Leptospirosis

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Collaborative Course on Infectious
Diseases January 2009
LECTURE 45 Leptospirosis Albert Icksang Ko,
MD aik2001_at_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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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

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Field Investigation, Minas Gerais, 1908
Identification of Chagas Disease
Fiocruz, Rio de Janeiro
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Demographic Changes in Brazil, 1940-2000
Urban
Rural
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Income Distribution and Inequitable Growth,
Brazil, 1970-1998
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One billion individuals, representing 32 of the
worlds 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 worlds urban slum population will double
to 2 billion in the next 25 years.
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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

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Agent

• Spirochete
• genus Leptospira
• 8 species
• gt200 serovars
• 6-20 µm x 0.1 µm
• Highly motile
• Periplasmic flagella
• Survives in environment weeks to months

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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)

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Scanning electron microscopy of a renal tubule
from an experimentally infected rat
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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
• Weills disease (jaundice, renal failure,
  bleeding)
• Pulmonary hemorrhage syndrome
• Case fatality rate is 5-40
• gt50 for pulmonary hemorrhage syndrome
• Major cause of hemorrhagic fever

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Leptospirosis, Dengue and Hantavirus
Infections Worldwide (2002)
Source Rudy Hartskeerl, WHO Collaborative
Laboratory Royal Tropical Institute
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Global Burden and Epidemiology of Leptospirosis

• 500,000 reported cases each year (WHO. Weekly
  Epid Rec. 199974237-242)
• 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

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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)

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Pau da Lima Cohort Site, Salvador, Brazil
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Annual Epidemics of Severe Leptospirosis Populati
on-Based Surveillance in Salvador, Brazil,
1996-2006 (N2,336)
1996 1997 1998 1999 2000 2001 200
2 2003 2004 2005 2006
No. Cases
Rainfall (mm)
Month of Hospitalization
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GIS Mapping of Leptospirosis Cases (N1,753),
1996-2006
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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 US25.44

Weils Disease
Pulmonary Haemorrhage Syndrome
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• 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
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Climate Environment Socioeconomic factors
Exposures that influence the inoculum
dose -Environmental, vector or reservoir Virulenc
e characteristics of the strain Host
susceptibility factors acquired or innate
Infection and disease progression
Outcomes and social and economic consequences
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Leptospirosis and Global Climate Change
BMJ 2005331337
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Temporal Association between Climate and Severe
Leptospirosis
A. Temporal patterns
B. Effect of climate on case counts
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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
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Climate Environment Socioeconomic factors
Exposures that influence the inoculum
dose -Environmental, vector or reservoir Virulenc
e characteristics of the strain Host
susceptibility factors acquired or innate
Infection and disease progression
Outcomes and social and economic consequences
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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
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Case Control Investigations Peri-Domicilary
Transmission of Urban Leptospirosis

• Case-control investigation (2000)

Am J Trop Med Hyg 200165657

• Household contact study (2001) PLoS Neglected
  Trop Dis 20082e154
• 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.

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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 1999354820 Am J Trop Med Hyg
200165657 Am J Trop Med Hyg 200265605
Emerg Infect Dis 200814505 PLoS Neglected
Trop Dis 20082e154 and e228
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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.
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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

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• 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.

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Pathogenic Leptospira in Environmental Surface
Waters in Slum and Rural Communities, Iquitos,
Peru
Ganoza, PLoS Med, 2006
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Distribution of Severe Leptospirosis Cases
(N36) at the Pau da Lima site, 1996-2004
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1959
1976
2002
1989
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Pau da Lima Cohort StudyMethods

• Census in 2003
• 14,122 inhabitants
• 57.8 severe cases per 100,000 pop.
• Cohort population
• 9,862 subjects
• Residents gt5 years of age
• Informed consent
• Exposure measurements
• Interviews on demographics and exposures
• Inspection of household environment
• GIS surveys for environmental sources

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Infection density
Topograpy
Refuse deposits
Open sewers
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Pau da Lima Cohort Study Design and Outcome
Measurements

• Baseline seroprevalence survey
• Sample of 3,163 cohort subjects
• Agglutination titer 125
• 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

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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

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Age and Gender-Specific Attack Rates for
Leptospirosis
Infection rate
Severe disease incidence
Mortality incidence
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Prospective Evaluation of Risk Factors for
Leptospira Infection
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Prospective Study on Urban Leptospirosis Summary

• Disease burden is significantly higher than
  believed.
• Severe disease-to-infection ratio 1152
• 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.

