8.3 Medicine_Tropical Infectious Diseases Leptospirosis 2014A

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Tropical Infectious Diseases: Dra. Rosario

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Outline Introduction: Case 4 Leptospirosis A. Pathogenesis B. Transmission C. Leptospirosis in the Philippines D. Clinical manifestations Weil’s Disease E. Treatment F. Laboratory Diagnosis G. Prognosis H. Prevention Key Concepts

CASE 4 A 28 year-old male, a government employee consulted the ER because of fever, jaundice, and oliguria o Reported abdominal and leg pains o Wading in floodwater 2 weeks ago PE: BP=120/90; HR=100/min; RR=26/min; T=39C With conjunctival suffusion, icteric sclerae Breath sounds clear No abnormal heart sounds Voluntary abdominal guarding; LS: 12 cms; Traube space obliterated Calf muscle tenderness

Primary Impression? 1. Dengue fever 2. Enteric fever 3. Malaria 4. Leptospirosis    

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ISSUES Early clinical recognition and diagnosis Management of complications Prevention and control LEPTOSPIROSIS Zoonotic disease caused by spirochetes of the genus Leptospira o Thin, flexible, finely coiled, Gram-negative bacteria o Obligately aerobic, slow-growing, fastidious Reservoir: Wild and domestic animals Human infection acquired through direct contact with infected animals or by contact with water/soil contaminated by infected urine Leptospires are tightly and regularly coiled, with characteristic hooked ends and are highly motile, spinning around their longitudinal axis and darting back and forth [Harrison’s]

Leptospira interrogans var. icterohaemorrhagiae on EM Question: What is the primary underlying problem in Leptospirosis? 1. Toxin secretion 2. Invasion of reticulo-endothelial system 3. Hypersensitivity reaction to leptospiral antigens 4. Systemic vasculitis   

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  Ang, Angulo, Añover; Edited by Añover

PATHOGENESIS Proliferation in bloodstream and spread to distant organs No tissue tropism Capillary leakage and hemorrhage due to disruption of endothelial cell membrane (systemic vasculitis) o Accounts for broad spectrum of clinical illness Leptospires infect humans through the mucosa/abraded skin. The organism will resist innate immune defenses and proliferate in the bloodstream or extracellularly within organs, and then disseminate hematogenously to all organs. Incubation period averages 5-14 days. Life cycle will be completed as leptospires traverse the interstitial space of the kidney, penetrate the basement membrane of the proximal renal tubules, cross through proximal renal tubuloepithelial cells, and become adherent to the proximal renal tubular brush border, whence they are excreted in the urine. In humans, colonization can last up to years, with unknown pathophysiologic consequences[Harrison’s]

TRANSMISSION OF LEPTOSPIROSIS Epidemics common after natural disasters in endemic areas (flooding, tropical storms, hurricanes) Risk factors: o Walking through streams, creeks, puddles o Swimming, kayaking, white-water rafting o Exposure to rodents Factors that facilitate human infection are those that bring susceptible persons into indirect contact with contaminated animal urine through surface waters, moist soil or other wet environments or into direct contact with urine and other excreta of infected animals. [Harrison’s]

LEPTOSPIROSIS IN THE PHILIPPINES Average of 680 cases and 40 deaths reported every year Prevalence of 10/100,000 Page 1 of 7

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Seasonal; peak incidence during the rainy months of July to October Urban domestic rats, rural field rats, water buffalo, cattle, pigs, dogs and monkeys: tested positive for leptospiral antibodies

October 2009 Outbreak  Declared by DOH two weeks after widespread flooding caused by Tropical Storm Ondoy (Sept. 26, 2009)  Average: 680 cases and 40 deaths per year  As of 13 November 2009: 2,292 suspected cases (257 confirmed) and 178 deaths (CFR 7.4%) in 15 hospitals in Metro Manila

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Classic leptospirosis is usually biphasic. Initial Leptospiremic phase with acute fever lasting for 310 days, wherein the organism may still be cultured from blood. Later Immune phase, fever will be unresponsive to antibiotics, but leptospires can be isolated from urine. [Harrison’s] Weil’s Syndrome can be monophasic and fulminant. [Harrison’s]

Severe Leptospirosis: Weil’s Disease  Rapidity of progression to fulminant illness is variable  Fatality rate: ranges from 5-40%  Highly dependent on severity of illness caused by different serovars and quality of supportive medical care  Weil’s Disease is characterized by variable combinations of jaundice, acute kidney injury, hypotension and hemorrhage, most commonly in the lungs.[Harrison’s]

