Excess cardiovascular inflammation in TB and HIV: EXFIN-TB - TB is the leading global killer among infectious diseases and the number one cause of death among those with HIV. Furthermore, the estimated 9 million TB survivors completing treatment each year have a 3-fold increased risk of death from any cause when compared to those without previous TB. While post-TB lung disease is a major contributor to the long-term morbidity and mortality faced by TB survivors with and without HIV coinfection, cardiovascular disease accounts for a greater proportion of post-TB deaths than pulmonary disease. Moreover, epidemiologic studies have found that adults with a history of previous TB have a ~50% increased risk of cardiovascular events. Importantly, many endpoints in existing studies occur years after TB treatment completion, raising the possibility that TB promotes subclinical vascular dysfunction, which then predisposes survivors to future cardiovascular disease events. If true, it may be possible to identify high-risk patients and intervene early—during or soon after TB treatment—before these events occur. Our overarching hypothesis is that TB promotes pulmonary inflammation that leads to subclinical vascular pathology characterized by increased arterial stiffness, vascular intima-media thickening, and endothelial dysfunction, all of which drive an increased risk of major cardiovascular events. Further, we hypothesize that patients with more severe pulmonary involvement, as determined by baseline chest high-resolution computed tomography (HRCT) scan, will display worse vascular pathology after TB treatment completion. Support for this hypothesis comes from studies linking more severe viral and bacterial respiratory infections with a greater risk of future cardiovascular events. In addition, we will investigate the role of inflammasomes, which are molecular complexes of the innate immune system that are activated by TB and known to be causally involved in the development of atherosclerosis, ischemic heart disease, and stroke. For this “Excess Cardiovascular Inflammation in TB and HIV: EXFIN-TB” study, we will leverage our ongoing prospective cohort study of post-TB lung disease in patients with and without HIV coinfection. In Aim 1, we hypothesize that TB patients with greater initial involvement on HRCT will have more arterial stiffness 36 months after TB diagnosis. In Aim 2, we hypothesize that higher sputum levels of the inflammasome cytokine IL-1β during the first month of TB treatment will have more arterial stiffness 36 months after TB diagnosis. Given the importance of HIV to the TB epidemic, both aims will be evaluated in parallel cohorts with equal numbers of people with and without HIV (n = 125/group). We will also newly enroll 120 community controls without TB disease, with whom all outcomes will be compared. Secondary analyses will incorporate additional measures of TB severity, functional assays of inflammasome activity, and complementary measures of vascular pathology. Knowledge gained from this study will directly inform future mechanistic and therapeutic studies with the goal of reducing the burden of post-TB cardiovascular disease for millions of TB survivors.
