Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).

The age-adjusted incidence rate of TB attributable to reinfection after successful treatment was four times that of new TB. People who had TB once are at a strongly increased risk of developing TB when reinfected.

In The Netherlands, patients with smear-negative, culture-positive TB are responsible for 13% of TB transmission. Countries that have ample resources should expand their TB-control efforts to include prevention of transmission from patients with smear-negative, culture-positive pulmonary TB.

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SettingThis study was conducted in a high tuberculosis (TB) burden area in Worcester, South Africa, with a notified all TB incidence rate of 1,400/100,000.Main ObjectiveTo compare the predictive value of a baseline tuberculin skin test (TST) with that of the QuantiFERON TB Gold (In-tube) assay (QFT) for subsequent microbiologically confirmed TB disease among adolescents.MethodsAdolescents aged 12–18 years were recruited from high schools in the study area. At baseline, blood was drawn for QFT and a TST administered. Participants were followed up for up to 3.8 years for incident TB disease (median 2.4 years).ResultsAfter exclusions, 5244 (82.4%) of 6,363 adolescents enrolled, were analysed. The TB incidence rate was 0.60 cases per 100 person years (pyrs) (95% CI 0.43–0.82) for baseline TST positive (≥5 mm) participants and 0.64 cases per 100 pyrs (95% CI 0.45–0.87) for baseline QFT positive participants. TB incidence rates were 0.22 per 100 pyrs (0.11–0.39) and 0.22 per 100 pyrs (0.12–0.38) among those with a negative baseline TST and QFT respectively. Sensitivity for incident TB disease was 76.9% for TST and 75.0% for QFT (p = 0.81). Positive predictive value was 1.4% for TST and 1.5% for QFT.ConclusionPositive TST and QFT tests were moderately sensitive predictors of progression to microbiologically confirmed TB disease. There was no significant difference in the predictive ability of these tests for TB disease amongst adolescents in this high burden setting. Therefore, these findings do not support use of QFT in preference to TST to predict the risk of TB disease in this study population.

A systematic literature review was performed with the objective of assessing the effectiveness of tuberculosis (TB) screening methods and strategies in migrants in European Union/European Economic Area (including Switzerland) countries.Extracted data on yield and coverage were used as indicators of effectiveness. Reported yields varied considerably between studies and countries. Considering only the 14 studies representative of national screening programmes, a median yield of TB disease of 0.18% (interquartile range 0.10-0.35%) was reported.The data did not indicate differences in effectiveness between the three main strategies: 1) screening at port of entry; 2) screening just after arrival in reception/holding centres; and 3) screening in the community following arrival in European Union countries. The variation seen probably reflects variation in risk factors for TB, in particular the composition of the migrants entering the country.Recommendations include the need for improved data for guiding the optimal frequency and duration of screening; assessment and improvement of cost-effectiveness; access to healthcare for migrants, including illegal migrants; ensuring a continuum of care for those screened; and consideration of screening for latent TB infection with caution. Finally, screening should be a component of a wider approach, rather than a stand-alone intervention.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-c release assays (IGRAs), QuantiFERON-TB1 Gold In-tube (QFT-GIT) and T-SPOT.TB1, and the tuberculin skin test (TST) in immigrants contacts.Immigrant close contacts of sputum smear-positive TB patients were included when aged o16 yrs and their TST result was o5 mm 0 or 3 months after diagnosis of the index patient.Contacts were followed for the next 2 yrs for development of TB disease.Of 339 immigrant contacts with TST o5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB1, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB1. The PPV for progression to TB during this period was 9/28853.1% (95% CI 1.3-5.0%) for TST o10 mm, 7/ 18453.8% (95% CI 1.7-5.9%) for TST o15 mm, 5/17852.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/ 18153.3% (95% CI 1.3-5.3%) for T-SPOT.TB1. Sensitivity was 100%, 88%, 63% and 75%, respectively.The predictive values of QFT-GIT, T-SPOT.TB1 and TST for progression to TB disease among immigrant close contacts were comparable.

The incidence and proportion of cases that are clustered in this area are higher than reported elsewhere. An overwhelming majority of TB cases in this area is attributed to ongoing community transmission, and only very few to reactivation. This may explain the lack of demographic risk factors for clustering.