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

Background: Tuberculosis (TB) killed 1·25 million people globally in 2023. Men have a 1·7-fold higher TB incidence than women, but it is not known to what extent this discrepancy is driven by greater exposure to Mycobacterium tuberculosis (Mtb). We performed a systematic review and meta-analysis of population-based Mtb immunoreactivity surveys, to analyse the effect of age and sex on Mtb immunoreactivity. Methods: We systematically reviewed the literature for population-based Mtb immunoreactivity (interferon-gamma release assay or skin test) surveys, performed in high TB incidence settings, from 1993 to 2022. We extracted data on Mtb immunoreactivity prevalence, disaggregated by sex and age group. We constructed Bayesian hierarchical models, firstly of immunoreactivity prevalence by age and sex, and secondly of the male-to-female prevalence ratio by age. We analysed the impact of covariables including region, TB incidence and study year. Results: We screened 26,517 studies and included 81 surveys, from 38 different countries, comprising data from 478,968 participants. We found little sex difference in Mtb immunoreactivity in childhood; however, from adolescence onwards, men experienced higher Mtb exposure than women (1·4-times higher Mtb exposure by age 30). This cumulative exposure drove a higher immunoreactivity prevalence in men, with a male-to-female prevalence ratio which peaked at 1·3 at age 53. Adult men had consistently higher Mtb prevalence across different settings. Discussion: Men experience significantly more intense exposure to Mtb than women, which is likely to be a key driver of the sex differences in global TB morbidity and mortality. This may be due to social and behavioural differences in time spent in congregate indoor spaces where TB transmission occurs, further amplified by longer duration of infectiousness in men, and age- and sex-assortative mixing. Public health interventions addressing men’s determinants of Mtb exposure will be critical to ending the TB epidemic.