown, as no difference in intestinal absorption of macromolecules was found between the three groups of mothers. 73
However there is evidence that passage of food antigens in breast milk can cause allergic symptoms in previously sensitized children 33 · 34 and that elimination of the offending foods from the mother's diet gives an improvement of symptoms.35 Various studies reported a sensitization to foods such as cow's milk, egg, and peanut in children believed to be exclusively breast fed, 33,34,36 b u t ¡t has not been possible to ascertain whether the sensitization occurred by passage in the mother's milk or by inadvertent ingestion of small amounts of these foods by the children. Another possibility is provided by crosssensitization to allergens shared by inhalant and food sources. This has been reported for allergic reactions to egg yolk, induced by sensitization to antigens of bird's serum, inhaled when birds are present in dwellings.37 Recently, the cross reacting allergen was identified as egg yolk αlivetin, corresponding to chicken serum albumin.38 In any case, avoidance of cow's milk (including maternal avoidance) in infants at risk was able to reduce the overall prevalence of both IgE sensitization and cow's milk allergy in a controlled study.19 Under conditions of uncertainty regarding the introduction of small amounts of potentially sensitizing foods, it is inadvisable to prolong breastfeeding excessively. It has been reported that exclusive breastfeeding for periods longer than three months was associated to a higher frequency of positive skin tests to egg and milk.39 As regards solid foods, it has been observed that the number of foods added to the diet during the first months of life correlated with the development of eczema, within the age of 10 years;40 though the causative role of food allergy was not demostrated, because food challenges were not performed. Another study suggested that the elimination of solid foods in the first year of life can only postpone the onset of food allergy, since no differences in positive food challenges at the age of three years were observed between two groups of children in which specific foods (fish and citrus) were eliminated or not from the diet during the first year.41
A recent study reported that measures of allergen avoidance including aeroallergens, had beneficial effects in highrisk infants, at least at the age of two years. 42 In fact, a group of children receiving breast milk and living in houses in which extensive measures for preventing indoor allergens were performed, had significantly lower prevalences of eczema and rhinitis (but not asthma) and of positive skin tests than children conventionally fed and with no environmental control.
Other factors, such as the antigen absorption in infants, may be involved in the development of food allergy. It has been reported that preterm newborns had a higher antigen absorption than term newborns.43 The absorption is likely to be influenced by the antigen's characteristics, as suggested by the differences in the various antigens (and specific antibodies) of cow's milk found in serum of preterm newborns.44 A controlled study demonstrated that early exposure to cow's milk increases the risk of preterm newborns to develop allergic diseases within 18 months.45 It is possible to hypothesize, despite contrasting observations, that breast milk, and particularly its IgA immunoglobulins, may oppose the intestinal absorption of antigen.11 This was indirectly support ed by the observation that children with IgA deficiency had an increased absorption, as demon strated by precipitins or immune complexes, of various food antigens.46 74
A number of studies was addressed to compare the effects of different feeding during the first year of life on the development of atopic diseases. In particular, they investigated the decrease or the delayed onset of atopy in children fed with breast milk, soya milk or hydrolysate formula compared to those fed with cow's milk. However, because of the impossibility to organize random double-blind studies, the data provided by these investigations have a limited value. In fact, as underlined by Zeiger,11 some differences in psychological and social characteristics between families of children differently fed may bias the results obtained, for example by modifying other factors such as the time of introduction of solid foods or the exposure to viral infections.
6 . 3 . 1 . Comparison
between
breast-feeding
and c o w ' s
milk
feeding
There is a similar number of studies reporting the favourable effects of breast-feeding on allergic manifestations as compared to cow's milk feeding 14 · 47 " 54 and no difference between the two methods. 8 · 55 " 59 The studies that reported positive results also found significant decreases of serum IgE levels in breast-fed infants within six months 48 · 51 or one year.49 However, in the study by Chandra et al. 54 cord blood IgE levels correlated with the development of allergy within two years from birth (being higher in subjects with subsequent allergic diseases than in those without allergic manifestations) in a group of breast-fed infants with no family history of allergy, but not in a group with family history of allergy.
A prospective study from Denmark reported that in a cohort of 1 749 newborns there was a significant difference in adverse reactions to cow's milk between breast-fed and cow's milk formula-fed infants regarding intolerance, meaning with no positive skin test and/or RAST, but not allergy to cow's milk.60 Some of the studies reporting negative results may be criticized because of the too short duration of breast-feeding, corresponding to 1-2 months, 8 · 55 . 56 but some recent studies fulfilling the same criteria used in the 'positive studies' observed no differences between breast-fed and bottle-fed infants in development of atopic diseases 57-59 as well as in IgE levels. 57 · 58
6 . 3 . 2 . Comparison
between
soya
feeding
and c o w ' s
milk
feeding
Soya milk was introduced in the 1950s following the observations of the reduced incidence of atopic dermatitis and hay fever in infants fed with soybean milk compared to those fed with cow's milk.61 However a number of randomized prospective studies was unable to demonstrate the beneficial effects of soya feeding on allergic manifestation, 6 · 12 · 52 · 54 · 56 · 62 " 64 except a significant decrease of perennial rhinitis and asthma in the study by Johnstone and Dutton. 62 One study considered also immunological parameters demonstrating atopy and found no difference in the development of atopic diseases within four years from birth between soya-fed and cow's milk-fed infants.12 A recent study reported that soya-protein-based formula sensitized atopic children, and especially those with gastrointestinal allergy.65 On the other hand it is now well known that soybean is an important allergenic source and a number of allergens have been identified. 66 · 67 Thus, feeding with soya-milk in infants at risk of atopic diseases is no longer indicated. 75
6 . 3 . 3 . C o m p a r i s o n between hydrolyzed and other kinds of f e e d i n g
cow's
milk
formulae
Cow's milk protein hydrolysates, and particularly the casein hydrolysate Nutramigen®, were introduced into the market in 1942 in order to reduce the allergenicity of cow's milk. This product was made by hydrolyzing the milk into small peptides with molecular weight lower than 1 500 daltons, providing nutritional adequacy but resulting non-immunogenic in animal experiments.11 Hydrolyzed formulae are obtained by heat or enzymatic hydrolysis, the former affecting the conformation of milk proteins, resulting in a decrease of allergenicity of whey but not of casein, whereas the latter breaks all the allergenic proteins including sequential epitopes.68 The hydrolysis can be extensive or partial and the hydrolyzed formulae thus obtained present important differences regarding taste and smell (better for partly hydrolyzed formulae, pHF) and allergenicity (lower with extensively hydrolyzed formulae, eHF). A significant proportion of proteins with molecular weight from 8 to 40 kd can be found in pHF, which instead are absent in eHF. Various studies evaluated the residual in vivo allergenicity of hydrolyzed formulae by skin tests and/or double-blind placebo-controlled food challenge.69"71 An effective hypoallergenicity of casein eHF was demonstrated by the negativity of these tests in children with cow's milk allergy, whereas whey eHF was reported to be as allergenic as casein eHF 72 but as yet there is not such a direct demonstration. In vitro, RAST-inhibition and ELISA-inhibition experiments showed that whey pHF was 60 times less allergenic than cow's milk and whey eHF was 20 million times less allergenic than cow's milk.69"73 Some prospective studies evaluated the preventive effect on development of allergic diseases of pHF and eHF and reported favourable results. 19 · 72 · 74 " 76 However, as stated in a recent position paper of the European Society of Pediatric Allergy and Clinical Immunology, none of these studies can be considered definitive, as they lack some or more requisites such as an adequate selection of high-risk infants, the statistical demonstration of a significant reduction of prevalence of cow's milk allergy as determined by DBPCFC, or the prospective randomized blind design of the study for a period long enough to develop atopic disease, that is, at least 18 months.68 In this position paper future studies fulfilling such prerequisites were strongly recommended.
6.4.
Conclusions To date, the only measure with a sure preventive effect on development of allergic diseases, and particularly of food allergy, in infants at high risk, as defined by a biparental history of atopy or by an uniparental history and an high level of IgE in cord blood, is breast-feeding. Some studies suggested that such preventive effect can be improved if during breast-feeding foods containing known allergens, such as cow's milk, egg, the 'nuts' group, fish, and seafood, are eliminated from the mother's diet. Being difficult to maintain such conditions for more than six months, it is not recommended to prolong breast-feeding beyond this period. To date there are not enough data to propose the use of hydrolyzed cow's milk formulae as an alternative to breast-feeding in the prevention of food allergy. When introducing solid foods into the infant's diet, food items known as allergenic sources should be postponed as late as possible.
76
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73
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74
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75
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76
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INTERACTION
WITH
LIFESTYLE
AND
PROFESSION
SYNOPSIS Food allergic patients need to change their eating habits to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of ARF. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. However food allergens, especially in an occupational setting, may induce allergic reactions even when inhaled or after skin contact. Foods most commonly involved in occupational food allergy are: cereal flour, egg, milk, seafoods and legumes. The most effective measure to prevent occupational diseases due to exposure to food allergens is primary prevention, that is prevention of exposure to food-related substances that can induce allergic reactions. A second step is secondary prevention, that is the detection of diseases at an early stage. The earlier the diagnosis is made, the more likely workers are to recover. Tertiary prevention consists of appropriate medical care of diseased workers. Due to that reported above, it is clear that any effort should be directed to primary and not to tertiary prevention.
