Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis
Humphrey Mulenga, Munyaradzi Musvosvi, Simon C. Mendelsohn, Adam Penn-Nicholson, Stanley Kimbung Mbandi, Andrew Fiore-Gartland, Michèle Tameris, Simbarashe Mabwe, Hadn Africa, Nicole Bilek, Fazlin Kafaar, Shabaana A. Khader, Balie Carstens, Katie Hadley, Chris Hikuam, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Onke Nombida, Masooda Kaskar, Mark P. Nicol, Slindile Mbhele, Judi Van Heerden, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T. Malherbe, Razia Hassan-Moosa, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Mark Hatherill, Thomas J. Scriba
Abstract
Abstract Rationale Performance of blood transcriptomic tuberculosis (TB) signatures in longitudinal studies and effects of TB-preventive therapy and coinfection with HIV or respiratory organisms on transcriptomic signatures has not been systematically studied. Objectives We evaluated longitudinal kinetics of an 11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort, or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomized to TPT or no TPT; RISK11− participants received no TPT. PLHIV received standard-of-care antiretroviral therapy and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by real-time quantitative PCR. Measurements and Main Results RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; more than 70% of RISK11+ participants reverted to RISK11− by 3 months, irrespective of TPT. By comparison, reversion from a RISK11+ state was less common in 645 PLHIV (42.1%). Non-HIV viral and nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control.