Studies and interventions in animals: Ecoepidemiology of leptospirosis in urban slums International Workshop of the /FIOCRUZ 5 th GLEAN Meeting November 10, 2015, Rio de Janeiro F Costa, E Wunder, DS Olveira, G Ghizzi, A Panti, T Carvalho, I Menezes, G Sacramento, S Serrano, A Pertile, A Minter, MGM Rodrigues; MG Reis, PJ Diggle, M Begon, JE Childs and AI Ko. Oswaldo Cruz Foundation, Brazil; Institute of Collective Health, Brazil; Zoonosis Control Center, Brazil; Department of Epidemiology of Microbial Diseases, Yale School of Public Health; University of Liverpool, UK. 1
Urban leptospirosis No. of monthly cases 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Monthly rainfall (mm) Epidemiological pattern Annual seasonal epidemics Same communities each year Single serovar, Copenhageni Domestic rat reservoir 90 80 70 60 50 40 30 20 10 0 No. cases Monthly rainfall (mm) 600 500 400 300 200 100 0 conditions of poverty and climate throughout the developing world. Case fatality rate >6% Pulmonary hemorrhage Month of Hospitalization No effective control or preventive measures Lancet 1999;354:820; Am J Trop Med Hyg 2001;65:657; Am J Trop Med Hyg 2002;65:605; Emerg Infect Dis 2008;14:505; PLoS Neglected Trop Dis 2008;2:e154 and e228 2
Estrategies to control leptospirosis GT Leptospirosis (Salvador, 2007) Education and Training Surveillance Risk stratification Rodent Control Program Surveilance and risk stratification Active hospital based surveillance and laboratory diagnostic Geocodification of leptospirosis cases Identification of 11 areas of higher risk (~15% city area)
Rodent Control Progam Metodology of rodent control in slum areas: Intervention: chemical, educational and environmental. Impact on the level of rodent infestation! ~25% <7% (2009, 2010, 2012, 2013, 2014, 2015). Impact on human leptospirosis? Comparation of treated vs non-treated areas No evidence of reduction on the incidence of leptospirosis
Major knowledge gaps? Ecology Maintenance Shedding? Dynamics? Infection 5
Ecoepidemiology of leptospirosis in the urban slums of Brazil (2013-2016) Determine how dynamics of the pathogen in host and environmental reservoirs influence human disease. Figure: Leptospiral life cycle in slum environment and project overview Rat population dynamics Intra-specific transmission Leptospire shedding Leptospiral abundance in environment Human infection Predict GLEAN Prevent
Pau da Lima Cohort Study Leptospirosis Cases (N=1,753), 1996-2006 Prospective study since 2003 From 2013 2421 subjects in 0.18km 2 area Seasonal serosurveys Active outpatient and hospital-based surveillance House visits, interviews, GIS surveys Pau da Lima Field Site
Approach pegadas Trapping sessions (2013-2014) 3 rain and 3 wet season over 2 years 152 households Tracking board and infestation surveys in >400 sites Analyses Rodent demographics Pathogen carriage and load in urine qpcr Lipl32 Necropsies to identify mode of transmission Genetic studies to evaluate migration Modeling Key output: spatiotemporal estimates of leptospire shedding 8
Flow diagram of the dynamic of infection and shedding in rodents Birth VT and pseudo VT (breastfeeding) β β SUSCEPTIBLES HT sexual ν 2 v 1 ν 4 INFECTED ν 3 HT environmental m m Deaths Production w L Leptospires in the environment Deaths 9