7.1
Interactions
with
lifestyle
Food allergic patients need to change their eating habits, to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of adverse reactions to foods. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. This is particularly true for highly sensitive patients and for foodallergic children. In these cases, a restaurant meal or a meal not consumed at home may be very dangerous, sometimes life threatening, for food-allergic persons and therefore the restriction of their lifestyle is very remarkable. The limitations concern a small number of individuals, who nevertheless should be protected to the maximum possible extent. In a descriptive study on fatal and near-fatal food-induced anaphylaxis, five of six fatal cases occurred in schools or public places, whereas all the non-fatal reactions occurred in private homes. Moreover, a delay in the administration of epinephrine was likely to be associated with a fatal outcome.1 This suggests the need for educating school personnel, day-care providers and restaurant personnel about foodinduced anaphylaxis. For instance, the Canadian Restaurant and Food-service Association has instituted an allergy awareness programme in which participating restaurants agree to maintain lists of food ingredients and to designate one on-site employee to answer customers' questions about ingredients.2 Patients highly sensitive to food must be taught the importance of having and using emergency kits containing epinephrine. In the case of food-allergic children, parents and child-care personnel should be trained in the appropriate administration of this medication. The American Academy of Pediatrics Committee on School Health has recommended that schools be equipped to treat anaphylaxis in children. 3 · 4 A Position Statement from the American Academy of Allergy and Immunology on the use of epinephrine in the treatment of anaphylaxis states that epinephrine 83
must be available in many first-aid situations for use by trained personnel.4 However many States of the USA do not permit non-medical personnel to administer epinephrine.2 Apart from the small number of food-allergic individuals, it is estimated that more than one quarter of Americans alter their eating habits based on misperceptions of food allergy.5 A study on women's opinions of food allergies indicated that 22% of women avoid particular foods on the mere possibility that the food may contain an allergen. Moreover 19% of family members were on diets to control food allergies.6 Another study investigating whether food avoidance in adults with self-reported food allergy leads to an unbalanced diet, indicated that, even after calcium supplementation, the mean calcium intake of patients who completely avoided milk and milk products was unacceptably low (441 mg/day). Only a small minority ( 3 for cow's milk. The following foods
166
were investigated: goat's milk, sheep's milk, human milk, cow's milk infant formula, goat's milk infant formula, casein hydrolysate (Pregestemil and Nutramigen), non-hydrolyzed casein formula, whey hydrolysate (Pepti-Junior, Almiron-Pepti, Altaré), soya milk (Wysoy), soya beef hydrolysate (Prejormin), elemental feed (Neocat). Modified cow's milk formula, goat's infant formula, sheep and goat's milk produced RAST results similar to cow's milk. RAST score > 3 was found in two patients for soya milk, in three patients for soya/beef hydrolysate, in two for Pregestemil, in one for Nutramigen, in seven with Pepti Junior, in five for Almiron-Pepti, in six for human milk, in 12 for non-hydrolyzed casein formula, in none for Neocat. RAST results for Altare were not reliable for technical reasons. The inhibition curves showed the least inhibition with Neocat and a very low inhibition with caseine hydrolysate, while soya formula showed a certain degree of inhibition, which were still more evident with soya/beef hydrolysate and with Pepti-Junior. Although the clinical implications of this in vitro study should be established by in vivo study, elemental food and casein hydrolysates seem to be the less allergenic milk substitutes. Wahn et al. 3 investigated the residual allergenicity of protein hydrolysate in 20 cow's milk allergic children by in vivo test (skin prick test and oral challenge) and in vitro method (RAST, RAST inhibition, crossed radioimmunoelectrophoresis, basophil histamine release). All tested hydrolysates induced significantly smaller mean wheal reactions compared with those induced by whole cow's milk. Casein hydrolysates and extensively hydrolyzed whey hydrolysates showed little IgEbinding activity. Oral challenges performed with eight children gave positive results in five with partial whey hydrolysate, in two with extensive whey hydrolysates and in one with soya-challenge hydrolysate. None reacted to oral challenge with casein hydrolysates. Thus, extensive casein hydrolysates showed the least residual allergenic activity. Among whey hydrolysates, more extensively hydrolysated formulas showed a lesser reactivity than the partial whey hydrolysates, confirming the importance of peptide lengths in determining the allergenicity of the hydrolysate: peptides of more than 1 500 daltons molecular weight have considerable allergenic activity. Bindels and Boerme4 determined the molecular weight of HF: casein hydrolysates (Alimentum, Nutramigen and Pregestemil) compared with whey hydrolysates (NAN-HA Nutrilon Pepti, Pepti Junior, Profylac) contain a higher proportion of small peptides (96.5-95% versus 54-88%) and lower proportion of petides with molecular weight > 6 000 (0.5% versus 2-18%). Animal studies confirm that the immunogenicity of HF depend on the degree of hydrolysis: rabbits hyperimmunized with formulas containing extensively hydrolyzed proteins (Alimentum, Nutramigen, and Pregestermil) generated very weak immune responses ( > 100 fold antibody increase), whereas products containing intact or partially hydrolyzed proteins (Similac, Enfamil, Good Start, Beba HA, and Nidina HA) elicited high level ( > 10 000 fold increase) immune response.5 Oldaeus et al 6 performed SPT with blinded extracts of various hydrolyzed formulas in children with a history of cow's milk allergy, as the first step in the clinical evaluation of the residual allergenicity of HF: 0/15 children demonstrated positive SPT to Nutramigen, 1/15 to Aliare, 7/15 to Beba HA (whey hydrolysate), 7/15 to formula A and 5/15 to formula B. The low allergenicity of extensively hydrolyzed casein formulas (Pregestemil and Nutramigen) was demostrated also by Gjesing et al 7 by using crossed radioimmunoelectrophoresis (CRIE) to study the presence of serum IgE against cow's milk allergens in 21 milk allergic patients. It was 167
found that the two casein hydrolysates consisted of such small molecules that the rabbit antiserum could not precipitate the hydrolyzed proteins in the gels on the CRIE plates. Although this does not imply a complete lack of allergenicity, the probability of having IgE-binding epitopes is reduced. The safety of a casein hydrolysate formula (Alimentum) has been investigated by Sampsom et al. 8 DBPCFCs with 10 gm of powdered cow's milk and Alimentum were performed in 25 children with cow's milk allergy. Some 23/25 had positive DBPCFC with cow's milk, whereas all children tolerated the challenge to casein hydrolysate and were fed the hydrolysate formula without experiencing adverse reactions. Allergic reactions to partial whey hydrolysate9 and to extensive whey hydrolysate10 formulas have been described. In some cases sensitization to these formulas seems to have occurred in the first days of life in the maternity hospital where the same formula was given to babies for prophylaxis of cow's milk allergy. Some cases of allergic reactions to extensively hydrolyzed casein-based formulas have been reported too. 11 · 12 · 13 Sampson et al 11 evaluated the safety of an aminoacid-derived infant formula (Neocate) in children allergic to cow's milk. DBPCFC were performed in 28 children; one child reacted to an extensive casein hydrolysate (Nutramigen) but none reacted to Neocate, although three of 16 showed a positive SPT to this formula. Unfortunately Neocate has an unpleasant taste and most children refused to drink it. Soya milks have been widely used as an alternative to cow's milk formulas. However soya allergy occurs as frequently as cow's milk allergy when introduced as initial formula.14. Moreover a consistent number of infants with cow's milk allergy and cow's milk-induced enterocolitis will develop soya allergy when fed on a soya formula. 1516 Although some investigators argue that soya formulas should be the preferred choice for children with IgE-mediated allergy to cow's milk,17 the Nutrition Committee of the American Academy of Pediatrics advises that unhydrolyzed soya formulas are not used for cow's milk protein allergy.18 Several studies compared casein and whey hydrolysates and soya formulas to cow's milk feeding in the prevention of allergic diseases in infants at high risk for atopy. Feeding soya formulas did not show any advantage over cow's milk in such infants.19 In particular a randomized prospective clinical investigation carried out by Kjellman and Johansson, in infants born from bilateral allergic parents, failed to demonstrate any protective effect of soya feedings on the development of allergic diseases in the first three years of life. 14 On the contrary extensive casein hydrolysate feeding led to a lower prevalence of allergic disease than cow's milk feeding in infants at risk for atopy at one year of age. 19 · 20 Another study demonstrated a lower incidence of eczema by 18 months in infants fed on casein hydrolysates when compared to either cow's milk or soya milk feedings.21 Recently a doubleblind study of high-atopic risk neonates showed that partial whey hydrolysate, when compared to cow's milk and soya formula feedings, reduced the prevalence of eczema at six months of age. 22 However further studies are needed to confirm the protective role of HF in the prevention of allergic manifestations in infants at high risk for atopy. 168
In conclusion in vitro and in vivo studies show extensively that casein hydrolysates are the less allergenic formulas in cow's milk allergic children. An elemental formula (Neocat) seems to be a good alternative as well. However it should be underlined that these formulas are hypoallergenic and not non-allergenic, because some highly sensitive milk-allergic infants may adversely react to feeding such formulas. In vitro and animal studies should select new formulas suitable for milk substitutes in cow's milk allergic children. Preclinical screening of these hydrolysates should demonstrate the absence of intact proteins and more than 99% of the peptides with molecular weight < 1.5 KDA, and nonanaphylaxis in animals challenged with the formula under investigation.19 Hydrolysates selected by preclinical studies should then be screened by DBPCFC and open consumption, showing to be tolerated in cow's milk allergic infants, in which the diagnosis of allergy to milk has been documented by positive DBPCFC. The American Academy of Pediatrics states that a formula can be designated as hypoallergenic when at least 90% of milk-allergic children can consume it without adverse reactions. Although some studies indicate a protective role of some hypoallergenic formulas in preventing allergic disease in high-risk babies, further studies are needed to elucidate this point Finally, studies are required to investigate the type of feeding given to new-borns during the first few hours after birth, before starting breast-feeding, because these feedings could have a sensitizing effect and in some ways influence the development of allergy to cow's milk.
REFERENCES 1
Kleinman R. E. 'Cow milk allergy in infancy and hypoallergenic formulas'. J. Pediatr., 121, pp. S116-S21, 1992.
2
Dean T.P., Adler B.R., Ruge F., Warner J.O. 'In vitro allergenicity of cow's milk substitutes'. Clin. Exp. Allergy, 23, pp. 205-210, 1993.
3
Wahn U., Wahl R., Rugo E. 'Comparison of the residual allergenic activity of six different hydrolyzed protein formulas'. J. Pediatr., 121, pp. S80-S84, 1992.
4
Letter to the editor. 'Hydrolyzed cow's milk formulae'. Pediatric Allergy and Immunol., 5, pp. 189-190, 1994.
5
Cordle CT., Duska McEwen G., Janas L.M., Malone W.T., Hirsch M.A. 'Evaluation of the immunogenicity of protein hydrolysate formulas using laboratory animal hyperimmunization'. Pediatric Allergy and Immunol., 5, pp. 14-19, 1994.
6
Oldaeus G., Bradley CK., Björksten B., Kjellman M. 'Allergenicity screening of "hypoallergenic" milk-based formulas'. 169
170
7
Gjesing Β., Osterballe O., Schwartz Β., Wahn U., Lowenstein H. 'Allergenspecific IgE antibo dies against antigenic components in cow milk and milk substitutes'. Allergy, 41, pp. 5156, 1986.
