Sex Bias in Infectious Disease Epidemiology: Patterns and Processes

Abstract

BackgroundInfectious disease incidence is often male-biased. Two main hypotheses have been proposed to explain this observation. The physiological hypothesis (PH) emphasizes differences in sex hormones and genetic architecture, while the behavioral hypothesis (BH) stresses gender-related differences in exposure. Surprisingly, the population-level predictions of these hypotheses are yet to be thoroughly tested in humans.Methods and FindingsFor ten major pathogens, we tested PH and BH predictions about incidence and exposure-prevalence patterns. Compulsory-notification records (Brazil, 2006–2009) were used to estimate age-stratified ♂:♀ incidence rate ratios for the general population and across selected sociological contrasts. Exposure-prevalence odds ratios were derived from 82 published surveys. We estimated summary effect-size measures using random-effects models; our analyses encompass ∼0.5 million cases of disease or exposure. We found that, after puberty, disease incidence is male-biased in cutaneous and visceral leishmaniasis, schistosomiasis, pulmonary tuberculosis, leptospirosis, meningococcal meningitis, and hepatitis A. Severe dengue is female-biased, and no clear pattern is evident for typhoid fever. In leprosy, milder tuberculoid forms are female-biased, whereas more severe lepromatous forms are male-biased. For most diseases, male bias emerges also during infancy, when behavior is unbiased but sex steroid levels transiently rise. Behavioral factors likely modulate male–female differences in some diseases (the leishmaniases, tuberculosis, leptospirosis, or schistosomiasis) and age classes; however, average exposure-prevalence is significantly sex-biased only for Schistosoma and Leptospira.ConclusionsOur results closely match some key PH predictions and contradict some crucial BH predictions, suggesting that gender-specific behavior plays an overall secondary role in generating sex bias. Physiological differences, including the crosstalk between sex hormones and immune effectors, thus emerge as the main candidate drivers of gender differences in infectious disease susceptibility.

Changes in the epidemiology of visceral leishmaniasis in Brazil from 2001 to 2014

“…The frequency of this disease in men increased with age ( Table 2). Physiological factors are the most likely cause for the increased risk in males, indicating that from a certain age, sex hormones and the immune system in men result in a higher susceptibility to infection and disease 41 .…”

Sex, the aging immune system, and chronic disease

“…Gender-specific behaviors do not appear to influence infection risk across the board, as a recent study found that most exposure-prevalence indices are sex-unbiased [64]. However, gender-related behavior in diseases in which the behaviors are expected to affect exposure (e.g., agricultural workers being more exposed to schistosomiasis, leptospirosis, the leishmaniases) or result in contrasting risk factors for disease progression (e.g., smoking or alcohol use for tuberculosis among older adults) do demonstrate sex-biases in exposure-prevalence indices [64]. Future studies addressing sex-differences in aging-related immunodeficiency must pay attention to these potential contributing factors as well.…”

Tuberculosis Vaccines and Prevention of Infection

“…There are similarities with the age distribution of meningococcal disease, which has a nadir between the ages of 7 and 14 years (30), followed by an adolescent peak that may be influenced by social mixing patterns but which is also characterized by more clonal genotypes affecting adolescents. A strikingly similar prepubescent nadir in cutaneous leishmaniasis caused by several species of the protozoan parasite Leishmania may support an immunological etiology (31). Human resistance to cutaneous leishmaniasis is dependent on Th1 responses (32).…”