Heterogeneity in Mycobacterium tuberculosis immunoreactivity in young children in Blantyre, Malawi: A community-based...

As tuberculosis (TB) incidence declines, transmission becomes increasingly concentrated in vulnerable populations and neighbourhoods. There is an urgent need for affordable surveillance strategies to monitor trends, identify high-risk groups and target interventions. TB disease prevalence surveys are no longer cost-effective in monitoring epidemiological trends as countries target TB elimination, while passive surveillance methodologies such as case-notification rates (CNRs) are biased by healthcare access disparities. Mycobacterium tuberculosis (Mtb) immunoreactivity surveys indirectly measure transmission and therefore undiagnosed infectious TB, and may provide valuable information to TB programmes globally. We conducted a pragmatic hybrid clinic- and household-based cross-sectional interferon-gamma release assay (IGRA) survey in healthy children aged 1-4 years in 33 high-burden neighbourhoods Blantyre, Malawi. Participants were recruited using novel convenience sampling in health facilities, alongside random household sampling guided by satellite imagery, and tested for Mtb immunoreactivity using QFT-Plus IGRA. We constructed hierarchical Bayesian logistic regression models for IGRA positivity, with neighbourhood-level random effects. Of 1,545 participants, 102 (6.6%) had a positive IGRA: an annual risk of Mtb infection (ARTI) of 2.7% (95% CrI 2.2-3.2%). Immunoreactivity was higher in the poorest third of households (8.7% vs 4.9%; adjusted odds ratio: 1.88, 95% CrI 1.08-3.01) compared to the richest, but was not associated with HIV exposure, malnutrition or reported household TB exposure. There was substantial between-neighbourhood heterogeneity (ARTI range 1.1-4.1%). There was no association between neighbourhood-level TB case notifications and ARTI. Measuring Mtb immunoreactivity in young children, using innovative recruitment strategies, revealed a high burden of immunoreactivity suggestive of recent TB transmission. Children in the poorest households were at highest risk, highlighting the importance of social and economic inequity in driving the TB epidemic. Case notification rates may not reflect the areas with the highest transmission, and Mtb immunoreactivity surveillance may support identification of high-risk populations, monitoring of trends and targeting of public health interventions.