Effect of Inflammatory Cytokines/Chemokines on Pulmonary Tuberculosis Culture Conversion and Disease Severity in HIV-Infected and -Uninfected Individuals From South Africa.

Novel tuberculosis (TB) prevention and control strategies are urgently required. Utilising specimens from the Improving Retreatment Success (NCT02114684) trial we assessed the associations between inflammatory markers, measured during active TB, with treatment response and disease severity in HIV-infected and uninfected individuals. Multiplex immunoassays and ELISA were used to measure plasma expression of 24 cytokines/chemokines. Cytokines were log transformed to adjust for skewness. We conducted a nested, un-matched, case (n= 31) - control (n=101) study with cases defined as those participants who failed to sputum culture convert within 8-weeks of TB treatment initiation. Additionally, we examined the association between the measured cytokines and time to culture conversion and presence of lung cavitation using cox proportional hazards and logistic regression models, respectively. Multivariable analyses adjusted for a wide range of baseline clinical and demographic variables. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks overall (aOR 4.255, 95% CI 1.025 - 17.544, p=0.046)) and among HIV-infected individuals (OR 10.204, 95% CI 1.247 - 83.333, p=0.030). Increased MCP-3 (aHR 1.723, 95% CI 1.040 - 2.855, p=0.035) and IL-6 (aHR 1.409, 95% CI 1.045 - 1.899, p=0.024) expression was associated with a shorter time to culture conversion in the total cohort. Higher plasma expression of IL-6 (aHR 1.783, 95% CI 1.128 - 2.820, p=0.013), IL-1RA (aHR 2.595, 95% CI 1.136 - 5.926, p=0.024), IP-10 (aHR 2.068, 95% CI 1.034 - 4.137, p=0.040) and IL-1α (aHR 2.008, 95% CI 1.053 - 3.831, p=0.035) were significantly associated with shorter time to culture conversion among HIV-infected individuals. Increased IL-6 and IL-1RA expression was significantly associated with the presence of lung cavitation during active TB in the total cohort (OR 2.543, 95% CI 1.254 - 5.160, p=0.010), (OR 4.639, 95% CI 1.203 - 21.031, p=0.047) and in HIV-infected individuals (OR 2.644, 95% CI 1.062 - 6.585, p=0.037), (OR 7.795, 95% CI 1.177 - 51.611, p=0.033) respectively. Our results indicate that inflammatory cytokines/chemokines play an important role in TB disease outcome. Importantly, the observed associations were stronger in multivariable models highlighting the impact of behavioural and clinical variables on the expression of immune markers as well as their potential effects on TB outcome.