Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis is a life-threatening disease and recognized as an important cause of pulmonary haemorrhage syndrome, the lack of global estimates for morbidity and mortality has contributed to its neglected disease status. We conducted a systematic review of published morbidity and mortality studies and databases to extract information on disease incidence and case fatality ratios. Linear regression and Monte Carlo modelling were used to obtain age and gender-adjusted estimates of disease morbidity for countries and Global Burden of Disease (GBD) and WHO regions. We estimated mortality using models that incorporated age and gender-adjusted disease morbidity and case fatality ratios. The review identified 80 studies on disease incidence from 34 countries that met quality criteria. In certain regions, such as Africa, few quality assured studies were identified. The regression model, which incorporated country-specific variables of population structure, life expectancy at birth, distance from the equator, tropical island, and urbanization, accounted for a significant proportion (R² = 0.60) of the variation in observed disease incidence. We estimate that there were annually 1.03 million cases (95% CI 434,000–1,750,000) and 58,900 deaths (95% CI 23,800–95,900) due to leptospirosis worldwide. A large proportion of cases (48%, 95% CI 40–61%) and deaths (42%, 95% CI 34–53%) were estimated to occur in adult males with age of 20–49 years. Highest estimates of disease morbidity and mortality were observed in GBD regions of South and Southeast Asia, Oceania, Caribbean, Andean, Central, and Tropical Latin America, and East Sub-Saharan Africa. Leptospirosis is among the leading zoonotic causes of morbidity worldwide and accounts for numbers of deaths, which approach or exceed those for other causes of haemorrhagic fever. Highest morbidity and mortality were estimated to occur in resource-poor countries, which include regions where the burden of leptospirosis has been underappreciated. Leptospirosis is a zoonotic bacterial disease that affects vulnerable populations such as rural subsistence farmers and urban slum dwellers. Although leptospirosis causes life-threatening clinical manifestations, such as pulmonary hemorrhage syndrome, and has a worldwide distribution, the key barrier to addressing this neglected disease has been insufficient data on its disease burden. We searched published literature and grey literature studies on leptospirosis and using information collected on disease incidence and case fatality, estimated leptospirosis incidence and mortality at country, regional and global level. Overall leptospirosis was estimated to cause 1.03 million cases and 58,900 deaths each year. These estimates place leptospirosis as a leading zoonotic cause of morbidity and mortality. In addition, morbidity and mortality was greatest in the poorest regions of the world and in areas where surveillance is not routinely performed.

Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis can cause life-threatening disease, there is no global burden of disease estimate in terms of Disability Adjusted Life Years (DALYs) available. We utilised the results of a parallel publication that reported global estimates of morbidity and mortality due to leptospirosis. We estimated Years of Life Lost (YLLs) from age and gender stratified mortality rates. Years of Life with Disability (YLDs) were developed from a simple disease model indicating likely sequelae. DALYs were estimated from the sum of YLLs and YLDs. The study suggested that globally approximately 2·90 million DALYs are lost per annum (UIs 1·25–4·54 million) from the approximately annual 1·03 million cases reported previously. Males are predominantly affected with an estimated 2·33 million DALYs (UIs 0·98–3·69) or approximately 80% of the total burden. For comparison, this is over 70% of the global burden of cholera estimated by GBD 2010. Tropical regions of South and South-east Asia, Western Pacific, Central and South America, and Africa had the highest estimated leptospirosis disease burden. Leptospirosis imparts a significant health burden worldwide, which approach or exceed those encountered for a number of other zoonotic and neglected tropical diseases. The study findings indicate that highest burden estimates occur in resource-poor tropical countries, which include regions of Africa where the burden of leptospirosis has been under-appreciated and possibly misallocated to other febrile illnesses such as malaria. Leptospirosis is a zoonotic bacterial disease that affects vulnerable populations such as rural subsistence farmers and urban slum dwellers. Although leptospirosis can cause life-threatening clinical manifestations such as pulmonary hemorrhage syndrome and has a worldwide distribution, to date, the global burden of leptospirosis has not been estimated. The estimated 1.03 million cases annually result in a total of approximately 2.90 million Disability Adjusted Life Years. For comparison, this is over 70% of the global burden of cholera. Most of this burden of leptospirosis is the result of premature death and is suffered disproportionately by young adult males in resource-poor tropical countries. These estimates place leptospirosis as a leading cause of disease burden amongst zoonotic agents.

