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LECTURE # 45 Leptospirosis Albert Icksang Ko, MD aik2001@med.cornell

Collaborative Course on Infectious Diseases January 2009. LECTURE # 45 Leptospirosis Albert Icksang Ko, MD aik2001@med.cornell.edu. Harvard School of Public Health Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz) Brazil Studies Program, DRCLAS, Harvard University.

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LECTURE # 45 Leptospirosis Albert Icksang Ko, MD aik2001@med.cornell

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  1. Collaborative Course on Infectious Diseases January 2009 LECTURE # 45 Leptospirosis Albert Icksang Ko, MD aik2001@med.cornell.edu Harvard School of Public Health Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz) Brazil Studies Program, DRCLAS, Harvard University

  2. Objectives • Describe the changing pattern of health problems which has emerged in Brazil due to rapid urbanization • Illustrate leptospirosis as an example of a slum health problem • Define factors that influence transmission and the natural history of the disease • Provide examples of study designs and methods that can be applied to field epidemiology investigations • Describe current approaches for control and prevention • Identify questions that need to be addressed in order to design effective policy and intervention

  3. Field Investigation, Minas Gerais, 1908 Identification of Chagas Disease Fiocruz, Rio de Janeiro

  4. Demographic Changes in Brazil, 1940-2000 Urban Rural

  5. Income Distribution and Inequitable Growth, Brazil, 1970-1998

  6. One billion individuals, representing 32% of the world’s urban population, live in slums. The UN Millennium Declaration pledged to achieve “significant improvement in the lives of at least 100 million slum dwellers by the year 2020.” The world’s urban slum population will double to 2 billion in the next 25 years.

  7. Examples of Diseases Whose Health Impacts Have Been Influenced by Urbanization and Urban Poverty • Hypertension, obesity • Asthma • Occupational diseases • Violence • Dengue • Visceral leishmaniasis • Tuberculosis • Bacterial meningitis • Acute rheumatic fever • Leptospirosis

  8. Agent • Spirochete • genus Leptospira • 8 species • >200 serovars • 6-20 µm x 0.1 µm • Highly motile • Periplasmic flagella • Survives in environment weeks to months

  9. Transmission and Pathogenesis of Leptospirosis • The most widespread zoonosis • Persistent colonization and shedding from renal tubules • Transmission: • Direct contact with reservoir • Indirect contact with an environment contaminated with reservoir urine • Penetrate mucous membranes and breaks in skin • Rapid dissemination and trophism to kidneys of reservoir hosts • Tissue damage in susceptible hosts (immunopathogenic or toxin mediated process)

  10. Scanning electron microscopy of a renal tubule from an experimentally infected rat

  11. Leptospirosis in Humans • Incubation period: 2-30 days, usually 5-14 days • Broad spectrum of manifestations • Acute undifferentiated fever • Dengue-like syndrome (fever, headache, myalgia) • Aseptic meningitis • Weill’s disease (jaundice, renal failure, bleeding) • Pulmonary hemorrhage syndrome • Case fatality rate is 5-40% • >50% for pulmonary hemorrhage syndrome • Major cause of hemorrhagic fever

  12. Leptospirosis, Dengue and Hantavirus Infections Worldwide (2002) Source: Rudy Hartskeerl, WHO Collaborative Laboratory Royal Tropical Institute

  13. Global Burden and Epidemiology of Leptospirosis • 500,000 reported cases each year (WHO. Weekly Epid Rec. 1999;74:237-242) • Burden underestimated due to misdiagnosis and lack of effective diagnostic tests • Traditionally, sporadic occupation-related disease • Veterinarians, abattoir workers, domestic animal herders • Rural-based subsistence farming • Wet-land farming (i.e. rice harvesting) • Dry-land farming (i.e. sugar cane) • Ubiquitous environmental exposures