Question: What is the pathophysiologic mechanism of hepatic failure in Weil’s disease? 1. Hepatocyte degeneration 2. Centrilobular necrosis 3. Periportal necrosis 4. 2 and 3 only

Figure 1. Showing increased incidence of leptospirosis cases in 2009  

CLINICAL MANIFESTATIONS Subclinical manifestation with subsequent seroconversion Two clinical syndromes: o 90%: self-limited, systemic illness o 10%: severe, potentially fatal illness characterized by renal and hepatic failure and pneumonitis with a hemorrhagic diathesis (Weil’s disease)

Hepatic Failure in Weil’s Disease  Results from hepatocyte degeneration with cholestasis and concomitant vascular injury  Hepatosplenomegaly (>25% of icteric patients)  Bilirubin: normal or slightly increased (80mg/dL)  AST, ALT rarely >200 U/L, Inc. PT rare  Hepatocellular necrosis is absent  Hepatic histopathology in fatal cases is associated with disruption of cellular cohesion, plugging of bile canaliculi, occasional acute inflammatory infiltrates, and focal periportal cellular necrosis and steatosis. Widespread hepatocellular necrosis is NOT FOUND. [Harrison’s]

Question: What is the primary pathophysiologic mechanism of renal failure in Weil’s disease? 1. Renovascular obstruction 2. Rapidly progressive glomerulonephritis 3. Interstitial nephritis 4. Diffuse acute tubular necrosis Renal Failure in Weil’s Disease  Hallmarks: impaired sodium reabsorption, increased distal sodium delivery, and K+ wasting  Rapid onset of uremia, oliguria (2nd week)  If with thrombocytopenia (even without DIC) or anuria – poor prognosis  BUN: Usually 300mg/dL

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Creatinine: Usually 2-8, may be >18mg/dL Biopsy: interstitial nephritis with focal ATN Leptospirosis and Renal Failure o Leptospirosis can account for up to 40% of cases of acute renal failure in Asia (Sitprija et al. 1975) o Correlates well with prognosis (Marcial M, Phil J Microbiol Infect Dis 1995)  Oliguria and need for dialysis  Hemorrhage  Duration of jaundice Acute kidney injury manifests after several days of illness and can be nonoliguric or oliguric, with serum electrolyte abnormalities reflecting proximal renal tubular dysfunction. Hypokalemia and hypomagnesemia are common in nonoliguric renal failure. Hypotension is associated with acute tubular necrosis and oliguria. Renal function typically returns to normal in survivors of severe disease [Harrison’s]

Cardiopulmonary Dysfunction in Weil’s Disease  Hemorrhagic pneumonitis, ARDS: seen in severe infection o CXR: multiple patchy infiltrates = suggestive of alveolar haemorrhage

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Mainly due to widespread vasculitis Worsened by impaired hepatic production of coagulation factors Aggravates existing jaundice and further compromises renal function

Question: Which patient will need hospital admission? 1. Outpatient (Mild LEPTOSPIROSIS)  Any suspected case of leptospirosis presenting with acute febrile illness and various manifestations BUT o Stable vital signs o Anicteric sclerae o With good urine output o No evidence of meningismus/meningeal irritation, sepsis/septic shock, difficulty of breathing nor jaundice o Can take oral medications (Grade A) 2. Healthcare/Hospital Setting (Moderate to Severe)  Any suspected case of leptospirosis presenting with acute febrile illness associated with o Unstable vital signs o Jaundice/icteric sclerae o Abdominal pain, nausea, vomiting and diarrhea o Oliguria and anuria o Meningismus, meningeal irritation o Sepsis/septic shock o Altered mental states o Difficulty of breathing and hemoptysis TREATMENT OF LEPTOSPIROSIS

Figure 3. Pulmonary hemorrhage in Leptospirosis  Cardiac arrhythmias in up to 20% of patients; may progress to cardiovascular collapse with shock  Histopath: Pulmonary congestion and intraalveolar hemorrhage with severe airspace disorganization; myocarditis; acute coronary arteritis and aortitis  Severe pulmonary hemorrhage in leptospirosis is a

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clinical problem, manifesting with cough, chest pain, and hemoptysis but without purulent sputum. Cases of severe pulmonary hemorrhage syndrome that come to autopsy are characterized by the absence of inflammation, the paucity of organisms visible by silver or immunohistochemical staining, and grossly obvious frank hemorrhage. Immunoglobulin and complement deposition have been demonstrated in lung tissue involved in leptospiral pulmonary hemorrhage. Cardiac involvement is commonly reflected on the electrocardiogram as nonspecific ST and T wave changes but also as right-bundle-branch block and right- and/or left-sided ventricular dilation indicating myocarditis. [Harrison’s]