8
Sampson H.A., BernhiselBroadbent J., Yang E., Scanion S.M. 'Safety of casein hydrolysate formula in children with cow milk allergy'. Pediatr., 118, pp. 520525, 1991.
9
Businco L., Lucenti P., Árcese G., Ziruolo G., Cantani A. 'Immunogenicity of a socalled hypoallergenic formula in atrisk babies: Two case report'. Clin. Exp. Allergy., 24, pp. 4245, 1994.
10
Businco L., Cantani Α., Longhi Α., Giampietro P.G. 'Anaphylactic reactions to a cow's milk whey protein hydrolysate (AlfaRè, Nestle) in infants with cow's milk allergy'. Ann. Allergy, 62, pp. 333335, 1989.
11
Sampson H.A., James J.M., BernhiselBroadbent J. 'Safety of an amino acid derived infant formula in children allergic to cow milk'. Pediatrics, pp. 463464, 1992.
12
Bock S.A. 'Probable allergic reaction to caseine hydrolysate formula'. J. Allergy Clin. Immunol., 84, p. 272, 1990.
13
Schwatz R.H., Amonette M.S. 'Cow milk protein hydrolysate infant formulas not always hypoallergenic'. J. Pediatr., 119, p. 839, 1991.
14
Kjellman Μ.Ν., Johansson S.G.A. 'Soya versus cow's milk in infants with biparental history of atopic disease: Development of atopic disease and immunoglobulins from birth to four years of age'. Clin. Allergy, 9, pp. 347358, 1979.
15
Hide Q.W., Gant C. 'Hypoallergenic formulae have they a therapeutic role?'. Clin. Exp. Allergy, 24, pp. 35, 1994.
16
Burks A.W., Casteel H.B., Fiedorek S.C, Williams L.W., Pumphrey C L . 'Prospective oral food challenge study of two soyabean protein isolates in patients with possible milk or soya protein enterocolitis'. Pediatr. Allergy Immunol., 5, pp. 4045, 1994.
17
Businco L., Bruno G., Giampietro P.G., Cantani A. 'Allergenicity and nutritional adequacy of soya protein formulas'. J. Pediatr., 121, pp. S21S28, 1992.
18
American Academy of Pediatrics Committeee on Nutrition. 'Soyprotein formulas: Recommen dation for use in infant feeding'. Pediatrics, 72, pp. 359363, 1983.
19
Zeiger R.S. 'D evelopment and prevention of allergic disease in childhood'. In Middleton E., Reed CE., Ellis E.F., Adkinson F.N., Youginger J.W., Busse W.W. editors. 'Allergy principles and practice'. Ed IV Mosby, St Louis, pp. 11371171, 1993.
20
Zeiger R.S., Heller S., Mellon M.H. et al. 'Effect of combined maternal and infant foodallergen avoidance on development of atopy in early infancy: A randomized study'. J. Allergy Clin. Immunol., 84, p. 72, 1989.
13.2.
21
Chandra R.K., Shakuntla P., Hamed A. 'Influence of material diet during lactation and use of formula feeds on development of atopic eczema in high risk infants'. Br. Med. J., 299, p. 228, 1989.
22
Chandra R.K., Singh G., Shridhara B. 'Effect of feeding whey hydrolysate soya and conventional cow milk formulas on incidence of atopic disease in high risk infants'. Ann. Allergy, 63, p. 102, 1989.
Non-allergenic
food
A new idea of prevention in food allergy must take into account the production of hypo- or nonallergenic food. Current means used to induce hypoallergenicity are heating, enzymatic hydrolysis and selection of vegetable stocks which synthesises little or no major allergenic protein (e.g. wheat deficient in gliadins). This last goal could be obtained by biogenetic engineering with the production of transgenic plants.
The unique current therapy of food allergy is the avoidance of the culprit food, since the elimination of the specific food allergen from the diet will achieve resolution of the symptoms. In many instances, however, the elimination of one food implies the elimination of an entire class of foodstuffs thus making it very difficult to follow an acceptable diet. The complete knowledge of the molecular structure and chemical properties of the allergens involved in any single case could allow the setup of methodologies able to degrade them directly to a non-allergenic configuration. An even more substantial procedure would be based on the modification at a molecular level of the allergenic proteins by acting on their synthesis. Thus a new approach in the prevention of food allergy can be advanced and must take into account the concept of hypoallergenicity or non-allergenicity obtainable by modifying food proteins by different techniques. The predictable commercial importance of this new approach, as the development of hypoallergenic milk already shows, will be another considerable incentive to rapidly improve this field of research. The allergenicity of a foodstuff mainly depends on the number of major allergens and their stability during bleaching, pulverization, roasting and cooking processes.1 Current means which can be used to induce hypoallergenicity are heating and enzymatic hydrolysis.2 A crude, global approach is heating, which denatures the conformational epitopes of proteins (tertiary structure).3 Thermolabile allergens are often observed among fruits and vegetables, which can be tolerated after cooking by allergic subjects.4 However, sometimes heating increases the allergenicity of some foods. 5 " 6 So we must know the characteristics of every allergenic protein in food in order to choose the appropriate technique. In milk, for example, we know that casein withstands heat7 and obviously we need an alternative method, that is enzymatic digestion by pepsin and trypsin. 8 9 In fact heating reduces, but does not eliminate whey protein allergenicity.10"11
171
A hypoallergenic rice has been obtained by hydrolysis of the globulinic fraction of grains by a protease associated with a surfactant.12 The destruction of the major allergen (globulin, w.16kda), is shown by the sodium dodecyl sulphatepolyacrylamide gel electrophoresis study and the negative radioallergosorbent test with this new extract. Most children sensitized to rice have no recurring problems when they are fed with this rice. Agronomically, a possibility is represented by the selection of vegetable stocks which synthesises little or no major allergenic protein. An example is wheat deficient in gliadins. 13 · 14 Glutenfree diet is mandatory in celiac disease, 1518 but the compliance of the patients to the diet is often difficult and sometimes gluten is ingested inadvertently. 1924 Gliadins are a heterogeneous group of proteins with a wellknown genetic map. Loci encoding gliadins are located at the end of the short arm of the chromosomes of groups 1 and 6 of wheat, and are designated as GNA1, GNB1, GND1 (Gli1 loci), GNA2. GMB2, GND2 (Gli2 loci)25. Gli1 loci encode for γ and ω gliadin; Gli2 loci encode for α and β gliadin. Genotypes lacking a whole cluster of gliadin components, controlled by genes at a given complex locus, exists in durum and bread wheat.26 Crosses between these lines have also resulted in production of lines lacking gliadin components controlled by two or more complex loci. Using an in vitro model of celiac disease Corazza28 (1995) tested the toxicity of lines of bread wheats lacking all the GIÌA2 encoded gliadin components and a line lacking at once GND 1 and GMA2 controlled gliadin component. Using a peptictryptic digest of these wheats in an in vitro organ culture system, a significantly lower toxicity was found in respect to bread wheat containing all gliadin fractions. Even if it cannot be excluded that daily exposure to flour obtained from the gliadin deficient wheats tested in the mentioned study, may cause in vivo mucosal damage in celiac patients it suggests a new perspective in the treatment of celiac disease and seems particularly promising since further generations of wheat lines, more and more deficient in toxic gliadins, have been already breeding.
