Quantifying Within-Household Tuberculosis Transmission: A Systematic Review and a Prospective Cohort Study

Household-based studies are widely used to assess tuberculosis (TB) transmission and evaluate preventive strategies. These studies typically assume that household contacts (HHCs) who develop TB are infected by their index patient, but community-acquired infections may introduce misclassification, potentially biasing results. We aimed to quantify the extent of within-household TB transmission using genetic linkage data. We first analyzed a prospective cohort study conducted in Lima, Peru, where we enrolled microbiologically confirmed TB index patients and their HHCs, following them for one year. We applied whole-genome sequencing (WGS) and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping to determine genetic relatedness between index-HHC pairs. We then conducted a systematic review of household TB transmission studies that applied genotyping methods to assess the proportion of genetically linked index-HHC pairs across diverse settings. In Lima, we analyzed 175 index-HHC pairs with high-quality WGS data. We classified 62% as genetically linked, suggesting household transmission. Matching proportions were higher for secondary HHC cases (68%) than co-prevalent cases (52%). Our systematic review identified 13 studies across various epidemiological settings. Among statistically robust studies, household transmission predominated in moderate TB incidence settings (<250 cases per 100,000 person-years), with genetic linkage exceeding 68%. However, in high-burden settings, within-household transmission varied widely, likely due to community-acquired infections and methodological differences. In summary, our findings suggest that in settings with [&le;]250 TB cases per 100,000 person-years, 20-35% of household TB cases may be misclassified due to community transmission, with lower misclassification among child and female contacts. The extent of this issue in high-burden settings remains unclear.