Zika dynamics in South America: The infection dynamics of Zika virus (ZIKV) are difficult to characterize. Many ZIKV infections are asymptomatic, and the clinical presentation of ZIKV is nonspecific. Rodriguez-Barraqueret al.took advantage of a long-term health study under way in Salvador, Brazil, the epicenter of the recent outbreak in the Americas. They used multiple serological assays, from before and after the emergence of ZIKV in October 2015, to distinguish ZIKV immune responses from those against Dengue virus (DENV). About 73% of the population was attacked by ZIKV. The presence of preexisting antibodies to DENV was associated with less risk of ZIKV infection and fewer symptoms.Science, this issue p.607

Rat-borne leptospirosis is an emerging zoonotic disease in urban slum settlements for which there are no adequate control measures. The challenge in elucidating risk factors and informing approaches for prevention is the complex and heterogeneous environment within slums, which vary at fine spatial scales and influence transmission of the bacterial agent. We performed a prospective study of 2,003 slum residents in the city of Salvador, Brazil during a four-year period (2003–2007) and used a spatiotemporal modelling approach to delineate the dynamics of leptospiral transmission. Household interviews and Geographical Information System surveys were performed annually to evaluate risk exposures and environmental transmission sources. We completed annual serosurveys to ascertain leptospiral infection based on serological evidence. Among the 1,730 (86%) individuals who completed at least one year of follow-up, the infection rate was 35.4 (95% CI, 30.7–40.6) per 1,000 annual follow-up events. Male gender, illiteracy, and age were independently associated with infection risk. Environmental risk factors included rat infestation (OR 1.46, 95% CI, 1.00–2.16), contact with mud (OR 1.57, 95% CI 1.17–2.17) and lower household elevation (OR 0.92 per 10m increase in elevation, 95% CI 0.82–1.04). The spatial distribution of infection risk was highly heterogeneous and varied across small scales. Fixed effects in the spatiotemporal model accounted for the majority of the spatial variation in risk, but there was a significant residual component that was best explained by the spatial random effect. Although infection risk varied between years, the spatial distribution of risk associated with fixed and random effects did not vary temporally. Specific “hot-spots” consistently had higher transmission risk during study years. The risk for leptospiral infection in urban slums is determined in large part by structural features, both social and environmental. Our findings indicate that topographic factors such as household elevation and inadequate drainage increase risk by promoting contact with mud and suggest that the soil-water interface serves as the environmental reservoir for spillover transmission. The use of a spatiotemporal approach allowed the identification of geographic outliers with unexplained risk patterns. This approach, in addition to guiding targeted community-based interventions and identifying new hypotheses, may have general applicability towards addressing environmentally-transmitted diseases that have emerged in complex urban slum settings. Leptospirosis is a rat-borne infectious disease that occurs worldwide, predominantly among vulnerable populations, such as urban slum communities with poor sanitation infrastructure. However, urban slums are complex local settings, where transmission of the disease varies over space and time, and the factors that influence this risk difference are unknown. An improved understanding of the environmental and social factors that modify the risk of this infection is needed in order to guide interventions to reduce the disease burden. We recruited a cohort of 2003 community residents of a high- risk urban slum in Salvador, Brazil. We followed them for a four-year period to understand yearly variation in individual and spatial risk factors for infection using spatiotemporal statistical modeling techniques. Our findings suggest that environmental factors related to topology such as household elevation and inadequate sewage drainage systems increase the risk of transmission in the slum microenvironment by promoting contact with mud contaminated with the pathogenic leptospiral bacteria, and that individual characteristics such as age and gender increase risk through behaviors that lead to increased exposures to a contaminated environment. Through this technique, we also identified local geographic areas where the risks are not well explained by these factors. This will help generate new hypotheses and identify intervention strategies for targeted prevention of leptospirosis in urban slum populations.

