Tuberculosis (TB) is the leading cause of death by an infectious disease. Identifying affected individuals, particularly if they are asymptomatic, however, remains a challenge as the infectious organisms are primarily contained within lung granulomas and/or draining lymph nodes. Biomarkers in the host’s blood compartment may be used in identifying individuals that are progressing from M. tuberculosis infection or latent disease, to active TB disease. In this longitudinal cohort study, 6,363 M. tuberculosis-infected, HIV-negative South African adolescents age 12 to 18 years who participated in the Adolescent Cohort Study (ACS, 2005-2007) were followed up for 2 years to identify proteomic biomarkers of TB progression, with the aim of developing a non-sputum, blood-based, point-of-care diagnostic. Researchers found that 46 individuals developed microbiologically confirmed TB disease within 2 years of follow-up. These participants were selected as progressors; 106 non-progressors, who remained healthy, were matched to the progressors. Using a highly multiplexed proteomic assay (SOMAscan), 3,000 human proteins were quantified in plasma. Of these, 361 proteins were of differential abundance between the progressors and non-progressors. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR). The prognostic performance of both signatures was subsequently validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia, a small West African country, where individuals age 15 to 60 years were followed up for 2 years, sampled at baseline, month 6, and month 18. Researchers found that the prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (AUC 0.96, 95% CI 0.93 to 0.99) and 6-12 months (AUC 0.76, 95% CI 0.65 to 0.87) before TB diagnosis. In the Gambian validation cohort, TRM5 validated with an AUC of 0.66 (95% CI 0.56 to 0.75) within 1 year of TB diagnosis, while the 3PR signature yielded an AUC of 0.89 (95% CI 0.84 to 0.95) within 6 months of TB diagnosis and 0.72 (95% CI 0.64 to 0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (95% CI 0.55 to 0.75) within 1 year of TB diagnosis in the Gambian validation cohort. This study therefore shows that proteomic biomarkers such as TRM5 and 3PR may play a role in predicting progression to incident TB. Further validation, particularly in cohorts from non-African countries, is necessary in determining the utility of these proteomic biomarkers in other affected populations.
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