Leptospirosis. acute febrile illness in humans & animals. the most widespread zoonosis in the world. one of (re) emerging infectious diseases

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1 Update on Pathogenesis of Leptospirosis CENTRID Muhammad Hussein Gasem Div Infectious Disease, TropMed, and Immunology Dr. Kariadi Hospital, Diponegoro University Semarang, Indonesia Leptospirosis and Weil's syndrome: cause for concern? In October, 2010, former British Olympic rower Andy Holmes died suddenly from Weil's syndrome Fatal cases are exceptionally rare in the UK but it was particularly shocking and tragic that an extremely fit, 51-year-old sportsman could die from an infection caught from freshwater in Lincolnshire within days of exposure Leptospirosis, the underlying bacterial infection that leads to Weil's syndrome, is more common in tropical regions Leptospirosis acute febrile illness in humans & animals the most widespread zoonosis in the world one of (re) emerging infectious diseases an often overlooked disease 1

2 Leptospirosis, dengue and hantavirus infections worldwide (2002) Leptospirosis Dengue Hantavirus infection (HFRS) Total number annually Unknown Unknown Severe forms Mortality (severe forms) 5 30% 5 15% 3 10% HFRS : Hemorrhagic Fever with Renal Syndrome Leptospirosis & Hantavirus infection with hospitalization; Dengue, DHF Mortality of 40% and higher reported for a number of outbreaks and/or strains or forms of disease R. Hartskeerl (2011) Leptospirosis: under-reported disease Lack of diagnostic facilities Lack of reliable diagnostic test kits Clinically underreported due to Sub-clinical infection Difficulty in diagnosis Misdiagnosed as other febrile illness Lack of awareness of doctors/clinicians Less public awareness Clinical presentations 2 clinical syndromes Mild, anicteric leptospirosis 85-90% Flu-like or acute undifferentiated fever Most cases are misdiagnosed as other febrile illness Patient may not seek medical attention Severe, icteric leptospirosis 10-15% Weil`s disease (Weil syndrome) High mortality rate 5-40% Icterus, hemorrhage and renal failure are indicators for severity of Leptospirosis 2

3 Anicteric Leptospirosis First Stage 3-7 days (SEPTICEMIC) Clinical progression Second Stage 0 days - 1 month (IMMUNE) Icteric Leptospirosis (Weil's Syndrome) First Stage 3-7 days (SEPTICEMIC) Second Stage days (IMMUNE) Fever Important Clinical Findings Myalgia Headache Abdominal pain Vomiting Conjunctival suffusion Meningitis Uveitis Rash Jaundice Hemorrhage Renal failure Myocarditis Leptospires Present Blood Blood CSF CSF Feigin et al Urine Urine Severe leptospirosis Organ involvement / dysfunction / failure Gastro-hepatobiliary icterus is the most important parameter of leptospirosis severity hyperbilirubinemia: in all severe cases elevated liver transaminases are relatively rare and mild liver pathology: mild, with complete resolution without necrosis hematemesis, acute pancreatitis, acalculous cholecystitis etc Renal acute kidney injury, usually non-oliguric, hypokalemic form acute tubular necrosis, interstitial nephritis Ocular conjuctival suffusion, retinal hemorrhage, uveitis, optic disc oedema, retinal vasculitis Immunochemistry staining of kidney Severe leptospirosis Organ involvement / dysfunction / failure Hematologic involvement Ptechiae, echymosis, hematemesis, epistaxis, bleeding of multi-organs, thrombocytopenia, uremic platelet dysfunction, coagulation disorders, fibrinolysis, post haemorrhagic anemia CNS involvement (neuro-leptospirosis) Altered mental status, decreased consciousness (due to acidosis / uremic syndrome, intra-cerebral hemorrhage, meningoencephalitis), radiculopathy, parapharesis, stroke-like, GB syndrome etc 3

4 Cardiovascular involvement ECG abnormality is common in severe leptospirosis Cardiac arrythmias: AF, AV block, VES, LAHB etc ST-T changes, may mimic myocardial infarction Mostly without cardiac dysfunction; heart failure is rare Pathophysiology not clear: myocarditis? or inflammation of conduction system, electrolytes disturbance, coronary artetitis? Pathology on autopsy: showed as acute myocarditis and/or hemorrhage in peri-myocardium Sacramento E et al. 2002; Rajiv C et al ECG alteration may change over-time & persist until 6 month MH Gasem et al, 2005 Pancreatic involvement Pancreatic involvement is rare in patients with severe leptospirosis. In our series, pancreatic involvement is not rare. 12/52 (22%) pts showed acute pancreatitis : elevated pancreatic enzymes & pancreatic edema on USG CT scan ) High mortality rates (usually with concomitant multi-organ dysfunction) Pathological finding: hemorrhage in pancreatic tissue ) unpublished data, Dr. Kariadi Hospital 4

