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

Summary

Background

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.

Methods

In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).

Findings

In total, study groups from 46 cohort studies in 34 countries—29 (63%) prospective studies and 17 (37%) retrospective—agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4–37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30–0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05–0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit.

Interpretation

The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches.

Funding

National Institutes of Health.

Introduction

Tens of millions of children are exposed to Mycobacterium tuberculosis every year,1, 2 and tuberculosis remains a leading infectious cause of global childhood morbidity and mortality.3, 4, 5 Historically, paediatric tuberculosis has been largely understudied, and its natural history in children remains poorly understood. Because of this, there is considerable uncertainty regarding the effectiveness of public health strategies for detection and prevention of tuberculosis among exposed children.

The majority of evidence concerning the natural history of tuberculosis in children relies on studies which took place before 1950.6, 7, 8, 9, 10, 11 Many changes have occurred in the control of tuberculosis and in the health of populations more broadly, including the introduction of tuberculosis drug chemotherapy, widespread administration of the BCG vaccination, substantial decline of the prevalence of undernutrition in children, and the HIV epidemic.12, 13, 14, 15, 16 A reassessment of age-specific risks of tuberculosis and identifying risk factors for disease in exposed children is necessary to inform clinical and policy decision making. Public health interventions targeting exposed children are urgently needed but remain poorly measured; the population impact of paediatric case finding and preventive interventions is currently unknown.

Research in context

Evidence before this study

No contemporary studies have attempted to quantify the risk of developing paediatric tuberculosis after close exposure to a tuberculosis case or recently acquired tuberculosis infection. One narrative review of seven historical studies from before 1940 synthesised results from these studies, and found that approximately 50% of children below the age of 1 year with recent infection developed tuberculosis. This risk dropped to 10–15% in children 1–2 years of age, 5–6% in children 2–5 years of age, 2% in children 5–10 years of age, and rose to 10% among children above 10 years of age. We searched MEDLINE and Google Scholar for articles published before April 6, 2018. We used the search terms “child”, “tuberculosis”, “transmission”, “household”, “pediatric”, “paediatric”, “contact”, and “close”, among others. We also reviewed reference lists, bibliographies, and other narrative reviews on incident tuberculosis for additional relevant articles. We found several contemporary household contact exposure studies that included children but none that focused on children or that included a large sample size. We did not identify estimates of longitudinal risk of tuberculosis in infants and young children with close exposure or recent infection. Because of this knowledge gap, the effectiveness of contact investigations and preventive therapy remains poorly understood.

Added value of this study

In this systematic review and meta-analysis, we used individual-level data from 46 cohort studies in 34 countries to provide the first contemporary estimates of tuberculosis risk in children after close exposure. 137 647 exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. We found that exposed children below the age of 1 year, who were positive for tuberculosis infection and did not receive preventive therapy had an 18% risk of developing disease within 2 years of enrolment. In contrast to previous estimates suggesting risk falls to 5% in children aged 2–5-years, we found that this age group had a 2-year cumulative tuberculosis risk of 19%. Additionally, the effectiveness of preventive therapy to prevent incident tuberculosis was high—91% among children with tuberculosis infection. Despite this, the majority of children (82% of children with tuberculosis infection and 83% of all children below 5 years of age) developed tuberculosis within weeks of the initial baseline contact investigation visit.

Implications of all the available evidence

Results from this multi-cohort collaboration indicate that greater focus should be placed on the first 5 years of life as a period of high risk of progression from tuberculosis infection to disease. The risk of developing tuberculosis among exposed infants and young children was very high, approaching 20% 2 years after exposure. Despite the effectiveness of preventive therapy, most cases occurred within weeks of initiation of the contact investigation. Although contact tracing is a high-yield means for early case detection, many children are reached too late to prevent disease. Earlier diagnosis of adult cases or community-wide screening approaches in children might be needed to improve prevention of tuberculosis in children.

To address these knowledge gaps, we pooled data from longitudinal cohort studies conducted since 1998. We estimated the risk of developing tuberculosis in children after close exposure, stratified by age and individual-level determinants of risk. We also examined how disease risk was affected by preventive therapy, BCG vaccination, and time since tuberculosis exposure to better understand the role of various public health interventions.