Male predominance in reported Visceral Leishmaniasis cases: Nature or nurture? A comparison of population-based with health facility-reported data

Background: Bangladesh, India, and Nepal aim for the elimination of Visceral Leishmaniasis (VL), a systemic parasitic infectious disease, as a public health problem by 2020. For decades, male patients have comprised the majority of reported VL cases in this region. By comparing this reported VL sex ratio to the one observed in population-based studies conducted in the Indian subcontinent, we tested the working hypothesis that mainly socio-cultural gender differences in healthcare-seeking behavior explain this gender imbalance. Methodology/Principal findings: We compared the observed sex ratio of male versus female among all VL cases reported by the health system in Nepal and in the two most endemic states in India with that observed in population-based cohort studies in India and Nepal. Also, we assessed male sex as a potential risk factor for seroprevalence at baseline, seroconversion, and VL incidence in the same population-based data. The male/female ratio among VL cases reported by the health systems was 1.40 (95% CI 1.37–1.43). In the population cohort data, the age- and study site-adjusted male to female risk ratio was 1.27 (95% CI 1.08–1.51). Also, males had a 19% higher chance of being seropositive at baseline in the population surveys (RR 1.19; 95% CI 1.11–1.27), while we observed no significant difference in seroconversion rate between both sexes at the DAT cut-off titer defined as the primary endpoint. Conclusions/Significance: Our population-based data show that male sex is a risk factor for VL, and not only as a socio-cultural determinant. Biological sex-related differences likely play an important role in the pathogenesis of this disease. Author summary: Visceral Leishmaniasis (VL) is a parasitic disease that is lethal if not treated timely and mainly affects impoverished populations. Bangladesh, India, and Nepal have targeted the elimination of this disease as a public health problem by 2020. The majority of VL patients attending the health services are male, and this is usually attributed to unequal access to health care for men and women in this sociocultural context. We analyzed two large datasets obtained in population surveillance projects, including regular door-to-door screening for VL, in India and Nepal. Thereby we minimized any potential differences in access to health care between both sexes, as every suspect VL case occurring in the community received a full diagnostic work-up, and the research project facilitated transport to treatment centers if needed. By comparing the observed sex ratio in the health services records with those of the population surveillance records, we aimed to reach meaningful conclusions about the pathway through which male gender exerts its leverage for increasing VL risk: socio-cultural determinants blocking women from accessing care (nurture) or biological factors (nature) making men more vulnerable to VL. Because in the population-based age adjusted-data, male VL cases were significantly more frequent than female, our findings strongly suggest that in the Indian subcontinent, biological differences between men and women play a more critical role in the pathogenesis of VL than previously assumed, and the observed male predominance in VL cases in health services cannot be explained by socio-cultural factors only. Moreover, data show that above the age of 14 years, males are seropositive more often than females and are at higher risk to develop VL disease.