Technologically the manufacture of protein isolates could be deliberately oriented towards a decrease in major allergens. Certain soybean proteins isolated have a lower Kunitz inhibitor content than others, for example, and are less sensitizing for animals.29 Other techniques for modifying allergenicity have been explored, such as disulphide bond reduction for the tryptic inhibitor of soybean and bond breaking with sialic acid for milk proteins; 30 · 31 but the most promising aid in the production of hypo or nonallergenic food, in the last few years, has derived from the recent advances in biotechnology. Immunoblotting technique associated to RAST inhibition, monoclonal antibodies and ricombinant D NA techniques have allowed the identification of the amino acid sequence of many allergens and sometimes of their different epitopes, as well as the determination of the nucleotide sequence of the genes coding for these epitopes and allergens. 3 · 3238 This background, joined with the biogenetic engineering that can transfer a specific gene from one source to a target plant, has provided the possibility of producing nonallergenic food. The first transgenic plant was obtained in 1984.39 Since then many economically important crops have been genetically engineered in order to obtain plants with high efficiency.40 The most transgenic plants produced so far have been obtained using two general methods which are Acrobacfer/i/mmediated41 and direct D NA uptake, with the latter including such specific method as particle bombardment, electroporation and polyethylene glycol permeabilization.42·45 The main properties obtained in transgenic plants are: insect protection, delayed ripening, virus resistance, herbicide tolerance, disease resistance, modified starch, 172
modified oils and male sterility.46 Most of the qualities introduced in transgenic crops result from the expression of one or more new proteins, which usually are expressed at low levels and represent a minor percentage of the total plant proteins. Current technology is limited to the introduction of genes to ectopic (away from the normal locus of a gene) position in the genoma.47 Ideally, gene expression would be modified by gene 'replacement' at the normal locus of a gene, but such technology is still in its infancy and is not available in any practical sense. Until gene replacement does become practical, the scientist is faced with the necessity of manipulating gene expression via the expression of extra copies of the gene engineered to interfere with, or amplify the expression of the homologous, endogenous gene. Antisense RNA is one popular approach to interference with endogenous gene expression. 48 Potentially this technology can also be used to suppress target gene expression in a celltype-specific manner, by the appropriate use of a cell-type-specific promoter.49 Another approach to modifying gene expression is over-expression by the introduction of additional copies of an endogenous gene. 40 This can be successfully used to increase the endogenous level of expression of a gene. 40 However, as it turns out, this is not the only possible result.40 The attempted over-expression of endogenous genes by the introduction of additional copies of a gene can also result in the co-suppression of the expression of both the endogenous gene and the transgene, resulting in loss of expression just as in the case of antisense transgenes.47 This phenomenon appears to be quite common, and even extends to interaction between two unlinked transgenes. All these characteristics can be potentially useful in inhibiting the expression of a gene coding for an allergenic protein. Genetic engineering provides a unique opportunity to eliminate or, at least to reduce, the amount of a specific allergen in a food. By introducing genes in the antisense orientation (the opposite orientation required to produce a protein), the levels of protein produced by the 'sense' orientation can be dramatically reduced. This technique has been used to reduce significantly the major allergen in rice. 50 · 51 Matsuda et äl. cloned the gene encoding the 16 kDa allergenic protein from rice and introduced the gene encoding this protein in the antisense orientation into rice. The levels of the 16 kDa protein were significantly reduced in rice seed from 312 mg per seed to 60 mg per seed. Further studies are underway to achieve greater reductions in this allergenic protein. The antisense technique could be applied to other food crops such as peanuts and soybeans to selectively reduce the amounts of the specific allergens, although the presence of multiple allergens and multigene families makes this solution more difficult. Dealing with the problem of non-allergenic food a particular consideration must be reserved to food allergens hidden in 'theoretically non-allergenic foodstuff'. The past decade has witnessed a number of advances in food technology and the novel use of many food products (e.g., partially hydrolyzed proteins for flavouring, binders, protein enrichment, etc.) to improve the taste, quality and desirability of many foods while keeping the price down. These advances have clearly had a favourable impact for the average consumer and the food industry, but have made it increasingly difficult for the patient with true food allergies to avoid accidental ingestion of food allergens. The wellbeing of these subjects depends on complete and accurate disclosure of all ingredients on the labels of all foods. All ingredients present in foodstuff must be on the product's label since there is no threshold below which all patients may tolerate a food. Food-allergic individuals can react to a mere trace of the offending food allergens. 52 · 53 Indeed allergic reactions, sometimes life-threatening or fatal, have been reported even after only utilizing the utensils (e.g. spoon, fork, etc.), 173
cleaned but previously used with the culprit food, as well as after fortuitous inhalation of the offending food or kissing the lips of a person who has recently eaten the offending food. 38 On the other hand total avoidance can be extremely difficult. A few foods are responsible for the majority (90%) of allergic reactions, including egg, milk, peanuts, soybean, and wheat in children, and peanuts, tree nuts, fish and shellfish in adults.54 Unfortunately most of them are used to ameliorate the qualities of other foods by the food industry, restaurants and other food-service settings. Yunginger et al. 55 (1983) reported several adverse reactions due to a contamination with allergenic offending food following an inadequate cleaning of the equipment used. Moreover several deaths of food allergic patients have been reported following inadvertent ingestion of food allergens and most of these incidents occurred in restaurants or food services.56 Sampson (1991)57 reported similar life-threatening or fatal reactions among young children accidentally exposed to the offending food. Gern (1991)58 reported several cases of allergic reactions to foods due to unlabelled use of milk-based ingredients in foods. Thus food processors should attempt to avoid the processing errors and oversights that cause the inadvertent contamination of one food with another and result in such allergic reactions, sometimes with devastating consequences. At the same time they must improve the labelling of their food products by an exhaustive list of all the ingredients, also those in very small amounts, and, if feasible they have to avoid the use of the prevalent allergenic foods. In other words they have to produce 'non-allergenic' foods. Biotechnology, and in particular genetic engineering, represent a new challenge in the field of the allergenicity of foods. Indeed it has been demonstrated that food derived from transgenic plants can be more allergenic than the natural one. It depends on the allergenicity of the protein encoded by the new gene transferred into a food crop from a source that can be allergenic. An actual example was the demonstration that a gene encoding a Brazil nut 2S albumin storage protein which has been engineered into soybean59 and canola60 encodes a major allergen.61 The Brazil nut 2S albumin storage protein was selected as an ideal candidate gene to enhance the nutritional seed quality because it contains 18.8% of the essential amino acid methionine.62 However, since anaphylaxis due to Brazil nut are known, 63 · 64 the transferred gene should be surveyed as an allergic source. The Brazil nut 2S protein expression in soybean represented a significant fraction of total soybean proteins. Eight of nine patients allergic to Brazil nut reacted with transgenic soybean containing Brazil nut gene when their sera were tested by RAST and immunoblot assays. 65 · 66 This transgenic soybean would have to be labelled as containing Brazil nut, if marketed, to alert Brazil nut allergic subjects. Since a lot of foods from transgenic plant varieties are on the market (e.g. tomato, cucumber, carrot, soybean, apple, kiwi, orange, etc.) and many more are expected, it is mandatory to evaluate the allergenicity of the food derived from these crops. When a gene is obtained from an allergenic food source, it should always be investigated if it encodes for an allergen, and then labelled with the name of the allergen when marketed. A practicable alternative is to introduce into plants, by genetic engineering, proteins obtained from non-allergenic sources, that do not encode allergens, produced at low doses and extremely labile in model digestive conditions. A combination of these parameters provides assurance that proteins encoded by genes transferred into food crops will not increase the allergenicity of the food supply. 174
In all the cases discussed above three steps are needed before labelling a food as hypo- or nonallergenic. The first step in the decision tree employs in vitro tests that are RASTs,67 ELISAs68 or immunoblotting assays69 and uses IgE from pooled serum of patients truly allergic to the food that might be present in the examined foodstuff. A clear positive result from the in vitro test would require the specification on the label that that allergen is present in that food. The second step is based on in vivo skin-prick testing 67 that has to be performed only if the first step is negative for allergy. A positive result of this SPT would raise the same concern as the in vitro tests above. Only when the second step also is negative for food allergy can the last step be done. It provides for double-blind placebo-controlled food challenges (DBPCFC) performed in sensitive and nonsensitive patients under controlled clinical conditions. This type of assessment requires some ethical considerations regarding the likelihood of inducing anaphylaxis, the availability of adequate safety precautions, and approval of local institutional review boards. The term hypo-/non-allergenic can be accepted only for those foods that have completed this trial.
REFERENCES 1
Taylor S.L. 'Food allergy — The enigma and some potential solutions'. J. Food Protect., 1980, 43, pp. 300-306.
2
Jost R., Monti J.C, Pahud J.J. 'Whey protein allergenicity and its reduction by technological means'. Food Technol., 1987, 41, pp. 118-121.
3
Crespo J.F., Pascual C , Martin Esteban M. 'New perspective in food allergens'. In: Anonymous (ed). Proceedings of the XIV European Congress of Allergy and Clinical Immunology ECACI 1995. Madrid (Spain). May 24-25, 1995, pp. 889-895.
4
Ortolani C , Ispano M., Pastorello E.A., Ansaloni R., Magri C. 'Comparison of results of SPT (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome'. J. Allergy Clin. Immnol. 1989, 83, pp. 683-690.
5
Herían A.M., Taylor S.L., Bush R.K. 'Identification of soyabean allergens by immunoblotting with sera from soya-allergic adults'. Int. Arch. Allergy Appi. Immunol., 1990, 92, pp. 193-198.
6
Asselin J., Amiot J., Gauthier S.F., Mourad W., Hebert J. 'Immunogenicity and allergenicity of whey protein hydrolysates'. J. Food Sci., 1988, 53, pp. 1208-1211.
7
Jost R., Fritsche R., Pahud J.J. 'Reduction of milk protein allergenicity through processing'. In Somogyi J.C, Müller H.R., Ockhuizen Th. (eds). 'Food allergy and food intolerance'. Karger, Bazel 1991, pp. 127-137.
8
Asselin J., Hebert J., Amiot J. 'Effects of in vitro proteolysis on the allergenicity of major whey proteins'. J. Food Sci., 1989, 54, pp. 1037-1039.
175
176
9
Guesry P.R., Secretin M.C, Jost R., Pahud J.J., Monti J.C. 'Hypoallergenic formulas'. In Hamburger R.N. (ed). 'Food intolerance in infancy'. New York, Raven Press, 1989, vol. I, pp. 253-265.
10
Kilsjaw P.J., Heppell L.M.J., Ford J.E. 'Effects of heat treatment of cow's milk and whey on the nutritional quality and antigenic properties'. Arch. Dis. Child., 1982, 57, pp. 842-847.
11
Heppell L.M.J., Cant A.J., Kilshaw P.J. 'Reduction in the antigenicity of whey proteins by heat treatment: A possible strategy for producing a hypoallergenic infant milk formula'. Br. J. Nutr., 1984,51, pp. 29-36.
12
Watanabe M., Miyakawa J., Ikezawa Z., Suzuki Y., Hiaro T., Yoshizawa T., Arai S. 'Production of hypoallergenic rice by enzymatic decomposition of constituent proteins'. J. Food Sci., 1990, 55, pp. 781-783.
13
Kasarda D., Qualset CO., Mecham D.K., Goodemberger D.M., Straber W. 'A test of toxicity of bread made from wheat lacking alpha-gliadins coded for by 6A chromosome'. In: McNicholl B., McCarty CF., Fottrell P.F., (eds). Lancaster, MPT Press, 1978, pp. 55-61.
14
Ciclitira P.J., Hunter J.O., Lennox E.S. 'Clinical testing of bread made from nullisomic 6A wheat in coeliac patients'. Lancet, 1980 ii, pp. 234-236.
15
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17
Trier J.S., Falchuk Z.M., Carey M.C, Schreiber D.S. 'Celiac sprue and refractory sprue'. Gastroenterology, 1978, 75, pp. 307-309.
18
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21
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22
Mayer M., Greco L., Troncone R., Auricchio S., Marsh M.N. 'Compliance of adolescents with coeliac disease with a gluten-free diet'. Gut., 1991, 127, pp. 963-965.
23
Mulder C.J.J., Van Bergeijk J.D., Jansen T.L.T., Uil J.J. 'Coeliac disease: Diagnostic and therapeutic pitfalls'. Scand. J. Gastroenterol., 1993, 28 Suppl. 200, pp. 42-47.
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Congdom P., Mason M.K., Smith S., Crollik Α., Steel Α., Littlewood J. 'Smallbowel mucosa in asymptomatic children with celiac disease'. Am. J. Dis. Child., 1981, 135, pp. 118121.
25
Payne P.I. 'Genetics of wheat storage proteins and the effect of allele variation on bread making quality'. Annual review of plant physiology 1987, 38, pp. 141153.
26
Lafiandra D ., Colaprico G., Kasarda D .D ., Porceddu E. 'Null alleles for gliadin blocks in bread and durum wheat cultivars'. Theoretical and applied genetics 1987, 74, pp. 610616.
