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

Abstract

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.

Figure 1.

Risk of Developing Tuberculosis Over Time Among Exposed Children Not Receiving Preventive Therapy. Abbreviations. py, person-years. TST, Tuberculin Skin Test. IGRA, Interferon Gamma Release Assay. Only prospective studies are included in this analysis. Only children who did not receive preventive chemotherapy were included. The dotted vertical line represents 90 days. Circles represent mean estimates and bars represent 95% confidence intervals for each estimate. Bars may not be visible for some estimates at ‘>730 days’ because the confidence intervals are narrow. Tuberculosis prevalence and incidence are measured on distinct left and right y-axes on the left and right of the Figure. Shown are tuberculosis prevalence within 90 days of enrollment (left y-axis) and subsequent tuberculosis incidence over various intervals (right y-axis), stratified by baseline tuberculin skin test (TST) or interferon gamma release assay (IGRA) status. A positive tuberculin skin test was defined as an induration ≥10 mm, and a positive IGRA result was defined as a positive QuantiFERON-TB Gold In-Tube (QFT) (interferon-γ - nil ≥0.35 IU/mL), or TB-Spot (>8 spot forming cells per well).

Figure 2.

Proportion of All Tuberculosis Cases Diagnosed Over Follow-up Time. Abbreviations. py, person-years. TST, Tuberculin Skin Test. IGRA, Interferon Gamma Release Assay. Only prospective studies are included in this analysis. Only children who did not receive preventive chemotherapy were included. The ‘All’ group represents all participants regardless of TST and/or IGRA testing, which is a much larger group of children than those with TST/IGRA+ or TST/IGRA−; the detection proportion for ‘all children’ therefore does not appear as a weighted average between those two groups. A positive tuberculin skin test was defined as an induration ≥10 mm, and a positive IGRA result was defined as a positive QuantiFERON-TB Gold In-Tube (QFT) (interferon-γ - nil ≥0.35 IU/mL), or TB-Spot (>8 spot forming cells per well). Dotted vertical line represents 90 days in both Figure 2a, 2b, and 2c.

Figure 2.

Proportion of All Tuberculosis Cases Diagnosed Over Follow-up Time. Abbreviations. py, person-years. TST, Tuberculin Skin Test. IGRA, Interferon Gamma Release Assay. Only prospective studies are included in this analysis. Only children who did not receive preventive chemotherapy were included. The ‘All’ group represents all participants regardless of TST and/or IGRA testing, which is a much larger group of children than those with TST/IGRA+ or TST/IGRA−; the detection proportion for ‘all children’ therefore does not appear as a weighted average between those two groups. A positive tuberculin skin test was defined as an induration ≥10 mm, and a positive IGRA result was defined as a positive QuantiFERON-TB Gold In-Tube (QFT) (interferon-γ - nil ≥0.35 IU/mL), or TB-Spot (>8 spot forming cells per well). Dotted vertical line represents 90 days in both Figure 2a, 2b, and 2c.

Figure 2.

Proportion of All Tuberculosis Cases Diagnosed Over Follow-up Time. Abbreviations. py, person-years. TST, Tuberculin Skin Test. IGRA, Interferon Gamma Release Assay. Only prospective studies are included in this analysis. Only children who did not receive preventive chemotherapy were included. The ‘All’ group represents all participants regardless of TST and/or IGRA testing, which is a much larger group of children than those with TST/IGRA+ or TST/IGRA−; the detection proportion for ‘all children’ therefore does not appear as a weighted average between those two groups. A positive tuberculin skin test was defined as an induration ≥10 mm, and a positive IGRA result was defined as a positive QuantiFERON-TB Gold In-Tube (QFT) (interferon-γ - nil ≥0.35 IU/mL), or TB-Spot (>8 spot forming cells per well). Dotted vertical line represents 90 days in both Figure 2a, 2b, and 2c.

Figure 3.

Two-year Cumulative Incidence of Tuberculosis Development in Children Not on Preventive Therapy, Stratified by Age and Infected (left), Uninfected (middle), and All (right) Children. Abbreviations. py, person-years. TST, Tuberculin Skin Test. IGRA, Interferon Gamma Release Assay. The two-year cumulative incidence of tuberculosis includes prevalent and incident tuberculosis in the first two years of follow-up from prospective cohort studies, stratified by age and baseline results of tuberculin skin test or interferon gamma release assay. Only children not given preventive therapy are included in this analysis. Panel A includes only children with tuberculosis infection. Panel B includes only children without tuberculosis infection. Panel C includes all children, including those not tested for tuberculosis infection. A positive infection was determined by one of the following criteria: a tuberculin skin test induration ≥10 mm, a QuantiFERON-TB Gold In-Tube (QFT) (interferon-γ - nil ≥0.35 IU/mL), or a positive TB-Spot (>8 spot forming cells per well). Bars represent mean estimates and lines represent 95% confidence intervals. The two-year cumulative incidence of tuberculosis for children with tuberculosis infection was consistent within each age group bin. For example, the two-year cumulative incidence of tuberculosis was 19% for infected children <5 years of age and ranged from 17% to 21%. Risk of tuberculosis for one-age year bins can be seen in the Supplementary Appendix. In Panel A, the cumulative risk among children <5 years old with positive baseline TST/IGRAs was statistically higher when compared to 5–9 year old TST/IGRA positive children (P<0.0001), 10–14 year old TST/IGRA positive children (P<0.0001), and 15–18 year old TST/IGRA positive children (P=0.0006). In Panel B, the cumulative risk among children <5 years old with negative baseline TST/IGRAs was statistically higher when compared to 5–9 year old TST/IGRA negative children (P=0.0189), but not compared to 10–14 year old TST/IGRA negative children (P=0.1576) or 15–18 year old TST/IGRA positive children (P=0.8335). In Panel C, the cumulative risk among all children <5 years old with positive baseline TST/IGRAs was statistically higher when compared to 5–9 year old TST/IGRA positive children (P=0.0027) and 10–14 year old TST/IGRA positive children (P=0.0145), but not compared to 15–18 year old TST/IGRA positive children (P=0.3491).

Figure 4.

Study-specific Prevalent (a) and Incident (b) Tuberculosis in Children, Stratified by the Study Design and Region. All children were included in Figure 4a and 4b

Figure 4.

Study-specific Prevalent (a) and Incident (b) Tuberculosis in Children, Stratified by the Study Design and Region. All children were included in Figure 4a and 4b