Blood Test Predicts Onset of TB in Advance

Tuberculosis, caused by infection with Mycobacterium tuberculosis (TB), is the world's leading cause of death brought on by a single pathogen. More than 10 million new cases of TB are diagnosed each year, and almost two million people die from the disease.

Those living with someone with active TB are at highest risk for developing the disease, yet only about 5% to 20% of people infected with tuberculosis actually develop the disease. A blood test that predicts the development of TB without putting large numbers of lower-risk people through unnecessary preventative treatment is not currently available.

An international consortium of scientists working with those at Stellenbosch University (Stellenbosch, South Africa) enrolled 4,466 HIV-negative, healthy study participants from the households of 1,098 index cases, that were people with active TB, who allowed the teams to enroll members of their household who did not have TB in its active stage. Blood samples were taken from the 4,466 study participants, and stored.

At the end of the initial study period, when it was apparent who had progressed to TB and who had not, the blood samples of 79 individuals who progressed to active TB between three and 24 months following exposure, and 328 who remained healthy during the two years of follow up, were analyzed. Various biosignatures, combinations of gene or protein levels, that together result in a test readout that relates to current or future risk for developing the condition, were measured. The scientists employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach.

The consortium found that a four-transcript signature (RISK4) which is a combination of four genes associated with inflammatory responses, derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all three countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, Complement C1q C Chain/ T Cell Receptor Alpha Variable 27 (C1QC/ TRAV27) that would consistently predict TB progression in household contacts from multiple African sites, but not in infected adolescents without known recent exposure events.

Gerhard Walzl, MMed, PhD, a professor and lead study author, said, “This signature, known as 'RISK4,' was found to be present in all cohorts in the study, from South Africa, Gambia and Ethiopia. The individual components of this signature may not be sufficient to deliver an accurate diagnosis of prediction, but a combination of these markers improves its accuracy. We are hoping that primary health clinics will be able to use such a test and the reagents would then be readily available in that format, similar to the tests that are currently used to diagnose TB.” The study was published on April 6, 2018, in the American Journal of Respiratory and Critical Care Medicine.

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