27
Lafiandra D ., Splendido R., Tomassini C , Porceddu E. 'Lack of expression of certain storage proteins in bread wheats; Distribution and genetic analysis of null forms'. In Lasztity R., Bekes F. (eds). Proceedings 3rd international workshop on gluten proteins. Singapore: World Scienti fic Publishing, 1987, pp. 7190.
28
Frisoni M., Corazza G.R., Lafiandra D ., D e Ambrogio E., Filipponi C , Bonvicini F., Borasio E., Porceddu E., Gasbarrini G. 'Wheat deficient in gliadins: Promising tool for treatment of coeliac disease'. Gut., 1995, 36, pp. 375378.
29
Mazo V.K., Samenkova Ν.F., Gmoshinskii I.V., Pepeliav I.V., Zorin S.N., Krzhechkovskaia V.V., Malikova N.A., Marokko I.Ν., Ushakov V.V. 'Complex experimental assessment of potential allergenicity of various isolates of soya proteins'. Vopr. Pitan. (USSR), 1989, 6, pp. 2227.
30
Brandon D .L., Haque S., Friedman M. 'Antigenicity of native and modified Kunitz soyabean trypsin inhibitors'. Adv. Exp. Med. Biol. 1986, 199, pp. 449469.
31
Heine W., Wutske K.D ., Radke M. 'Zur Verminderung der Immunogenität von Milchproteinen durch D esialinisierung'. Infusionstherapie, 1989, 16, pp. 264266.
32
King T.P., Hoffman D ., Lowenstein Η., Marsh D .G., Plattsmills T.A.E., Thomas W. 'Allergen nomenclature'. J. Allergy Clin. Immunol., 1995, 96, pp. 514.
33
O'Neil C , Helbling A.A., Lehrer S.B. 'Allergie reactions to fish'. Clin. Rev. Allergy, 1993,11, pp. 183200.
34
Burks A.W., Williams L.W., Helm R.M., Connaughton C , Cockrell G., O'Brien T. 'Identification of a major peanut allergen, Ara hl, in patients with atopic dermatitis and positive peanuts challenges'. J. Allergy Clin. Immunol., 1991, 88, pp. 172179.
35
Burks A.W., Williams L.W., Connaughton C , Cockrell G., O'Brien T., Helm R.M. 'Identification and characterization of a second major peanut allergen; Ara hil, with use of sera of patients with atopic dermatitis and positive peanut challenge'. J. Allergy Clin. Immunol., 1992, 90, pp. 962969.
36
Burks A.W., Cockrell G., Connaughton C , Karpas Α., Helm R.M. 'Epitope specificity of the major peanut allergen, Ara hil'. J. Allergy Clin. Immunol., 1995, 95, pp. 607611.
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Shimojo N., Katsuki T., Coligan J.E., Nishimura Y., Sasazuki T., Tsunoo H., Sakamaki T., Kohno Y., Miimi H. 'Identification of the disease-related Τ cell epitope of ovalbumin and epitope-targeted Τ cell inactivation in egg allergy'. Int. Arch. Allergy Immunol., 1994, 105, pp. 155-161.
38
Taylor S.L. 'Chemistry and detection of food allergens'. Food Technol., 1992, May, pp. 146152.
39
Horsch R.B., Fraley R.T., Rogers S.G., Sanders P.R., Lloyd Α., Hoffman N. 'Inheritance of functional foreign genes in plants'. Science, 1984, 223, pp. 496-498.
40
Fisk H J . , Dandekar A.M. 'Direct gene transfer technology and progress: The introduction and expression of transgenes in plants'. Sei. Hort., 1993, 55, pp. 5-36.
41
Dandekar A.M., McGranaham G.H., James D.J. 'Transgenic woody plants'. In Shaindow and R. Wu (eds), Transgenic plants, 2. Academic Press, San Diego (Calif.), pp. 129-151, 1994.
42
Klein T.M., Wolf E.D., Wu R., Sanford J.C. 'High-velocity microprojectiles for delivering nucleic acids into living cells'. Nature, 1987, 327, pp. 70-73.
43
Fromm M., Callis J., Taylor L.P. Walbot V. 'Electroporation of DNA and RNA into plant protoplasts'. Methods Enzymol, 1987, 153, pp. 351-366.
44
Lindsey K., Jones M.G.K. 'Electroporation of cells'. Physiol. Plant., 1990, 79, pp. 168-172.
45
Shillito R.D., Saul M.W., Paszkowski J., Muller M., Potrykus I. 'High frequency direct gene transfer to plants'. Bio/technology, 1985, 4, pp. 1099-1103.
46
Anonymous. Health aspects of marker genes in genetically modified plants. World Health Organization Food Safety Unit, Geneva 1993.
47
Jorgensen R. 'The modification of horticultural plant phenotypes by direct gene transfer'. Sci. Hort., 1993, 55, pp. 1-4.
48
Van de Krol A.R., Mol J.N.M., Stuitje A.R. 'Antisense genes in plants: An overview'. Gene, 1988, 72, pp. 45-50.
49
Cannon M., Platz J., O'Leary M.O., Soojdeo C , Cannon F. 'Organ-specific modulation of gene expression in transgenic plants using antisense RNA'. Plant. Mol. Biol., 1990, 15, pp. 39-47.
50
Matsuda T., Alvarez Am Tada Y., Adachi T., Nakamura R. 'Gene engineering for hypo allergenic rice: Repression of allergenic protein synthesis in seeds of transgenic rice plants by antisense RNA'. In Anonymous (ed): Proceedings of the international workshop on life science in production and food-consumption of agricultural products, October 24-28, Japan, 1993.
51
Matsuda T., Nakase M., Adachi T., Nakamura R. 'Allergenic proteins in rice: Strategies for reduction and evaluation'. In Anonymous (ed): Food allergies and intolerances'. Bonn, DFG Senate Commission on the evaluation of food safety, 1995.
52
Taylor S.L., Bush R.K., Busse W.W. 'Avoidance diets — How selective should we be?' New. Eng. Reg. Allergy Proc, 1986, 7, pp. 527-532.
53
Taylor S.L. 'Food allergies and related adverse reactions to foods: A food science perspective'. In Perkin J. (ed), Food allergies and adverse reactions. Gaithersburg: Aspen Publishers Inc., 1990, pp. 189-206.
54
Eigenmann P.A., Sampson H.A. 'An update on food hypersensitivity'. Fund. Clin. Immunol., 1994, 2, pp. 121-133.
55
Yunginger J.W., Gauerke M.B., Jones R.T., Dahlberg M.J.E., Ackerman S.J. 'Use of radioim munoassay to determine the nature, quantity and source of alergenic contamination of sun flower butter'. J. Food Protect., 1983, 46, pp. 625-628.
56
Yunginger J.W., Sweeney K.G., Stumer W.Q., Giannandrea L.A., Teigland J.D., Bray M., Benson P.A., York J.A., Biedrzycki L., Squillace D.L., Helm R.M. 'Fatal food-induced anaphy laxis'. JAMA, 1988, 260, pp. 1450-1452.
"Sampson H.A., Mendelson L., Rosen J.P. 'Fatal and near-fatal food anaphylaxis reactions in children and adolescents'. N. Engl. J. Med., 1992, 327, pp. 380-384. 58
Gern J.E., Yang E., Evrard H.M., Sampson H.A. 'Allergic reactions to milk-contaminated "nondiary" products'. New. Eng. J. Med., 1991, 324, pp. 976-979.
59
Townsend J.J., Thomas L.A., Kullisek E.S., Daywalt M.J., Winter K.R.K., Altenbach S.B. 'Improving the quality of seed proteins in soyabean'. In Anonymous (ed): Proceedings of the fourth biennial conference of molecular biology of soyabean, Iowa State University, Ames 1992, p. 4.
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Altenbach S.B., Kuo C-C, Staraci L.C, Pearson K.W., Wainwright C , Georgescu Α., Town send J. 'Accumulation of Brazil nut albumin in seed of transgenic canola results in enhanced levels of seed protein methionine'. Plant. Mol. Biol., 1992, 18, pp. 235-245.
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Shewry P.R., Napier J.Α., Tatham A.S. 'Seed storage proteins: Structures and biosynthesis'. Plant. Cell. 1995, 7, pp. 945-956.
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Sun S.S.M., Altenbach S.Β., Leung F.W. 'Properties, biosynthesis and processing of sulfur-rich protein in Brazil nut (Bertholletia excelsa HBK)'. Eur. J. Biochem., 1987, 158, pp. 597-604.
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Gillespie D.N., Nakajima S., Gleich G.J. 'Detection of allergy to nuts by the radioallergosorbent tests'. J. Allergy Clin. Immunol., 1976, 57, pp. 302-309.
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Arshad S.H., Malmberg E., Kraft Κ., Hide D.W. 'Clinical and immunological characteristics of Brazil nut allergy'. Clin. Exp. Allergy, 1991, 21, pp. 373-376. 179
73.3.
65
Nordlee J.A., Taylor S.L., Townsend J.A., Thomas L.A. 'High methionine Brazil nut protein binds human IgE'. J. Allergy Clin. Immunol., 1994, 93, pp. 209.
66
Nordlee J.A., Taylor S.L., Townsend J.A., Thomas L.A., Townsend R. 'Investigations of the allergenicity of Brazil nut 2 storage protein in transgenic soyabean'. In Anonymous (ed). Proceedings from the OECD workshop on food safety evaluation. Paris, OECD Environmental Health and Safety Division, 1995, pp. 121-125.
67
Sampson H.A., Albergo R. 'Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis'. J. Allergy Clin. Immunol., 1984,74, pp. 26-33.
68
Burks A.W., Sampson H.A., Buckley R.H. 'Anaphylactic reactions following gammaglobulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA'. N. Engl. J. Med., 1986, 314, pp. 560-564.
69
Burks A.W., Brooks J.R., Sampson H.A. 'Allergenicity of major component proteins of soybean determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting in children with atopic dermatitis and positive soya challenges'. J. Allergy Clin. Immunol., 1988, 81, pp. 1135-1142.
