Heart and Lung Outcomes Post-TB (HALO Post-TB)

ABSTRACT: HEART AND LUNG OUTCOMES POST-TUBERCULOSIS (HALO Post-TB) The global prevalence of post-tuberculosis lung disease (PTLD) is estimated to be ~50%, but our understanding of PTLD is incomplete as studies have not performed full pulmonary function testing (PFTs). Furthermore, the prevalence of cardiovascular sequelae of TB is largely unknown as few post-TB studies have included

assessments of cardiac structure and function. HIV is a risk factor for TB. We and others have shown that HIV is associated with cardiopulmonary markers associated with worse mortality including decreased diffusion capacity for carbon monoxide (DLco) on PFTs, elevated pulmonary artery systolic pressure (PASP) on

echocardiography, and reduced cardiorespiratory fitness (CRF) on cardiopulmonary exercise testing (CPET). These US-based studies have included few, if any, individuals with prior TB. To our knowledge, no prior study has examined pulmonary and cardiac outcomes after TB and the role of HIV as an effect modifier for the

cardiopulmonary phenotypes seen. This Heart and Lung Outcomes Post-TB (HALO Post-TB) study will fill these gaps. Our central hypothesis is that TB is associated with a higher prevalence of cardiopulmonary disease and that HIV coinfection modifies cardiopulmonary phenotypes post TB. The overall objectives of this proposal are

to elucidate prevalence, trajectory, and mechanisms of cardiopulmonary abnormalities post-TB in a high TB and HIV burden country. HALO Post-TB will be a longitudinal cohort study that will enroll people with and without HIV in Kampala, Uganda including 480 individuals at completion of treatment for pulmonary TB and 120 healthy

comparators who have never had pulmonary TB disease. Specific Aim 1 will perform full PFTs (spirometry, DLco, and lung volumes), echocardiography, 6-minute walk test, and validated questionnaires to determine the impact of HIV coinfection on cardiopulmonary function at baseline (completion of TB treatment) and the persistence of

these findings at 2-years. Aim 2 will perform CPET at baseline (completion of TB treatment) in a random subset of 50% of participants to determine the impact of HIV coinfection on mechanisms underlying cardiorespiratory fitness. Finally, Aim 3 will examine a panel of 11 plasma biomarkers and use an unbiased machine learning

approach to identify phenotypic clusters and determine whether there are differences in biomarkers that may identify mechanistic pathways that explain the different phenotypes. The proposed research will include specimen banking and will serve as the foundational study of the effect of HIV on cardiopulmonary involvement

in post-TB disease, a necessary precursor to identifying mechanisms and potential treatment. The expected outcome to develop a well-characterized post-TB cohort that includes comprehensive cardiopulmonary measures to identify distinct cardiopulmonary phenotypes and whether HIV is an effect-modifier on these

phenotypes to enable future mechanistic studies, targeted interventions, and improvements in clinical care.