Predicting active tuberculosis progression by RNA analysis.

www.thelancet.com Published online March 23, 2016 http://dx.doi.org/10.1016/S0140-6736(16)00165-3 1 WHO’s goals for tuberculosis c ontrol after 2015 are to reduce the number of deaths by 95% and the number of new cases by 90% by 2035. These ambitious goals will require development of new approaches for preventing emergence of active tuberculosis from the vast pool of individuals with latent tuberculosis infection. Latent tuberculosis infection describes individuals who have been infected with Mycobacterium tuberculosis, but in whom the infection has been contained by the immune response. Latent tuberculosis infection is defi ned by tuberculin skin test or in-vitro T-cell reactivity to mycobacterial antigens. A third of the world’s population have latent tuberculosis infection, but only 5–10% progress to active disease. Progression is most common in the years soon after infection and in young children, those with HIV infection, people who have had renal dialysis, or those with other immunesuppressive conditions. Patients who progress from latent tuberculosis infection to active disease might be symptomatic and infectious for months before tuberculosis is diagnosed. Thus, the epidemic is sustained by emergence of new cases of tuberculosis from the 2 billion people with latent tuberculosis infection and onward infection of their contacts. Antimycobacterial drugs are eff ective in reducing the risk of progression from latent tuberculosis infection to active tuberculosis. However, routine treatment of all latently infected individuals in high-burden countries is not feasible because of the large numbers who would require treatment. Additionally the prolonged courses of antimycobacterial drugs needed, the potential toxic eff ects of the drugs, and the danger of increasing drug resistance through inadvertent treatment of active tuberculosis cases with prophylactic rather than therapeutic regimens are prohibitive to population-level treatment. A test that identifi es individuals with latent tuberculosis infection who are at risk of progression would transform tuberculosis control, enabling targeted treatment of the population at risk. In The Lancet, Daniel Zak and colleagues report the results of a multicentre study investigating blood RNA expression to predict progression from latent tuberculosis infection to active disease. 6363 South African adolescents were screened by skin testing or interferon gamma release assay to identify those with latent tuberculosis infection, who were then followed up for 2 years. Sequential blood samples from 153 latent tuberculosis infection cases who either progressed to active tuberculosis or from controls who did not progress by the end of the study were analysed by RNA sequencing to identify genes that were diff erentially expressed between the two groups. A 16 gene signature was identifi ed that discriminated progressors from non-progressors, which was then validated using quantitative real-time PCR, fi rst in the adolescent cohort, and then in independent Gambian and South African cohorts of 4466 screened household contacts of sputum-smear positive cases of tuberculosis. The 16 gene signature predicted progression to tuberculosis in the adolescent cohort in the 12 months preceding tuberculosis diagnosis, with sensitivity of 66·1% and specifi city of 80·6%. In the household contact cohorts the signature had a sensitivity of 53·7% and a specifi city of 82·8% for progression to tuberculosis within 12 months. Predictive performance of the signature in both cohorts decreased with increasing time to diagnosis. The signature not only identifi ed progression from latent tuberculosis infection to active disease; it also distinguished active from latent tuberculosis infection with high sensitivity when applied to published tuberculosis RNA expression data. As the authors fi rst identifi ed RNA expression diff erences between progressors and non-progressors using blood samples taken closest to time of tuberculosis diagnosis, it is Predicting active tuberculosis progression by RNA analysis