Sex differences in the risk of Mycobacterium tuberculosis infection: a systematic review and meta-analysis of population-based immunoreactivity surveys

<h4>Background</h4>Tuberculosis killed 1·25 million people globally in 2023. Men have a 1·7 times higher tuberculosis incidence than women, but it is not known to what extent this discrepancy is driven by greater exposure to Mycobacterium tuberculosis. We aimed to analyse the effect of age and sex on M tuberculosis immunoreactivity.<h4>Methods</h4>In this systematic review and meta-analysis, we reviewed Embase, Global Health databases, Science Citation Index Expanded, and Global Index Medicus for population-based M tuberculosis immunoreactivity (with interferon-γ release assay or skin test) surveys done in high tuberculosis incidence settings from Jan 1, 1993, to Dec 31, 2022, with a sample size of at least 150 people. We included cross-sectional surveys, baseline surveys for interventional or cohort studies, and control groups of case-control studies with population-representative groups. We extracted data on M tuberculosis immunoreactivity prevalence, disaggregated by sex and age group. We constructed Bayesian hierarchical models, first of immunoreactivity prevalence by age and sex and second of the male-to-female (M:F) prevalence ratio by age. We analysed the effect of covariables including region, tuberculosis incidence, and study year. This study was registered on PROSPERO (CRD42022360483).<h4>Findings</h4>We screened 26 517 studies, of which 167 met our inclusion criteria. Sex-disaggregated results were available from 80 studies (81 surveys), from 38 different countries, comprising data from 478 968 participants. We found little sex difference in M tuberculosis immunoreactivity in childhood (M:F prevalence ratio for children younger than 10 years was 0·95; 95% credible interval 0·90-1·01). However, from adolescence onwards, men experienced higher immunoreactivity conversion than women (1·4 times higher by age 30 years). This higher conversion rate cumulatively drove a higher immunoreactivity prevalence in men, with a prevalence ratio of 1·07 (95% credible interval 1·01-1·13) in those aged 10-19 years, 1·13 (1·06-1·20) in those aged 20-39 years, and 1·28 (1·19-1·37) for those aged 40 years and older. Adult men had consistently higher M tuberculosis prevalence across different settings, with low between-study heterogeneity in M:F prevalence ratio.<h4>Interpretation</h4>Men have higher M tuberculosis immunoreactivity risk than women, which is likely to be a key driver of the sex differences in global tuberculosis morbidity and mortality. This difference could be due to higher exposure through social and behavioural differences in time spent in congregate indoor spaces where tuberculosis transmission occurs, further amplified by longer duration of infectiousness in men, and age-assortative and sex-assortative mixing. Public health interventions addressing men's determinants of M tuberculosis exposure will be crucial to ending the tuberculosis epidemic.<h4>Funding</h4>Wellcome Trust and UK Foreign, Commonwealth & Development Office.