5 Pulmonary involvement Pulmonary hemorrhage has been increasingly reported Lepto patients with PH highest mortality rates (50-70%) Most cases are clinically unrecognized (underdiagnosis) Clinical signs vary : sudden increase of RR to impending RF ARDS, chest pain, low Hb/Ht, hemoptysis not always found Histopathology (autopsy): diffuse intra-alveolar hemorrhage with or without alveolar damage Pathogenesis is not well understood Organ dysfunction in severe Leptospirosis (n: 87) # Organ/system n (%) Renal (oliguric or non-oliguric acute kidney injury) 87 (100) Hepatic (hiperbilirubinemia / icterus) 87 (100) Hematologic (thrombocytopenia with or without coagulation disorders) 85 (98) Cardiovascular (ECG changes, heart failure, shock etc) 74 (87) Gastrontestinal ( pancreatitis, hematemesis) 16 (19) Pulmonary (pulmonary hemorrhage, ARDS) 5 (6) Opthalmologic (retinal bleeding $, uveitis) 4 (5) Cerebral (unconscious, with or without hemorrhage) 4 (5) Note: # , patients admitted to Dr Kariadi Hospital All confirmed by MAT; 18 patients by Dri-dot only Not all tested for coagulation study $ Retinal funduscopy is not routinely done Pathogenesis - Pathology Penetration through skin, conjunctiva or mucous membranes Multiplication of organisms and dissemination via the bloodstream Damage to endothelium of small blood vessels, vasculitis, and inflammatory infiltrates Haemorrhage Muscle Subcutaneous tissue Pathological changes in body organs / tissues Liver Changes are nonspecific, but if severe, may include slight centrilobular necrosis. Hypertrophy & hyperplasia of Kupffer cells. Kidney Renal Intralobular lessions biliary include stasis tubular may occur necrosis, cortical ischaemia and medullary congestion Renal changes may resemble interstitial nephritis Lungs Pulmonary congestion may accompany pulmonary haemorrhage

6 Many studies on the pathophysiologiy- pathogenesis of (severe) Leptospirosis have been done so far but still not clearly elucidated Severe Leptospirosis : Hemorrhages problem Hemorrhages is common and fatal complication in severe leptospirosis From ptechiae, echimosis, hematemesis, hemoptysis to multi-organ hemorrhages (pancreas, myocardium, lung, gaster, adrenal, cerebral, etc) confirmed by post-mortem examination (Salkade et al, JPGM,2005) Thrombocytopenia (84% of severe leptospirosis in Dr. Kariadi Hospital) Thrombocytopathy (f.i. platelet dysfunction caused by uremic syndrome) Vaculitis and endothelial injury- and activation in severe leptospirosis Coagulation and fibrinolysis disorders (Wagenaar et al TMIH 2010) Increased PAI-1 plasma levels in severe cases (Partiningrum, et al unpublished) Studies on Inflammation and gene polymorphism Injected TNF alpha in human will activates coagulation cascade through tissue factors and leads to coagulation disorders (van der Poll et al, 1990). Our studies have shown coagulation disorders in severe leptospirosis Increased TNF alpha, sst2, IL-6, IL-8, IL10 levels were found in leptospirosis patients, and associated with leptospirosis severity and mortality TNF-alpha G-308A polimorphisms is thought to play a role in leptospirosis clinical manifestation PAI-1 gene polymorphism G4/G5 is a common allele in patients with severe leptospirosis (preliminary data) 6

7 vwf(%) E-selectin (ng/ml) Cascade of Coagulation and Inflammation Crit Care Med (1): Deficiency of the ADAMTS-13, as observed in most forms of thrombotic thrombocytopenia purpura (TTP) increases the level of large VWF multimers in plasma leads to platelet aggregation and/or thrombus formation, especially in small arterioles microvascular failure MOF Normal subject Patient with TTP Moake JL. NEJM 2002; 347 (8): Severe Sepsis 250 Severe Leptospirosis controls Days Time course of plasma levels of vwf in patients with severe leptospirosis controls Days Time course of plasma levels of vwf in patients with severe leptospirosis Kayal S et al Am J Respir Crit Care Med 1998 Wagenaar JF, Gasem MH, Meijers JC, van Gorp EC,

8 On-going study in Dr Kariadi Hospital (2010-now) In-depth clinical studies and gene polymorphisms in patients with Leptospirosis in Semarang ADAMTS13 levels in severe Leptospirosis with and without apparent bleeding manifestation Severe Leptospirosis Mild Leptospirosis Severe Leptospirosis with bleeding without apparent bleeding Pangarso EP, Farhanah N, Gasem MH (manuscript in preparation) Thrombocyte, vwf antigen, and ADAMTS13 8

9 PAI-1 gene polymorphism in patients with severe Leptospirosis Frequency distribution A preliminary data of PAI-1 gene alleles in patients with leptospirosis (n=71) Alelles Severe Leptospirosis Mild Leptospirosis Total G4/G G4/G G5/G Note: PAI-1 plasma level increased significanly in patients with severe lcompared to mild leptospirosis. (Partiningrum DL, Gasem MH, Faradz SMH) Gambar RSDK Department of Microbiology Dr. Kariadi Semarang has been approved by Indonesian MoH (2012) as the National Reference Laboratory for Leptospirosis 9