Drivers of sex differences in Mycobacterium tuberculosis immunoreactivity among adolescents and adults in Blantyre, Malawi

Background : Sex differences in Mycobacterium tuberculosis (Mtb) exposure likely contribute to sex differences in tuberculosis (TB). However, population-level age- and sex-specific patterns of Mtb exposure among adolescents and adults have not been recently characterised in Malawi. We therefore conducted a cross-sectional survey to estimate age- and sex-specific Mtb immunoreactivity prevalence in Blantyre City, Malawi, and to assess whether prevalence diverges by sex with increasing age. Methods : We used an open-access dataset of building footprints (Open Buildings) to obtain a random sample of households from 33 peri-urban neighbourhoods in Blantyre City. Adolescents and adults aged 10-40 years were recruited, participant characteristics recorded, and venous blood samples collected for measurement of Mtb immunoreactivity using the QuantiFERON-TB Gold Plus (QFT-Plus) assay. The sample size was calculated to detect male-to-female prevalence ratios of ≥1.3 across three age groups, assuming 80% power and a 5% type I error. We fitted Bayesian multilevel logistic regression models to estimate the association between age, sex, and other risk factors with Mtb immunoreactivity, and used model-based predictions to compare immunoreactivity prevalence across age-sex strata. Results : Of 2833 participants, 40.0% (1133/2833) were male, the median age was 21 years (interquartile range: 16-28 years), and 8.7% (179/2047) self-reported living with HIV. Overall, 17.8% (503/2833) participants were positive, Mtb immunoreactivity prevalence was 17.8% (95% credible interval [CrI]: 16.4-19.2%), corresponding to an annual risk of TB infection of 0.88% (95% CrI: 0.80%-0.95%). Prevalence was similar by sex among 10-19- and 30-40-year-olds. However, among 20-29-year-olds, prevalence was higher among males compared to females: 26.3% (95% CrI: 22.0%-30.8%) and 17.7% (95% CrI: 14.8%-20.8%), respectively. The annual risk of Mtb immunoreactivity conversion increased, on average, at a faster rate among males compared to females from age 10 years, peaking at 21 years, where it was 1.58 (95% CrI: 0.82-2.80) times among males compared to females. Tobacco smoking and alcohol drinking, more prevalent among males compared to females, were associated with increased immunoreactivity probability. Conclusion : Adolescence appears to be a critical window for Mtb exposure, during which sex-specific vulnerabilities begin to emerge. Identifying the biological and social drivers of these vulnerabilities could inform targeted strategies to reduce sex disparities in tuberculosis.