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Introduction: Host blood transcriptomic biomarkers have potential as rapid point-of-care triage, diagnostic, and predictive tests for Tuberculosis disease. We aimed to summarise the performance of host blood transcriptomic signatures for diagnosis of and prediction of progression to Tuberculosis disease; and compare their performance to the recommended World Health Organisation target product profile., Methods: A systematic review and meta-analysis of the performance of host blood mRNA signatures for diagnosing and predicting progression to Tuberculosis disease in HIV-negative adults and adolescents, in studies with an independent validation cohort. Medline, Scopus, Web of Science, and EBSCO libraries were searched for articles published between January 2005 and May 2019, complemented by a search of bibliographies. Study selection, data extraction and quality assessment were done independently by two reviewers. Meta-analysis was performed for signatures that were validated in ≥3 comparable cohorts, using a bivariate random effects model., Results: Twenty studies evaluating 25 signatures for diagnosis of or prediction of progression to TB disease in a total of 68 cohorts were included. Eighteen studies evaluated 24 signatures for TB diagnosis and 17 signatures met at least one TPP minimum performance criterion. Three diagnostic signatures were validated in clinically relevant cohorts to differentiate TB from other diseases, with pooled sensitivity 84%, 87% and 90% and pooled specificity 79%, 88% and 74%, respectively. Four studies evaluated signatures for progression to TB disease and performance of one signature, assessed within six months of TB diagnosis, met the minimal TPP for a predictive test for progression to TB disease., Conclusion: Host blood mRNA signatures hold promise as triage tests for TB. Further optimisation is needed if mRNA signatures are to be used as standalone diagnostic or predictive tests for therapeutic decision-making., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Thomas J. Scriba and Adam Penn-Nicholson are inventors of blood transcriptomic signatures of risk of TB. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Adolescents in the Western Cape Province of South Africa had high force of Mycobacterium tuberculosis (MTB) infection (14% per annum) and high TB incidence (710 per 100,000 person-years) in 2005. We describe subsequent temporal changes in adolescent TB disease notification rates for the decade 2005-2015., Method: We conducted an analysis of patient-level adolescent (age 10-19 years) TB disease data, obtained from an electronic TB register in the Breede Valley sub-district, Western Cape Province, South Africa, for 2005-2015. Numerators were annual TB notifications (HIV-related and HIV-unrelated); denominators were mid-year population estimates. Period averages of TB rates were obtained using time series modeling. Temporal trends in TB rates were explored using the Mann-Kendall test., Findings: The average adolescent TB disease notification rate was 477 per 100,000 for all TB patients (all-TB) and 361 per 100,000 for microbiologically-confirmed patients. The adolescent all-TB rate declined by 45% from 662 to 361 per 100,000 and the microbiologically-confirmed TB rate by 38% from 492 to 305 per 100,000 between 2005-2015, driven mainly by rapid decreases for the period 2005-2009. There was a statistically significant negative temporal trend in both all-TB (per 100,000) (declined by 48%; from 662 to 343; p = 0·028) and microbiologically confirmed TB (per 100,000) (declined by 49%; from 492 to 252; p = 0·027) for 2005-2009, which was not observed for the period 2009-2015 (rose 5%; from 343 to 361; p = 0·764 and rose 21%; from 252 to 305; p = 1·000, respectively)., Interpretation: We observed an encouraging fall in adolescent TB disease rates between 2005-2009 with a subsequent plateau during 2010-2015, suggesting that additional interventions are needed to sustain initial advances in TB control., Competing Interests: The authors have declared that no competing interests exist.

Objective: Diagnosis of childhood tuberculosis is limited by the paucibacillary respiratory samples obtained from young children with pulmonary disease. We aimed to compare accuracy of the Xpert® MTB/RIF assay, an automated nucleic acid amplification test, between induced sputum and gastric lavage samples from young children in a tuberculosis endemic setting., Methods: We analyzed standardized diagnostic data from HIV negative children younger than four years of age who were investigated for tuberculosis disease near Cape Town, South Africa [2009-2012]. Two paired, consecutive induced sputa and early morning gastric lavage samples were obtained from children with suspected tuberculosis. Samples underwent Mycobacterial Growth Indicator Tube [MGIT] culture and Xpert MTB/RIF assay. We compared diagnostic yield across samples using the two-sample test of proportions and McNemar's χ2 test; and Wilson's score method to calculate sensitivity and specificity., Results: 1,020 children were evaluated for tuberculosis during 1,214 admission episodes. Not all children had 4 samples collected. 57 of 4,463[1.3%] and 26 of 4,606[0.6%] samples tested positive for Mycobacterium tuberculosis on MGIT culture and Xpert MTB/RIF assay respectively. 27 of 2,198[1.2%] and 40 of 2,183[1.8%] samples tested positive [on either Xpert MTB/RIF assay or MGIT culture] on induced sputum and gastric lavage samples, respectively. 19/1,028[1.8%] and 33/1,017[3.2%] admission episodes yielded a positive MGIT culture or Xpert MTB/RIF assay from induced sputum and gastric lavage, respectively. Sensitivity of Xpert MTB/RIF assay was 8/30[26.7%; 95% CI: 14.2-44.4] for two induced sputum samples and 7/31[22.6%; 11.4-39.8] [p = 0.711] for two gastric lavage samples. Corresponding specificity was 893/893[100%;99.6-100] and 885/890[99.4%;98.7-99.8] respectively [p = 0.025]., Conclusion: Sensitivity of Xpert MTB/RIF assay was low, compared to MGIT culture, but diagnostic performance of Xpert MTB/RIF did not differ sufficiently between induced sputum and gastric lavage to justify selection of one sampling method over the other, in young children with suspected pulmonary TB., Trial Registration: ClinicalTrials.gov NCT00953927.