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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

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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.

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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 200165657)
• 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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Need for Rapid Diagnostics for Leptospirosis

• Current serologic tests have
• lt30-50 sensitivity during the
• 1st week of illness
• Lig proteins are immunodominant antigens (J Clin
  Microbiol 2007451528)
• Sensitivity and specificity gt90-95
• Improved sensitivity (80) during the 1st week of
  illness.
• Fiocruz-Cornell is developing a Lig-based lateral
  flow assay
• Point-of-care diagnosis
• Clinical evaluation in 2009

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Control of Rodent Sources of Transmission

• Reduce reservoir density
• Pesticides
• Deny access to human living environment
• Deny access to food and water
• Remove food sources and ecological habitats
• Limitations
• Pesticides are costly.
• Rodent control can not be accomplished by
  chemical interventions alone (recrudescence,
  pesticide resistance).

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Use of GIS for Risk Stratification and Targeting
Interventions
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Prevent Exposures to Transmission Sources

• Disinfecting areas of contaminated environment
  (hypochlorite)
• Protective clothing (boots, gloves)
• Cleaning wounds after exposure
• Prevention of contact with ill or dead animals
• Health education on risk exposures
• Remove transmission sources

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What good does it do to treat people's illnesses
...
then send them back to the conditions that made
them sick?
Michael Marmot, Commission of Social Determinants
of Health, WHO
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Implementation of Sewerage Network (Bahia Azul),
Salvador, Brazil
Pau da Lima
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Sewerage coverage increased from 26 to 80
between 1997 and 2003 due to Bahia Azul
Program Decrease in diarrhoea prevalence from
92 (9095) to 73 (7075) days per
child-year. Overall prevalence reduction of 22
(1926), After adjustment for baseline sewerage
coverage and potential confounding variables
Barreto M Lancet 2007.
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Temporal Trends in Leptospirosis Morbidity and
Mortality in Salvador, Brazil, 1996-2007
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Implementation of Closed Sewage System in Pau da
Lima Success of Community-Driven Initiatives for
Prevention
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One billion individuals, representing 32 of the
worlds 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 worlds urban slum population will double
to 2 billion in the next 25 years.
62
References

• Bharti AR, Nally JE, Ricaldi JN, et al.
  Leptospirosis a zoonotic disease of global
  importance. Lancet Infect Dis 20033757-71
• Ko AI, Reis MG, Dourado CR et al. Urban epidemic
  of severe Leptospirosis in Brazil. Salvador
  Leptospirosis Study Group. Lancet
  1999354820-825.
• Sarkar U, Nascimento SF, Barbosa R, et al. A
  population-based case-control investigation of
  risk factors for leptospirosis during an urban
  epidemic. Am J Trop Med Pub Hyg
  200266(5)605-10.
• Ganoza CA. Determining risk for severe
  leptospirosis by molecular analysis of
  environmental surface waters for pathogenic
  Leptospira. PLoS Medicine 200631329-1340
• Reis RB, Ribeiro GS, Felzemburgh RDM, et al.
  Impact of environment and social gradient of
  Leptospira infection in urban slums. PLoS
  Neglected Trop Dis 20082(4)e228.
• Barreto M, Genser B, Strina A, Teixeira MG and
  Assis AM. Effect of city-wide sanitation
  programme on reduction in rate of childhood
  diarrhoea in northeast Brazil assessment by two
  cohort studies. Lancet 2007 3701622-1628
• Riley LW, Ko AI, Unger A, Reis MG. Slum health
  Diseases of neglected populations. BMC Intl
  Health Human Rights. 200772.

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Questions

• Should additional resources be allocated to the
  prevention of leptospirosis and other neglected
  diseases given competing disease priorities? How
  would you decide?
• What approaches can be used to focus
  interventions given limited resources?
• Why do adult men have higher risk for developing
  severe leptospirosis?
• How can risky behaviours in this group be
  addressed effectively? If so, what further
  information do we need?
• Can rodent control strategies be feasibly
  implemented in urban slum environments?
• Is improved sanitation a cost-effective health
  intervention?