Matrix Metalloproteinases in Tuberculosis-Immune Reconstitution Inflammatory Syndrome and Impaired Lung Function Among Advanced HIV/TB Co-infected Patients Initiating Antiretroviral Therapy

• Matrix metalloproteinases (MMP), capable of degrading lung collagen, can increase rapidly on ART in HIV/TB patients.
• Increases in plasma MMP-8 concentrations after ART initiation are associated with the development of paradoxical TB-IRIS.
• Increases in CD4 T-cells and MMP-8 concentrations after ART initiation are correlated with decreased lung function post-TB cure.TB-associated pulmonary morbidity can persist after TB cure. However, causal mechanisms for lung damage, which may involve immune mechanisms and tissue proteases, in TB are unclear. Less is known in this regard among patients with HIV/TB, who are at risk for inflammatory reactions following ART initiation, otherwise known as TB-immune reconstitution inflammatory syndrome (IRIS). In this study, rapid ART-induced increases in certain tissue degrading proteins called matrix metalloproteinases (MMP) were associated with TB-IRIS. Furthermore, rapid recovery of CD4 T-cells and MMP-8 concentrations were associated with decreased lung function in an exploratory subset. In HIV/TB, robust increases in cellular immune function and MMPs on ART may underlie lung injury and long-term pulmonary deficits.

BackgroundHIV-infected patients with pulmonary TB (pTB) can have worsening of respiratory symptoms as part of TB-immune reconstitution inflammatory syndrome (TB-IRIS) following antiretroviral therapy (ART) initiation. Thus, reconstitution of immune function on ART could drive incident lung damage in HIV/TB.MethodsWe hypothesized that increases in matrix metalloproteinases (MMPs), which can degrade lung matrix, on ART are associated with TB-IRIS among a cohort of advanced, ART naïve, HIV-infected adults with pTB. Furthermore, we related early changes in immune measures and MMPs on ART to lung function in an exploratory subset of patients post-TB cure. This study was nested within a prospective cohort study. Rank sum and chi-square tests, Spearman's correlation coefficient, and logistic regression were used for analyses.ResultsIncreases in MMP-8 following ART initiation were independently associated with TB-IRIS (p = 0.04; adjusted odds ratio 1.5 [95% confidence interval: 1.0–2.1]; n = 32). Increases in CD4 counts and MMP-8 on ART were also associated with reduced forced expiratory volume in one-second post-TB treatment completion (r = − 0.7, p = 0.006 and r = − 0.6, p = 0.02, respectively; n = 14).ConclusionsART-induced MMP increases are associated with TB-IRIS and may affect lung function post-TB cure. End-organ damage due to TB-IRIS and mechanisms whereby immune restoration impairs lung function in pTB deserve further investigation.