Specific
immunotherapy
in
food
allergy
SYNOPSIS The optimal treatment of food allergy is to avoid the culprit food, but this may be very difficult because masked foods are present in a number of preparations, exposing the allergic subject to unaware consumption of the culprit food. A series of fatal reactions derived from eating apparently unsuspected foods has been reported. In recent years, specific immunotherapy was considered as a treatment of food allergy and a first double-blind placebo-controlled study performed on patients allergic to peanut with a defatted peanut extract demonstrated, by a marked reduction of symptoms scores to DBPCFC and decrease of skin sensitivity to peanut extract in actively treated patients, that this treatment may be effective.
The optimal treatment of food allergy is represented by avoidance of the responsible food identified by the elimination/challenge procedure.1 However, for some foods it is extremely difficult to avoid small amounts hidden in food preparations apparently unrelated to the culprit food. This is the case of milk, contained for example in hot dogs, canned tuna and margarine,2 and of peanut, which is used in USA in a number of food supplies even changing its taste to mimic other foods. The presence of peanut allergens in a large series of food products has been demonstrated by analysing the food by immunoassays.3 Eating even negligible amounts of the culprit allergen in an unsuspected food may expose the allergic patients to life-threatening anaphylactic reactions. A study analysed a series of deaths in USA caused by food anaphylaxis and found that in 54% of cases there was an unaware ingestion of peanut.4 Currently, the only therapeutical measure offered to this kind of patient is represented by immediate administration of epinephrine, especially in pre-loaded automatic devices. Theoretically, in such cases specific 180
immunotherapy should have the same value as in patients with anaphylaxis from hymenoptera stings. However, despite encouraging results obtained in some uncontrolled studies in patients allergic to fish, 5 " 7 specific immunotherapy has not been considered as a treatment of food allergy until recently. In 1992, the first placebo-controlled study of immunotherapy in food allergy8 was published. The food chosen for the study was peanut, because it is, as reported above, a frequent cause of anaphylaxis which cannot be surely avoided and, moreover, allergy to peanut shows no tendency, unlike allergy to most other foods, to be outgrown with time. 9 For the study 11 patients were selected aged from 14 to 43 years with history of anaphylactic reactions (involving cardiovascular and respiratory systems) to peanut, and positive skin tests and DBPCFC for peanut. The patients were randomized to receive immunotherapy with either a defatted peanut extract or a placebo by a rush protocol in five days. Four increasing doses with a 60-minute interval were administered in days from one to four starting from a concentration of 1:10 000 wt/vol in the first day and reaching a concentration of 1:100 wt/vol in the fourth day. In the fifth day, two doses respectively of 0.4 and 0.5 ml of the 1:100 wt/vol concentration were administered. Then the patients received weekly maintenance doses for four weeks and underwent another DBPCFC. Respiratory peak flow was monitored during immunotherapy, and treatment was stopped for the day if its value decreased under > 20% of baseline or if systemic reactions occurred. Unfortunately, the study was not completed because of a fatal incident caused by administration of the peanut extract to a placebo-treated patient. The analysis of results at the time of stopping the study in the four patients who had repeated the DBPCFC showed that in the three actively treated patients there was a marked reduction of symptom score to the challenge, while in the only available placebo-treated patient no difference in symptom score in respect to the basal challenge was found. Moreover, the three actively treated patients had a marked decrease in skin-test sensitivity to the peanut extract, as opposed to the three placebo-treated patients in whom a slight increase of skin sensitivity occurred. Apart from the fatal incident, the frequency of systemic reactions to immunotherapy was 13.3% (16 out of 120 injections), urticaria being the most common (10 reactions), followed by conjunctivitis and asthma. No cardiovascular reaction occurred. These preliminary data, as stated by Sampson in an accompanying editorial, make it conceivable to think of specific immunotherapy as a form of treatment for food-allergic patients at risk from lifethreatening reactions to each ingestion of even small amounts of the culprit food. However, other controlled studies have to be performed, analysing various foods and different protocols of administration, before immunotherapy can be proposed as a practical treatment of food allergy.
REFERENCES 1
Kettelhut B.V., Metcalfe D.D. 'Food allergy in adults'. In Lichtenstein L.M., Fauci A.S. (eds): Current therapy in allergy, immunology and rheumatology. B.C. Decker, Philadelphia, 1988, pp. 56-9.
181
182
2
Gern J.E., Yang E.Y., Evard H.M., Sampson H.A. 'Allergie reactions to milk-contaminated "dairy-free" products'. N. Eng. J. Med., 1991, 324, pp. 976-79.
3
Keating M.V., Jones R.T., Worley N.J. 'Immunoassay of peanut allergens in food-processing materials and finished foods'. J. Allergy Clin. Immunol., 1990, 86, pp. 41-44.
4
Yunginger J.W., Sweeney K.G., Stumer W. 'Fatal food-induced anaphylaxis'. JAMA, 1988, 260, pp. 1450-52.
5
Freeman J. '"Rush" inoculation'. Lancet, 1930, 1, p. 744.
6
Aas K. 'Studies of hypersensitivity to fish. A clinical study'. Int. Arch. Allergy, 1966, 29, pp. 34666.
7
Dannaeus Α., Inganaes M. 'A follow-up study of children with food allergy. Clinical course in relation to serum IgE- and IgG-antibody to milk, egg and fish'. Clin. Allergy, 1981, 11, 533-9.
8
Oppenheimer J.J., Nelson H.S., Bock S.A., Christensen F., Leung D.Y.M. 'Treatment of peanut allergy with rush immunotherapy'. J. Allergy Clin. Immunol., 1992, 90, pp. 256-62.
9
Bock S.A., Atkins F.M. 'The natural history of peanut allergy'. J. Allergy Clin. Immunol., 1989, 83, pp. 900-4.
10
Sampson H.A. 'Food allergy and the role of immunotherapy'. J. Allergy Clin. Immunol., 1992, 90, pp. 151-2.
14.
I M P O R T A N C E OF FOOD H Y P E R S E N S I T I V I T Y IN P U B L I C H E A L T H , E C O N O M I C E F F E C T S , G R O U P S AT RISK
Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the users receive accessible information on food products, and to jointly promote studies to set in motion the farthest-reaching positive approaches.
14.1.
The
public
health
role
The importance of food allergy in public health has been affected by the overestimation of this disease. In fact, as mentioned in other chapters of this study, the true prevalence of food allergy is undoubtedly lower than figures quoted in the popular press, for instance in a prospective study on 480 children1 (Bock 1987) it was demonstrated that the prevalence of food allergy was actually 8% as compared to the parents' conviction which was 28%. The 'gold standard' for the diagnosis of food allergy is the DBPCFC 2 The only exception are the severe reactions, such as anaphylaxis or laryngeal edema, in which DBPCFC tests are not to be done. Several studies have demonstrated a tremendous discrepancy between subjective perception of food intolerance and the results of DBPCFC 1 · 3 · 4 Indeed the only two studies that estimate the prevalence of food allergy/intolerance in adults, using DBPCFC, confirm that actual food allergy/intolerance affect about 0.8-1.4-% of the population, in spite of the high percentage (12.4-20.4%) of adults complaining of food allergy/intolerance. More attention needs to be paid to epidemiologic studies in order to determine the actual prevalence of food allergy and disclose this data to the public and scientific community. The general practitioner must be informed by current medical education on the development of scientific protocols and position papers. EAACI has produced an understandable and pragmatic document that clearly defines the characteristics of food allergy and intolerance.2 The new classification, based on pathogenesis, will aid in avoiding improper definitions of food-adverse reactions. For example the term 'food intolerance' is often used improperly when the pathogenic mechanisms are vague or unknown. The DBPCFC can unravel all doubts in regard to the mechanisms involved in food-adverse reactions; if the DBPCFC is employed, the cases of assured food reactions that do not fall under the heading of IgE-mediated reactions become extremely rare. It is likely that the latter rare cases, for which the DBPCFC is positive are falsely negative for specific IgE, occur because standardized allergen extracts are lacking, hence reducing the sensitivity of tests. Unfortunately the prevailing opinion is that the DBPCFC should be performed only in particular cases and that the diagnosis of food allergy and intolerance may be reached 'more simply' by the patient history and positive tests for food specific IgE. On the contrary, public health facilities would greatly benefit from promoting the DBPCFC as the only bona fide method for a correct 183
clinical diagnosis of food allergy/intolerance. The role of public health facilities must be that of endorsing a correct diagnostic methodology in food allergy. In fact only the correct identification of the actually allergic patients allow us to protect them better against the culprit foods. The existing confusion and the insufficient clearness of the official medicine concerning food allergy and intolerance favour the delivery and multiplication of so-called 'unorthodox medical practices'. Many practitioners of 'alternative medicine' (clinical ecologists and natural healers) and popular magazines complicate the actual problem of food allergy, facilitating over-diagnosis of 'multiple food allergies'. The consequences of these blunders produces an elevated financial burden for the patient and society, mainly because of costly diagnostic procedures and diet regimens. Furthermore, the danger of disease due to a non-equilibrated diet impinges further on social health cost. It is often believed that implementation of high restrictive elimination diets by 'alternative' practitioners is benign. However there is a report of severe consequences, resulting also in death, arising from misdiagnosis of food allergy by 'alternative' practitioners in patients affected by other organic diseases.5 In all these cases the proper diagnosis was seriously delayed by the misdiagnosis of food allergy. A correct diagnosis of food allergy justifies the economic effects on health care. The cost is mainly due to the elimination diet that has to be respected throughout all daily activities (work, recreation, school and family), and to the educational programme required to instruct all personnel involved in these activities how to behave correctly in the preparation of food and when a food-allergic reaction occurs. On the other hand, at present, no study has analysed thoroughly the social and financial cost of the food allergy, that is the number of missing workdays, the cost of both chronic and acute treatment (drugs, emergency procedures, etc.), the prevalence of the severe reactions and their rate of mortality. Recent publications have emphasized the serious, sometimes fatal, consequences of foodinduced anaphylaxis.6"8 A retrospective study that encompassed 31/2 years and included 179 patients was conducted at the Mayo Clinic, Rochester, Minnesota, USA, for an assessment of patients who have experienced anaphylaxis, and food was the first cause of anaphylaxis in the current series, the tentative in 33% of patients.9 They used the term 'tentative' because no rechallenge was obviously conducted in each case for the possible dramatic consequences. The authors claim that no international classification of diseases code exists for food anaphylaxis, and many cases go unidentified without labour-intensive individual chart abstraction. Hence further studies on the incidence of food anaphylaxis are needed, its frequency being most likely underestimated. Many physicians do not account for the importance of allergic disease in adults. In particular a history suggestive of food allergy related by adult patients may be dismissed. The study by Yocum and Khan9 points out how serious such an error can be, since up to 37% of the patients had previously experienced severe reactions and 49% were atopic. This failure in communication between the patients and their physicians can and must be avoided because a thorough investigation at the time of an initial allergic reaction will help patients prevent future difficulties. Several cases of severe allergic reaction due to improperly labelled foods have been reported. 10 · 6 It is therefore anticipated that there will need to be specific laws that require a thorough and detailed labelling of all foods. Indeed in the abovementioned study five patients had previously 184
documented positive prick-skin tests to a specific food and had inadvertently ingested the food as a cause of their current anaphylactic episode.9 These observations highlight the need for all physicians who treat patients with allergies to emphasise education and to urge patients to identify food constituents before they are ingested. At the same time physicians also must educate their patients in self-help, both for questioning the contents of meals in restaurants and for self-administration of epinephrine. Prescribing EpiPen or Ana-Kit as prompt therapy for severe reactions is mandatory because studies have documented that any delay in treating food-induced anaphylaxis increases the possibility of a fatal outcome. 6 · 7 making it imperative to request the consultation of the allergist for all food allergic patients.