Leptospirosis has emerged as an urban health problem as slum settlements have rapidly spread worldwide and created conditions for rat-borne transmission. Prospective studies have not been performed to determine the disease burden, identify risk factors for infection and provide information needed to guide interventions in these marginalized communities. We enrolled and followed a cohort of 2,003 residents from a slum community in the city of Salvador, Brazil. Baseline and one-year serosurveys were performed to identify primary and secondary Leptospira infections, defined as respectively, seroconversion and four-fold rise in microscopic agglutination titers. We used multinomial logistic regression models to evaluate risk exposures for acquiring primary and secondary infection. A total of 51 Leptospira infections were identified among 1,585 (79%) participants who completed the one-year follow-up protocol. The crude infection rate was 37.8 per 1,000 person-years. The secondary infection rate was 2.3 times higher than that of primary infection rate (71.7 and 31.1 infections per 1,000 person-years, respectively). Male gender (OR 2.88; 95% CI 1.40–5.91) and lower per capita household income (OR 0.54; 95% CI, 0.30–0.98 for an increase of $1 per person per day) were independent risk factors for primary infection. In contrast, the 15–34 year age group (OR 10.82, 95% CI 1.38–85.08), and proximity of residence to an open sewer (OR 0.95; 0.91–0.99 for an increase of 1 m distance) were significant risk factors for secondary infection. This study found that slum residents had high risk (>3% per year) for acquiring a Leptospira infection. Re-infection is a frequent event and occurs in regions of slum settlements that are in proximity to open sewers. Effective prevention of leptospirosis will therefore require interventions that address the infrastructure deficiencies that contribute to repeated exposures among slum inhabitants. Leptospirosis is a disease that is transmitted by human contact with an environment contaminated with urine from animals, such as rodents, infected by the Leptospira bacteria. Human illness due to these bacteria can be mild, or can have very severe complications. Residents of urban slum settlements are at high risk for this disease, but the specific risk factors for transmission in these settlements are not understood because of the lack of prospective studies in this epidemiological setting. We performed a prospective study in a Brazilian slum community to measure the risk of infection, identify the environmental and social factors that place slum residents at risk for infection, and determine whether some individuals are at risk of repeated infections. We identified a burden of infection with leptospirosis among slum residents, and found that male gender and low income both increase the risk for infection. In addition, a significant proportion of slum residents had a second exposure to leptospirosis and re-infection occurred most frequently among young adults and the poorest members of the slum community who reside in proximity of open sewers. These risk factors are amenable to interventions aimed to reduce the burden that leptospirosis imparts in this high-risk setting.

The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-α were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P = 0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P = 0.0519) among fatal cases who developed SPHS than among who did not. This study shows that severe cases of leptospirosis are differentiated from mild disease by a “cytokine storm” process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis. Leptospirosis is a tropical bacterial disease that is transmitted to humans from infected animals. Leptospirosis symptoms can range from mild fever to fatal disease forms, such as massive bleeding into the lungs, called Severe Pulmonary Hemorrhage Syndrome (SPHS). It is not known what determines the severity of leptospirosis, but we hypothesized that it may be influenced by differences in the type and concentration of signaling proteins called cytokines that are produced by the immune system in response to infection. We collected blood from patients with mild and severe leptospirosis, and compared the concentration of eight different cytokines circulating in the blood. We found that patients with severe leptospirosis had higher levels of most cytokines. Among patients who had severe forms, higher levels of specific cytokines called IL-6 and IL-8 were predictive of death even after statistical adjustment for age and number of days of symptoms prior to hospitalization. IL-6 was higher in patients who died from SPHS compared to those who died of other leptospirosis complications. This knowledge suggests that severe forms of leptospirosis may be due to a specific kind of immune response, which may lead to targeted therapies to reduce the impact of this disease.