MILD LEPTOSPIROSIS:

Hemorrhagic Diathesis Ang, Angulo, Añover; Edited by Añover of 7

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Mild leptospirosis often is not specifically identified and typically resolves without antibiotic treatment. If clinical suspicion is high or the diagnosis is suggested or confirmed by laboratory findings in an appropriate context (e.g., clinical presentation, exposure history); mild disease should be treated with oral antibiotics particularly, doxycycline. [Harrison’s]

When Would You Suspect Pulmonary Complications of Leptospirosis?  Tachypnea (RR>30/min) is the first sign of pulmonary involvement  One should consider lung involvement: o Onset of cough o Hemoptysis o Dyspnea  Pulmonary symptoms usually appear on the 4th-6th day of disease Pulmonary complications in Leptospirosis:

MODERATE TO SEVERE LEPTOSPIROSIS:

Dosage of Antibiotics in ADULTS WITH RENAL IMPAIRMENT:

What Are the Indications for Acute Renal Replacement Therapy or Dialysis?  Any one of the following is an indication for dialysis: o Uremic symptoms – nausea, vomiting, altered mental status, seizure, coma o Serum creatinine >3mg/dL o Serum K >5meq/L in an oliguric patient o ARDS, pulmonary hemorrhage o pH 1:200 is considered strong evidence of infection; however, in regions where leptospirosis transmission and subclinical disease are common, higher titers are generally required for a confident diagnosis because of long-lasting antibodies after a previous infection. Because the MAT is generally negative in the first 7–10 days after the onset of infection, paired acute- and convalescent-phase serum samples are preferred to document seroconversion or a fourfold rise in titer. [Harrison’s]

2. Specific IgM Rapid Diagnostic Tests (LeptoDipstick®, Leptospira IgM ELISA (PanBio), MCAT and Dridot®)  Serologic tests in a single test format  Quick detection of Leptospira genus-specific IgM antibodies  Sensitivity improves if taken beyond 7 days (>90%) 3. Nonspecific Rapid Diagnostic Tests like LAATS (Leptospira Antigen-Antibody Agglutination Test (Leptospira Serology BioRad) Ang, Angulo, Añover; Edited by Añover of 7

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Detects Leptospira antibody in human serum through agglutination reaction Used as a screening test and should be confirmed with MAT PROGNOSIS Case fatality rate of about 10% in severe cases Dependent on several factors o Timely administration of effective chemotherapeutic agents o Quality of supportive care provided o Virulence of infecting serovar o Severity of the disease on admission o Presence of co-morbidities

Adverse Prognostic Factors  Strongest predictor of death: Altered mental status  Other poor prognostic signs: o Acute renal failure (oliguria, hyperkalemia, serum creatinine >3.0mg/dL) o Respiratory insufficiency (dyspnea, pulmonary rales, CXR infiltrates) o Hypotension o Arrhythmias **Hepatic failure alone (without renal failure) rarely leads to a fatal outcome 

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The severity of illness in terms of pulmonary and renal dysfunction is the most important determinant of prognosis. Advanced age, clinically evident pulmonary involvement, elevated serum creatinine level, oliguria, and thrombocytopenia are associated with a poor prognosis. [Harrison’s]

PREVENTION Avoid exposure Chemoprophylaxis?

Antibiotic Prophylaxis for Leptospirosis  The most effective preventive measure is avoidance of high-risk exposure  Pre-exposure antibiotic prophylaxis is NOT ROUTINELY RECOMMENDED  Recommended regimen for pre-exposure prophylaxis for non-pregnant, non-lactating adults: o Doxycycline 200mg once weekly (to begin 1 to 2 days before exposure and continued throughout the period of exposure [Grade B]) Recommended Post-Exposure Prophylaxis for Leptospirosis

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KEY CONCEPTS “Tropical” infectious diseases usually occur, but not exclusively, in developing countries with warmer climates Formulate a diagnosis of microbial infection based on clinical and epidemiologic evidence, supported by laboratory examinations Inexpensive and effective medications are available to treat most “tropical” infectious diseases Cost, as well as antimicrobial resistance, can become a barrier to effective treatment Adequate supportive measures are necessary, to prevent complications and mortality o Host factors, including the severity of the illness and co-morbid conditions, as well as the intervention-related factors, are important to consider in the overall management Many “tropical” infections are preventable by means of simple, inexpensive, and currently available methods

Algorithm for the MANAGEMENT OF OLIGURIA IN LEPTOSPIROSIS

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Getting Sick in the Tropics Dra. Rosario

Ang, Angulo, Añover; Edited by Añover

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