Physicians have to know that some factors can affect the quality and the magnitude of the allergic reactions to food. For instance they must know and teach their allergic patients that exercise and non-steroidal antiinflammatory drugs, increasing the intestinal permeability to food protein, could start or worsen a food reaction; 11 · 12 other drugs, such as ß-adrenergic blocking agents or angiotensinogen-converting enzyme (ACE)-inhibitors, can be a problem in patients with anaphylaxis because they may complicate the emergency treatment.13"16 These drugs do not increase the risk of allergic reactions, but predispose the patients to more severe systemic reactions and to be more refractory to therapy. The reason to avoid ß-blockers is generally clear to all physicians, but they have to know that a potential danger also exists with use of ACE inhibitors; as compensation for anaphylaxis-induced loss of plasma volume (up to 50% within 10 minutes), angiotensin II is produced as well as epinephrine and norepinephrine as reactive vasopressors.17 Moreover angiotensin II also inactivates bradykinin. Thus hypothetically the use of ACE inhibitors in patients with a history of anaphylaxis should be evaluated carefully in the future. Physicians who staff the emergency department should be adequately trained to assess and treat anaphylaxis as the majority of the patients with severe food allergic reactions initially seek assistance in this area. These physicians also need to know the importance of determining titres of serum tryptase or urinary histamine in patients suffering from severe allergic reaction since these tests are crucial to document generalized mediator release. In fact the diagnosis of food anaphylaxis is seldom coded correctly and these tests can become a useful tool for the allergists who often are consulted only when the acute reaction is over. The presence of these mediators is the evidence of the involvement of mast cells and basophils and therefore supports the allergic origin of the reaction.
Allergists must actively educate physicians and school nurses to identify patients with anaphylaxis. Emergency treatment of anaphylaxis in schools and in the workplace must be facilitated; fear of legal liability because of the use of epinephrine in such public places must be allayed even if a primary concern of school officials about the use of injectable epinephrine has been the possible side effects rather than its lifesaving benefits. Injectable epinephrine should be available in the classroom, rather than in the school nurse's office, for administration by affected children or their teacher, inasmuch as immediate availability is critical for preventing fatal reactions. Strict avoidance of school snacks and more careful supervision of casual ingestion of food at school parties and on school outings must be stressed by allergists to parents and school officials. Patients allergic to food and persons living with them have to be, of course, educated to avoid every food not appropriately labelled, in which all ingredients are not well identified and recorded. The gravity of anaphylaxis and the need to pursue the culprit food must also be emphasised to the general public. 185
Unfortunately even official medicine proposes often unsatisfactory methods of diagnosis, such as specific IgE determination and skin-prick tests that are useful but not diagnostic by themselves. These tests have a scarce overall accuracy because of the poor standardization of the food allergens used. 18 For example Brazil nut, chestnut, milk, walnut, codfish, halibut, chicken, and aniseed, all foods previously reported to cause severe life-threatening reactions, have many false negative at these tests, perhaps because the commercial extracts contain low levels of relevant allergens.19 In some cases diagnostic extracts are difficult to obtain because of the lability of the allergens which cannot stand up to the extraction procedures. This is mainly true for most fruit and vegetables, which give more reliable results when used as fresh material by prick + prick technique and which are very often responsible for OAS in the adult population.20·21 An effort has to be made to spread the knowledge that patients allergic to certain pollens (birch, mugwort, grass, etc.) can often later develop an OAS. 21 " 24 Potent antigens are concentrated in the seed and skin portions of various fruits and vegetables and are usually available using prick + prick method. Recently the use of fresh milk, peanut, egg and seafood have also shown better results than commercial extracts.25 Instead, the presence of specific IgE to a food is not necessarily associated with clinical symptoms and may occur as an effect of a cross-reactivity to allergen shared by foods and different sources. 26 · 27 Inadequate diagnosis often causes useless dietary restrictions causing unjustified sacrifice for the patients and their families. Moreover the official medicine still wrongly feeds the belief that foods rich in histamine may be responsible of Pseudoallergie reactions with cutaneous and respiratory complaints.29 Unfortunately more and more often patients without food allergy but with other allergic diseases are advised by their physicians to undergo a diet without histamine-rich foods. This method, originated from few non-validated studies, is rapidly spreading as advice for the allergic patients but also to non-allergic patients suffering from cutaneous and/or respiratory symptoms. The main role of the public health facilities, and particularly of the allergists, is to collaborate with food producers, recording allergenic food and aiding alimentary factories to adopt all the measures needed to prevent allergic reactions. The first basic rule is to label in a correct and exhaustive manner all the foods, even if there are only traces of some ingredients because trace amounts of food can trigger life-threatening allergic reactions. The European Community has to make an effort to provide public health facilities with stringent protocols and position papers on food allergy. The role of the members of the public health facilities is not limited to labelling and education, but they have to direct their research towards the production of non-allergenic foods. The previous chapter has already dealt with this problem and the enormous effort made in the development of hypoallergenic formula derived by extensively hydrolyzed whey has traced the pathway to be followed. However the rare, allergic reactions to hypoallergenic formula underline the difficuly in obtaining a safe allergen-free food product even after high protein degradation. Of course the control of biochemical, immunologic and clinical parameters to evaluate the food hypoallergenicity is another task of the public health facilities. Likewise difficult is the endeavour of modifying the specific immune response of the allergic patient towards the food allergen and this attempt requires principally the work of the allergists. Specific immunotherapy (SIT) to certain foods are still experimental and poorly standardized.29·30 186
Moreover SIT will be accepted only when doubleblind placebocontrolled studies have obtained unequivocal data in its favour; but this kind of study is at high risk for the dangerous life threatening reactions that can occur. A promising solution, lately suggested and partially applied, is the use of analogous peptides of epitopes responsible of food allergy which have been isolated and synthesized by D NArecombinant techniques. These peptides can compete with the aller genic epitopes at the level of the specific Tcell receptor for the allergen and can switch off the allergic immune response against the food allergen. Evidence of this potential employment has been actually documented, for instance, for ovalbumin allergy.31
74.2.
