Stellenbosch University (SU) researchers are part of an international consortium that developed a simple blood test that can predict the development of tuberculosis (TB) up to two years before its onset in people at high risk of developing TB.
“People in close contact with TB patients are at risk of also developing the disease, however it is not feasible to give preventative treatment to everyone that come into contact with the patient. Our research group developed a blood test that can predict which contacts are more likely to progress to active TB, and these individuals can then be singled out for preventative treatment,” explains Professor Gerhard Walzl, lead author of the study and head of the Immunology Research Group at SU’s faculty of medicine and health sciences.
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. “Preventative treatment is several weeks long and has potential side effects. One wants to limit the number of people who have to undergo such treatment to those most at risk for developing active TB,” says Walzl.
The test measures the expression level of four genes associated with inflammatory responses. This four-gene signature, known as ‘RISK4’, was found to apply in populations from South Africa, The Gambia and Ethiopia.
“This study was the first step, and now the impact of this test on prevention of TB will have to be tested in multi-centre clinical trials,” says Walzl. “In addition, the validity of the prediction in high-risk individuals in Asia, South America and other high-priority areas needs to be assessed.”
The international research consortium included researchers from Stellenbosch University (South Africa), the Max Planck Institute for Infection Biology (Germany), the South African TB Vaccine Initiative (SATVI) at the University of Cape Town (South Africa), the Medical Research Council Unit – The Gambia, the London School of Hygiene and Tropical Medicine (UK), Case Reserve Western University (Netherlands), the Armauer Hansen Research Institute (Ethiopia), Makerere University (Uganda), the Ethiopian National Research Institute (Ethiopia), the Karonga Prevention Study (Malawi), Statens Serum Institute (Denmark), AERAS Global TB Vaccine Foundation (US), Stanford University (US) and Sanquin Research (Netherlands).
Rationale: Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. Objectives: We investigated biosignatures with predictive ability for incident tuberculosis.
Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated.
Measurements and Main Results: A four-transcript signature (RISK4), 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 Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, 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.
Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.
Sara Suliman, Ethan Thompson, Jayne Sutherland, January Weiner 3rd, Martin OC Ota, Smitha Shankar, Adam Penn-Nicolson, Bonnie Their, Mzwandile Erasmus, Jeroen Maertzdord, Fergal J Duffy, Phillip C Hill, E Jane Huges, Kim Stanley, Katrina Downing, Michelle L Fisher, Joe Valvo, Shreemantha K Parida, Gian van der Spuy, Gerard Tromp, Ifeday MO Adetifa, Simon Donkor, Rawleigh Howe, Harriet Mayanja-Kizza, W Henry Boom, Hazel Dockrell, Tom HM Ottenhoff, Mark Hatherill, Alan Aderem, Willem A Hanekom, Thomas J Scriba, Stefan HE Kaufmann, Daniel E Zak, Gerhard Walzl and the GC6-74 and ACS cohort study groups