Results: Demographic characteristics Demography (n=793) Rainy (n=459) Dry (n=334) Male (%) 50.8 50.0 Reproductive rats (%) 83.8 81.3 Pregnant females (%) 50.4 50.5 Rate of offspring per day 0.26 0.28 Abundance 38 (24-52) 30 (25-40) Demography (n=793) Valley 1 (n=151) Valley 2 (n=214) Valley 3 (n=428) Male (%) 52 48 51 Sub adults & adults (%) 71 71 62 Pregnant females (%) 40 48 58 Rate of offspring per day 0.20 0.28 0.28 Abundance 25 (18-32) 33 (28-42) 46 (31-61) According to Emlen and Davis (1948); Adapted from Borchers et al (2002) Porter et al (2015). J. of Mammalogy 10
Estimating abundance Trapping Tracking boards pegadas 11
Kajacdsi et al 2013. Mol. Ecol Population genetics Site: 3 neighborhoods (9 sites) Data collection 147 rats Microsatellite analysis Genetic structure: 3 clusters ~400m Migration: 7% (joung ) Implications: Eradication units
log Leptospira GE/mL in urine Leptospira carriage and load Carriage (n=462) 80.1% (95% CI: 76.2 83.6%) 10 9 8 7 6 5 4 3 y = 0.95x + 0.34 R² = 0.8 n=45 Kappa=1 Load in rat urine (n=462) Mean log Geq per ml 9.1x10 4 (IQ= 1.3x10 3-3.4x10 6 ) 2 1 0 5 Costa et al, 2015. PLoS NTD 9(6): e 0 1 2 3 4 5 6 7 8 9 10 log Leptospira GE/mL in kidney Multivariate linear regression model to predict Leptospira load in urine Category β 95% CI p value Season Dry Ref. Rainy 0.53 0.07 0.99 0.02 Valley 1 2 3 Ref. -0.59-0.74-1.17-0.007 0.048-1.30-0.18 0.02 Length (continuous) 0.01 0.01 0.02 < 0.001
Identifying modes of transmission Leptospires in rat tissues Breast Milk Semen Testicles Uterine horns Fetuses Breast 30% Breast Modeling Sensitivity analysis Component Mean (Min, Max) Vertical transmission 0.125 (0,0.25) Milk Sexual transmission 0.361 (0,1.4) Environmental transmission 3.167 (0,84.9) 14
Started an environmental intervention to improve sanitation in one valley But when And in parallel.. Started to model the impact of potential interventions based in rat data Parametrizing a model on the environmental dynamics of leptospires Evaluating Leptospira infection in a cohort of 2421 residents in the same area/period The Pau da Lima study site was included in city program for rodent control
Evaluating interventions in Pau da Lima Time Pre-intervention 2013- April 2015 Intervention May- August 2015 Post-intervention Sep 2015- April 2016 Rats: Demographic Rat activity (TB) Pop. genetics Rats: Rodenticide Rats: Demographic Rat activity (TB) Pop. genetics Environment: Leptospira cc in sewer water Human risk Asymptomatic infection Environment: Sewer improvement Environment: Leptospira cc in sewer water Human risk Asymptomatic infection
Conclusions Importance of multidisciplinary prevention approaches Critical to develop models but also to generate parameters Rat population structure, abundance and Leptospira load varied in space. Lack of temporal differences in rat-specific factors but higher shedding was associated to rainy period. These Influence Leptospira shedding, environmental contamination and potentially human risk. Dynamics of the pathogen in the environment and human behavioral exposures may play a important role in the timing of seasonal epidemics in slum settlements.
Aknowledments Oswaldo Cruz Foundation Mitermayer Reis Guilherme Ribeiro Jose Hagan Claudio Ferreira Pinto Ana Amlia Nunes Érica Sousa Yale University Albert Ko James Child Kate Hacker Elsio Wunder Janet Lindow MS Simone, Fernanda and Eduardo Zoonosis Control Center Maria GM Rodrigues Isabel Guimarães Lucineide, Sheila, Lucinano, Ivã Liverpool University Peter Diggle Michael Begon Amanda Minter Fuding Carl Storm International Diversity Fellowship NIH- R01 TW009504 Wellcome Trust -102330/Z/13/Z CAPES (BR) Brazilian Ministry of Health (BR) GLEAN 18
Obrigado!!