Groups
at
risk
Several factors contribute to determine the risk of developing food allergy. First of all we could divide them into factors that facilitate a general atopic response and factors that affect more specifically the rise of a food allergy. Genetic determinants have an important role in atopic diseases. In fact children with nonatopic parents have a potential risk of being atopic of about 515%.32 The risk increases to 2040% if one parent or one sibling is atopic 32 The risk is higher (4080%) if both parents are atopic with the highest probability occurring when they suffer from the same atopic disease.32 Other parameters have been studied and proposed as predictive of the risk of atopic disease. 33 · 34 They are: (1) elevated total IgE in the cord blood;35 (2) increased total IgE in infancy and childhood; (3) significant specific IgE antibody (skin and serum); (4) elevated concentrations of salivary IgAanti casein in newborns; (5) delayed postnatal maturation of Tcell competence; (6) low in vitro production of IFNγ and TNFa often present in children born from atopic parents; (7) increased eosinophils in the cord blood, in blood and/or in the nasal mucosa An infancy; (8) increased monocyte phosphodiesterase activity; (9) alterations of the ratio of essential fatty acids in umbilical cord serum; (10) cord blood thrombocytopenia. Some of these assays, such as total IgE in the cord blood, are easily available and partially reliable, while some others have furnished controversial and questionable results.34 Concerning the specific risk of developing a food allergy, certain groups have been identified that are at higher risk than the general population. First of all children, who have an overall prevalence of true food allergy of 8%, 1 present a higher risk than the adult population in which the food allergy prevalence is estimated to be about 2%. 3 · 4 Some factors have been claimed to affect the rise of food allergy in children. These are: (1) brief or nonbreast feeding; (2) premature weaning; (3) maternal diet introducing food allergens through breast milk; (4) early solid foods; (5) transient or permanent IgA deficiency; 36 · 38 (6) maternal drug intake during pregnancy, e.g. ßblocking agents; (7) maternal smoking during pregnancy. Some of these risk factors have been deeply analysed but controversial results have often been reported by different authors. For instance Van Asperen (1984)39 was unable to show a protective effect of either breastfeeding or cow's milk or solid avoidance on the development of atopic disease in infancy; these results contrast with what has been reported by several other prospective studies that showed a protective role of breast feeding and cow's milk avoidance on the development of food allergy.34 Recent immunological confirmation that dietary allergens such as cow's milk proteins and egg allergens are frequently present in breast milk,40 combined with the early sensitization of exclusive breastfed infants to 187
egg and milk41, imply that exclusive breast-feeding would be less than optimal in preventing food hypersensitivity without also instituting maternal dietary restrictions of major allergenic foodstuffs. Moreover nowadays we know that small amounts of food allergen, like those present in breast milk, facilitate the pathway of the Th2 response towards a sensitization and specific IgE production. 42 Chandra et al. 43 documented that a maternal elimination diet avoiding major allergenic foods during lactation may help to prevent atopic dermatitis in their infants. Hattevig40 reported similar beneficial effects in infants of mothers avoiding egg, cow's milk, and fish during the first three months of lactation. Chandra et al. 4 4 noted also that there was an apparent comparability of the breast fed and formula fed groups in decreasing the prevalence of allergic disease by two years when infants with high cord blood IgE levels were studied. Infants exposed directly to multiple diverse solid food allergens early in infancy apparently develop a higher rate of eczema but similar incidence of asthma by two years;45 recommendations to withhold solid food feedings until after six months may therefore be well founded. Two studies have recently examined the effect of contemporary maternal and infant dietary restrictions on the development of atopic diseases. Chandra46 showed that a maternal diet excluding egg, milk, fish, peanut and beef during pregnancy and lactation, coupled with breast-feeding and delaying solid food introduction for six months reduced the incidence of eczema in infants at risk for atopy. Zeiger47 in a similar study on 288 children documented that the prevalence of atopic disorders were reduced at one year due to lower prevalences of food allergy in the prophylactic group. From these two studies it emerges that extensive food avoidance by both mother and infant transiently reduces food allergy without influencing allergic rhinitis and asthma; the prenatal avoidance likely did not contribute to any of the beneficial effects reported in these two studies. Maternal intake of metoprolol, a ßblocker, during pregnancy significantly increased the appearance of elevated neonatal IgE concentrations and the development of atopic symptoms before 18 months of age. 48 Maternal smoking during pregnancy gave a two- to five-fold increased risk for development of eczema, asthma and pneumonia during infancy.49 The role of early aeroallergen exposure is doubtful even if a recent study of 120 children, identified before birth as being at high risk for atopy, shows that a double approach to allergen avoidance, focusing on foods and aeroallergens, appears to be beneficial in preventing sensitization in these high-risk infants, but it does not clarify if food sensitization has been avoided or merely deferred.50 Burr (1993) in a randomized controlled trial involving 453 children with a family history of allergic disease showed that breast-feeding may confer long-term reduction of the incidence of wheeze that persists at seven years of age. 51 Another relevant group at risk for food allergy is represented by patients suffering from pollinosis, prevalently adult patients with inhalant allergy to pollen of birch, mugwort, grass and ragweed. Usually these patients are at high risk for developing OAS years after the rise of respiratory allergy. 20 · 21 · 24 Another group at risk for OAS is the group of patients with allergy to latex (Hevea brasiliensis): Pecquet reported that nearly half the patients with latex allergy in his study had an allergic reaction to a fruit, the most frequently mentioned being banana (34%), avocado (25%), and kiwi (20%). 52 Allergy to chestnut is also frequent in these patients, while reactions to apricot, grape, passion fruit, and pineapple are less frequently noted. 52 Since the prevalence of latex allergy is particularly elevated in three subgroups that are medical and nursing staff, employees working in a plant manufacturing latex products, and subjects with a history of repeated surgical procedures (mainly patients with spina bifida), these three subgroups have to be indirectly considered at risk for developing food allergy towards the abovementioned fruits. 188
Since the magnitude of allergen exposure is generally recognized as a driving factor in determin ing the prevalence of a certain food allergy, it is obvious that certain populations are at higher risk for developing allergic reactions to specific foods characteristic of their dietary habits, such as fish in Scandinavian countries53 and peanut in North American countries.19 A study by Scadding (1988)54 suggests an important role for poor sulphoxidation ability in facilitating the rise of food allergy. This study analyzed the sulphur and carbon oxidation ability in a population of welldefined food allergic patients and documented that the portion of poor sulphoxidizers (58 of 74) was significantly greater than that of a previously determined normal control population (67 of 200; ρ < 0.005). The proportion of poor carbon oxidizers was not significantly different from the controls. Hence the metabolic defect of sulphoxidation may play a role in the pathogenesis of adverse reactions to foods. Since about 35% of the subjects in the general population present a deficit in sulphoxidation they have to be considered a group at risk for food allergy compared with the normal population. In the field of food allergy/intolerance celiac disease holds a peculiar position. Indeed celiac disease is likely to be an abnormal immune response in individuals susceptible to the ingestion of certain cereal peptides. It is well known that some populations have a greater risk for developing celiac disease, such as, for instance, Irish people.55 It is also known that there is a clearly major prevalence of celiac disease in consanguineoses of patients with celiac disease.56 In the past years evidence is accumulating that particular HLA antigens are associated with celiac disease. HLA antigen analysis has determined that groups at elevated risk for celiac disease present frequently HLA B8, DR3, DR7 and DQw2. In conclusion, the analysis of the groups at risk from food allergy, besides defining the correct pathway to quickly foresee which subjects will likely develop a food allergy, allows us to project the best strategies to prevent the onset of food allergy.
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193
15.
CONCLUDING
REMARKS
Over the past few years public opinion has been showing increasing interest in food allergies. The lay press — in fact the mass media in general — has fuelled this curiousity. Unfortunately, however, the information published is not always entirely correct. It is for instance widely believed that food allergy or intolerance can cause a variety of diseases and disorders, ranging from the classical allergic manifestations such as eczema or urticaria to symptoms not normally attributed to allergies, such as arthritis and irritable bowel syndrome. The layman also tends to accept the suggestion that, in addition to true food allergies, diagnosable on the basis of skin reactions and assays for specific IgE for certain foods, much of the pathology arising in connection with foods is caused by food intolerance, although this 'disorder' lacks a precise pathogenic reference except for some rare diseases caused by enzymatic deficits. In 1995 the Subcommittee of the European Academy of Allergy and Clinical Immunology published a position paper, 'Adverse reactions to food' which set up a new classification and terminology for these reactions. Essentially this position paper gives priority to IgE-mediated reactions; while admitting that theoretically there could be non-lgE-mediated immune reactions, it indicates clearly that there is no real proof that they have any role in causing symptoms. The position paper is specific that food intolerance may be enzymatic or pharmacological; the first heading includes the rare reactions due to enzymatic deficits and the second heading those where the symptoms depend on the effects of certain amines that are either naturally present or develop in foods. The subheading of undefined food intolerance temporarily includes only celiac disease and adverse reactions to food additives. The position paper stressed the importance in all clinical situations of applying the appropriate diagnostic procedure which should be based on DBPCFC, the only way of confirming food intolerance or allergy. The new classification and particularly the general outline of the 'role of food in relation to the different hypotheses', presented in section 2 of this study casts ample light on the real problems of food allergy and intolerance. These are questions of public health relevance to which clinical and basic research must seek answers. Thus EC agro-industrial research projects developed in the future will have to take account of this approach and its related problems. The main point is that the IgE-mediated pathogenic mechanism is by far the most frequent and is also the most important as regards the severity of symptoms, hence the danger posed by the culprit foods, which may cause harm even only as trace contaminants. The next most important point is sensitivity to gluten, the main cause of celiac disease. Enzymatic intolerance can usually be traced to inborn metabolic errors; diseases in this group are extremely rare and precise dietary rules can usually be formulated to avoid problems. 194
Lactose intolerance is an exception, since it is very widespread. However, it is a relatively bland condition and generally raises difficulties only in preparing milk formulas for infants in countries where its prevalence is high. Pharmacological intolerance is another problem affecting limited numbers of people, and the foods containing the culprit amines have been clearly identified. Focusing on IgE-mediated allergies, therefore, several important question are still open. First of all we have to improve our knowledge of alimentary allergens. Many allergenic molecules have been identified in recent years, some have been sequenced and some allergenic epitopes have been recognized, but this research field is still in its infancy. Correct methods must be established for identifying the main allergens and intermediates and these require sera from at least 50 individuals, correctly diagnosed on the basis of DBPCFC as being intolerant to the study food. If at last 50 are used the resulting allergogram should meet stringent criteria. It would nevertheless be advisable to select these allergic individuals in different parts of the EU, so as to allow for the possibility of genetic and dietary differences. Identification of the major and intermediate allergens for the main foods should then be followed by purification of the major allergenic proteins and their immunological study, aimed at identifying the epitopes involved in the immune response. Immunological research will then provide purified allergenic molecules or allergens produced by recombinant DNA technology, and these can be employed for research into characteristics of their immunogenicity. From the practical viewpoint it is important if we are to prevent food allergies to reduce the allergenic potential of foods. In the past this has been tackled for cow's milk, the basic food item in infant formulas, and the market now offers a variety of hypoallergenic products. For milk and other animal proteins, egg and fish, the allergens are highly stable even to cooking and digestion, so reducing their allergenicity means breaking the molecule down so vigorously that the organo leptic attractions of the original food may be lost. Many plant allergens, however, are labile to heart and digestion, so methods will probably be found to reduce their allergenicity. Identification of the major allergenic molecules in specific foods will lead to considerable improve ments in the diagnosis of allergies, and in vitro diagnostic tests will then became possible with much better overall accuracy, so that it may eventually no longer be necessary to use the DBPCFC test. Knowledge and availability of the allergenic molecules for certain foods will also enable us to standardize food allergens used for specific immunotherapy. Right now these methods are not available, and research is still awaiting better standardization of the allergens. Recognition of the Τ epitopes of certain food allergens may open new prospects for modulating the IgE response. Identification of the allergenic molecules will boost research into the production of transgenic plants containing little or none of the allergens concerned. 195
While awaiting this scientific and technological progress we must draw on our current knowledge of the effects of food processing and preparation. This is particularly important for products prepared by new methods, such as the microparticulate proteins and certain additives; which may constitute a risk for people with allergies. The best policy for the EU is to make certain that the user receives correct and detailed information about each type of food and each ingredient in the final product, and that manufacturers respect these requirements. Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the user receives accessible information on food products, and jointly to promote studies to set in motion the farthest-reaching positive approaches.
196
European Commission EUR 16893 — Study of nutritional factors in food allergies and food intolerances C. Ortolani, E. A. Pastorello Luxembourg: Office for Official Publications of the European Communities 1997 — 196 pp. — 21.0 χ 29.7 cm ISBN 92-827-9554-3
The present study was launched as an initiative by the Agro-industrial Division E-2 of the European Commission, Directorate-General XII 'Science, Research and Develop ment'. This study forms part of a series of studies launched by the division on impor tant issues pertaining to food and non-food research. Their aim is to present the cur rent state of the art and give recommendations by the authors for future research which could remove obstacles in the way of introduction of new technologies and products from the agro-industrial sector into the marketplace. It should be stated that this document represents the findings and opinions of the authors and should not be considered as the opinions or recommendations of the Commission services.
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