  14. Leptospirosis as an Emerging Infectious Disease • Nicaragua outbreak of pulmonary hemorrhage syndrome (Trevejo Clin Infect Dis 1998) • Inner-city homeless population (Vinetz. Ann Intern Med 1996) • Disasters • Hurricane Mitch and George • Monsoons in India • Globalization and travel • EcoChallenge outbreak • Lake Springfield Triathlon Outbreak (Morgan Clin Infect Dis 2002)

  15. Pau da Lima Cohort Site, Salvador, Brazil

  16. Annual Epidemics of Severe Leptospirosis: Population-Based Surveillance in Salvador, Brazil, 1996-2006 (N=2,336) 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 No. Cases Rainfall (mm) Month of Hospitalization

  17. GIS Mapping of Leptospirosis Cases (N=1,753), 1996-2006

  18. Burden of Severe Leptospirosis in Salvador, Brazil • Annual incidence 7.8 cases per 100,000 pop. • Mean age 34.3 ±15.7 years • Male sex 81% • Case fatality 15% • ICU admission 30% • Dialysis 21% • Annual per capita health expenditure: US$25.44 Weil’s Disease Pulmonary Haemorrhage Syndrome

  19. Leptospirosis in Brazil • 12,000 annual cases • Epidemics in major cities • Case fatality rate: 10% A. Reported cases, 2000-2005 B. Kernel distribution Cases Population Pop. adjusted risk Araujo WN, SVS-MS, Brasil

  20. Climate Environment Socioeconomic factors • Exposures that influence the inoculum dose • -Environmental, vector or reservoir • Virulence characteristics of the strain • Host susceptibility factors: acquired or innate Infection and disease progression Outcomes and social and economic consequences

  21. Leptospirosis and Global Climate Change BMJ 2005;331:337

  22. Temporal Association between Climate and Severe Leptospirosis A. Temporal patterns B. Effect of climate on case counts

  23. Influence of Climactic Factors on Severe Leptospirosis: Generalized Additive Mixed Models using Bayesian Inference Modeling Temporal Effects Relative risk for weekly case counts Observed vs. Predicted Case Counts

  24. Climate Environment Socioeconomic factors • Exposures that influence the inoculum dose • -Environmental, vector or reservoir • Virulence characteristics of the strain • Host susceptibility factors: acquired or innate Infection and disease progression Outcomes and social and economic consequences

  25. A.Geographical distribution of severe leptospirosis risk in Salvador, 1996-2000 B. Association between severe leptospirosis incidence and poverty C. Distribution of leptospirosis cases and households with opens sewers

  26. Case Control Investigations: Peri-Domicilary Transmission of Urban Leptospirosis • Case-control investigation (2000): Am J Trop Med Hyg 2001;65:657 • Household contact study (2001):PLoS Neglected Trop Dis 2008;2:e154 • Prior infection: 30% (22 of 74)contacts of leptospirosis case 8% (16 of 196) neighborhood control subjects. • Index case contacts had 5.3 times (95% CI, 2.3-12.0) greater risk of having an infection.

  27. Leptospirosis as a Emerging Slum Health Problem • New epidemiological pattern • Annual rainfall-associated epidemics • Attacks the same favela communities each year • Single serovar agent, Copenhageni • Domestic rat reservoir • Household transmission • Outside of cholera, no other examples of an infectious disease for which rainfall influences annual outbreaks. • Same conditions of poverty and climate exist throughout the developing world. Lancet 1999;354:820 ; Am J Trop Med Hyg 2001;65:657 ; Am J Trop Med Hyg 2002;65:605 ; Emerg Infect Dis2008;14:505 ; PLoS Neglected Trop Dis 2008;2:e154 and e228

  28. Burden of Illness Pyramid Reported to Health Dept/MoH Lab-confirmed case Active surveillance Lab tests for organism Laboratory survey Physician survey Specimen obtained Population survey Person seeks care Person becomes ill Exposures in the general population.

