Mycobacterium tuberculosis infection and tuberculosis disease in the first decade of life: a South African birth cohort study.

Background: Paediatric tuberculosis leads to more than 200 000 deaths annually. We aimed to investigate the incidence of Mycobacterium tuberculosis infection and tuberculosis disease in the first decade of life in the Drakenstein Child Health Study (DCHS), a South African cohort in a community with high tuberculosis and HIV incidence.

Methods: In this prospective birth cohort study, we enrolled pregnant women aged 18 years or older who were between 20 and 28 weeks' of gestation in a peri-urban setting outside of Cape Town, South Africa. We followed up their children for tuberculosis until age 10 years. To measure M tuberculosis infection tuberculin skin tests were administered to children at age 6 months, 12 months, and then annually in children with a negative test, and at the time of a lower respiratory tract infection. Tuberculin skin test conversion was defined by an induration reaction of 10 mm or more. To measure tuberculosis disease, active surveillance was done throughout follow-up. Each episode of presumed tuberculosis disease was investigated using sputum induction, tested with Xpert MTB/RIF and liquid culture for M tuberculosis. Survival analyses were performed and multivariable Cox regression was used to measure factors associated with M tuberculosis infection or disease.

Findings: Between March 5, 2012, and March 31, 2015, 1137 women and their 1143 children (248 [21·7%] of 1143 children were HIV-exposed, two [0·2%] children with HIV) were included in the analysis. Children were followed up for 8870 person-years (median follow-up 9·1 years [IQR 8·2-10·2]). The annual risk of tuberculin conversion during follow-up was 6·6 infections per 100 person-years (95% CI 5·8-7·3) but ranged from 4-9 infections per 100 person-years over the follow-up period. 98 children developed tuberculosis (1105 cases per 100 000 person-years; 95% CI 906-1347). The cumulative hazard of tuberculin conversion was 36% (95% CI 32-41) at age 8 years and the cumulative hazard of tuberculosis disease was 10% (8-12) at age 10 years. Preventive treatment was associated with a reduction in tuberculosis disease among children who had tuberculin conversion (adjusted hazard ratio 0·23 [95% CI 0·12-0·47]). Most cases of tuberculosis disease (78 [79%; 95% CI 69-86] of 98 children) occurred among children who had tuberculin skin test conversion but were not administered preventive treatment.

Interpretation: In this prospective South African birth cohort, M tuberculosis transmission was consistently high throughout the first decade of life leading to approximately 10% of children developing tuberculosis disease. A multipronged approach to decrease paediatric tuberculosis is needed that combines preventive treatment for children at risk, reducing community M tuberculosis transmission, and active case finding.

Funding: Bill & Melinda Gates Foundation, Medical Research Council South Africa, and National Research Foundation South Africa.