The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

Abstract

Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood. We conducted an individual participant data meta-analysis of cohort studies in which children (<19 years of age) with close tuberculosis exposure were investigated for tuberculosis and followed for incident disease. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models, and estimated adjusted hazard ratios (AHR) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. We pooled participant-level data from 46 cohort studies in 34 countries. We included 137,647 exposed children followed for 429,538 child-years, during which 1,299 prevalent and 999 incident cases were diagnosed. The two-year risk of developing tuberculosis among infected children not receiving preventive therapy was 19.0% from 0 to 5 years of age. The effectiveness of preventive therapy was 63% (AHR, 0.37, 95% confidence intervals [CI], 0.30–0.47) among all exposed children, and 85% (AHR, 0.15, 95% CI, 0.11–0.20) among those with a positive test of infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit. The risk of developing tuberculosis among exposed infants and young children is very high. The majority of cases occurred within weeks of contact investigation initiation and may not be preventable through prophylaxis. This suggests that alternative strategies for prevention, such as earlier initiation of preventive therapy through earlier diagnosis of adult cases or community-wide screening approaches, are needed.