  29. Rational for Leptospirosis Cohort Studies • Un-recognized burden at the community level. • Limited understanding of the natural history • Infection-to-disease ratio? • Determinants for severe outcomes after infection? • New intervention strategies need to be identified. • Chemical control of rodents is costly. • Large-scale sanitation projects have neglected slum communities. • No prospective information available

  30. Reservoir investigation, 1998 Salvador Outbreak: • 142 Rattus norvegicus captured at case households. • Leptospires were isolated from 76% of the rats. • Same serovar Copenhageni clone as isolated from patients.

  31. Pathogenic Leptospira in Environmental Surface Waters in Slum and Rural Communities, Iquitos, Peru Ganoza, PLoS Med, 2006

  32. Distribution of Severe Leptospirosis Cases (N=36) at the Pau da Lima site, 1996-2004

  33. 1959 1976 2002 1989

  34. Pau da Lima Cohort StudyMethods Census in 2003 • 14,122 inhabitants • 57.8 severe cases per 100,000 pop. Cohort population • 9,862subjects • Residents >5 years of age • Informed consent Exposure measurements: • Interviews on demographics and exposures • Inspection of household environment • GIS surveys for environmental sources

  35. Infection density Topograpy Refuse deposits Open sewers

  36. Pau da Lima Cohort Study Design and Outcome Measurements • Baseline seroprevalence survey • Sample of 3,163 cohort subjects • Agglutination titer ≥1:25 • Four-year prospective cohort study • Severe leptospirosis • Cohort of 9,862 subjects • Hospital-based surveillance • Mild infection • Sub-cohort of 2,003 subjects • Seroconversion or 4-fold titer rise • Nested case-control study • Risk factors for severe disease vs. infection

  37. Three-Year Prospective Study: Pau da Lima Cohort • Follow-up completed for 1300 (65%) subjects • High infection-to-disease ratio: • Infection rate: 3.6% infections per year • Severe disease rate: 23.7 cases per 100,000 pop. • 157 infections (95% CI, 71.1-323.9) for each case of severe leptospirosis. • Re-infection is frequent: • Primary infection: 2.7% per year • Secondary infection: 15.4% per year

  38. Age and Gender-Specific Attack Rates for Leptospirosis Infection rate Severe disease incidence Mortality incidence

  39. Prospective Evaluation of Risk Factors for Leptospira Infection

  40. Prospective Study on Urban Leptospirosis: Summary • Disease burden is significantly higher than believed. • Severe disease-to-infection ratio: 1:152 • Re-infection is a frequent phenomenon. • Defined infrastructure deficiencies in the household serve as transmission sources. • Open sewers, inadequate drainage and refuse • Social gradient of health status within populations with high levels of absolute poverty. • Influence of social determinants which may be independent of poor environment.

  41. Control and Prevention of Urban Leptospirosis • Intervention strategies: • Prevent disease and severe outcomes in the human host • Control the animal reservoir • Interupt exposure to transmission sources

  42. Preventing Disease and Severe Outcomesin the Human Host • Chemoprophylaxis: Doxycycline 100 mg bid • Immunization: • Available bacterin-based vaccines are not effective and have unacceptable rates of adverse reactions • Timely identification and treatment of leptospirosis to prevent severe disease forms. • Community education • Access to care • Early warning/rapid response (disasters) • Training HCW to recognize early-phase illness • Developing point-of-care diagnostic tests.

  43. Barriers to Timely Identification and Treatment • Presentation of early-phase leptospirosis is non-specific. • Misdiagnosis is common: • Dengue • Malaria • Scrub typhus • Misdiagnosis leads to poor outcomes (Am J Trop Med Hyg 2001;65:657): • 42% of leptospirosis cases sought care in the 1st three days of illness • Of these, 61% were diagnosed as dengue • Associated with increased ICU admission (OR, 2.7 [0.8-9.5]) and mortality (OR, 5.1 [0.8-55.0]). A Tarde, Salvador, June 1996

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