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) followup 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 mixedeffects 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 9...

Tuberculosis rarely developed among contacts, and preventive chemotherapy effectively reduced the tuberculosis risk among IGRA-positive contacts. Although the negative predictive value of IGRAs is high, the risk for the development of tuberculosis is poorly predicted by these assays.

W e read with great interest the mathematical model presented by Fofana et al. (1) on the role of pyrazinamide (PZA) in the emergence of multidrug-resistant tuberculosis (MDR TB), particularly as the results of their model mirror our concerns regarding the amplification of PZA resistance during inappropriate first-line therapy and the dramatic negative consequences that this can have on the subsequent response to second-line therapy. Indeed recent data from Belarus suggest that approximately 50% of PZA resistance is acquired de novo (2). Fofana et al. (1) propose that this problem, a result of using the same important agent in first-and second-line therapy, might be circumvented by using an as-yet-unidentified new agent with characteristics similar to those of PZA in a new second-line regimen. Although considerable effort is being applied to the development of new targets for such agents (3), it is far from certain when or even if these miraculous drugs will be available for routine use. Consequently, PZA is currently a uniquely valuable agent, which we speculate will be very difficult to replace (4, 5). We therefore suggest that in settings where the a priori risk of MDR TB due to transmission is above a certain level, such as in Belarus, prescribing PZA to new patients before they have been screened for rifampin and isoniazid resistance is likely counterproductive. Screening for PZA resistance is still complicated and not in reach for many laboratories. Of course, in an ideal world, a full drug susceptibility test (DST) profile would be available for all patients before TB therapy is prescribed. Unfortunately, in reality, this is seldom the case; at best, there is a considerable delay before DST results are communicated to the physician, and at worst, DST is not performed at all until there is evidence of treatment failure, which may be between 2 and 6 months after starting the patient on first-line agents. As this scenario appears to account for 50% of the PZA resistance seen in MDR-TB cases in many settings (5), action is required now to prevent transmissible PZA-resistant mutants from becoming widely established (6, 7). Thus, we propose that, in settings with a high proportion of MDR-TB patients, PZA be withheld until there is evidence of susceptibility to other first-line agents, because of either a clinical response (acid-fast bacillus [AFB] smear conversion) or a solid laboratory diagnosis. Modeling the exact proportion of primary MDR-TB patients in whom PZA resistance was prevented, a population benefitting from this change, and discussion of the ethics of this approach would be highly informative. Delaying action Citation Anthony RM, Cynamon M, Hoffner S, Werngren J, den Hertog AL, van Soolingen D. 2017. Protecting pyrazinamide, a priority for improving outcomes in multidrug-resistant tuberculosis treatment. Antimicrob Agents Chemother 61:e00258-17. https://doi.

We evaluated the T-SPOT.TB and Quantiferon-TB Gold In tube (QFN-G-IT) tests for diagnosing Mycobacterium tuberculosis infection. T-SPOT.TB was more sensitive than QFN-G-IT in diagnosing both active and latent infection. Both gamma interferon tests were unaffected by prior Mycobacterium bovis BCG vaccination. Among children who were not BCG vaccinated but had a positive tuberculin skin test, QFN-G-IT was negative in 53.3% of cases, and T-SPOT.TB was negative in 50% of cases.