Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health.

Risk for tuberculosis in child contacts. Development and validation of a predictive score.

RATIONALE: Contact investigation of persons exposed to tuberculosis (TB) is resource intensive. To date, no clinical prediction rule for TB risk exists for use as a guide during contact investigation. OBJECTIVES: We sought to develop and validate a simple and easy-to-use predictive score for TB risk, using data routinely available during contact investigation. METHODS: The derivation cohort consisted of 9,411 children aged 0 to 12 years from 2008 to 2009 national contacts cohort. We used a multivariate Cox proportional hazards model to predict the risk of developing active TB. The validation cohort consisted of 2,405 children from the 2005 national contacts cohort. We calculated area under the receiver operating characteristic curves of the model as well as the predicted risk of TB for contacts with different scores. MEASUREMENTS AND MAIN RESULTS: An 8-point scoring system was developed, including reaction to tuberculin skin test of the contacts, as well as smear-positivity, residence in high-incidence areas, and sex of the index cases. Area under the receiver operating characteristic curve was 0.872 (95% confidence interval, 0.810-0.935) for the derivation cohort and 0.900 (95% confidence interval, 0.830-0.969) for the validation cohort. The risk of developing active TB within 3 years is 100, 7.8, 4.3, 1.0, 0.7, and 0.2% for contacts with risk scores of 7, 6, 5, 4, 3, and 2, respectively. CONCLUSIONS: A risk predictive score was developed and validated to identify child contacts aged 0 to 12 years at increased risk for active TB. This predictive score can help to prioritize active case finding or isoniazid preventive therapy among children exposed to TB.