Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: An eco-epidemiological community-based cohort study in Brazil

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    Evaluation Summary:

    Leptospirosis is an important zoonotic disease with a major global health impact. Although the role of rats as hosts is well known, it is less clear how important the fine-scale local and simultaneous presence of infected rats is relative to contact with water that could have been contaminated by rats elsewhere, or some time in the past. This study leverages a fine-scaled spatial dataset on human infection data and rat abundance to address this question, using a carefully developed statistical model that incorporates key variables and takes into account spatial variation. The models show that 'rattiness', a proxy for local rat abundance, might be an important driver of human infection risk, suggesting that rodent control measures might be an avenue for lowering the risk of infection with Leptospira bacteria.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Abstract

Zoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira , the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems.

Methods:

We conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of ‘rattiness’, our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk.

Results:

The estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95% CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95% CI 1.05, 1.53).

Conclusions:

These findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention.

Funding:

This work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB/JCB0020/2016). MTE was supported by a Medical Research UK doctorate studentship. FBS participated in this study under a FAPESB doctorate scholarship.

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  1. Author Response

    Reviewer #1 (Public Review):

    In their manuscript, these authors present a novel geostatistical framework for modelling the complex animal-environment-human interaction underlying Leptospira infections in a marginalised urban setting in Salvador, Brazil.

    In their work, the authors combine human infection data and the rattiness framework of Eyre et al. (Journal of the Royal Society Interface, 2020) . They use seroconversion defined as an MAT titer increase from negative to over 1:50 or a four-fold increase in titer for either serovar between paired samples from cohort subjects. Whereas this is a commonly used measure of infection; the work would benefit from answering the question about how robust results are related to this definition of seroconversion.

    Thank you for your comment. We have acknowledged this on line …

  2. Evaluation Summary:

    Leptospirosis is an important zoonotic disease with a major global health impact. Although the role of rats as hosts is well known, it is less clear how important the fine-scale local and simultaneous presence of infected rats is relative to contact with water that could have been contaminated by rats elsewhere, or some time in the past. This study leverages a fine-scaled spatial dataset on human infection data and rat abundance to address this question, using a carefully developed statistical model that incorporates key variables and takes into account spatial variation. The models show that 'rattiness', a proxy for local rat abundance, might be an important driver of human infection risk, suggesting that rodent control measures might be an avenue for lowering the risk of infection with Leptospira bacteria.

    (This …

  3. Reviewer #1 (Public Review):

    In their manuscript, these authors present a novel geostatistical framework for modelling the complex animal-environment-human interaction underlying Leptospira infections in a marginalised urban setting in Salvador, Brazil.

    In their work, the authors combine human infection data and the rattiness framework of Eyre et al. (Journal of the Royal Society Interface, 2020) . They use seroconversion defined as an MAT titer increase from negative to over 1:50 or a four-fold increase in titer for either serovar between paired samples from cohort subjects. Whereas this is a commonly used measure of infection; the work would benefit from answering the question about how robust results are related to this definition of seroconversion.

    The model framework relies on the concept of 'rattiness' previously defined by Eyre …

  4. Reviewer #2 (Public Review):

    Eyre et al. developed and applied a novel geostatistical framework for joint spatial modeling of multiple indices of pathogen (Leptospira) reservoir (rats) abundance and human infection risk. This framework enabled evaluation of infection risk at a fine spatial scale and accounted for uncertainty in the pathogen reservoir abundance estimates. The authors used data collected in two different field projects: (1) a rat ecology study in which three different approaches were used to detect rat presence "rattiness", and (2) a prospective community cohort study in which individuals were sampled during two different time periods to detect recent infections via seroconversion or a four-fold increase in anti-Leptospira antibody MAT titer. Univariable and then multivariable analyses were performed on these data to …

  5. Reviewer #3 (Public Review):

    The goal of the authors was to test how important local rat abundance is as a driver of Leptospira infection in humans. The authors approached this using a strong combination of datasets on human infection risk and rat abundance, across a spatial scale that is large enough to allow simultaneous assessment of multiple potentially important drivers of infection risk. This further enables the authors to develop infection prediction maps based on the fitted models.

    This study design is a major advance towards understanding link between rat abundance and human infection risk.

    Based on the top models tested in the study, the authors conclude that local rat abundance is indeed correlated with infection risk, and that this correlation is strongest at higher elevation.

    This is an impactful finding, but in my opinion …