Tuberculosis (TB) is a leading global killer among infectious diseases and the leading cause of death among people with HIV. Among the estimated 9 million TB survivors each year, up to half are left with impaired lung function and chronic respiratory symptoms. More than four times as many quality-adjusted life years (QALYs) are lost to post-TB lung disease (PTLD) as are lost to TB mortality. Although there has been growing recognition of PTLD in recent years, there are no known interventions to prevent or treat this devastating outcome. This knowledge gap is due in large part to a fundamental lack of data on mechanisms driving PTLD. Lung damage from TB is often viewed as an inevitable consequence in those who present “too late;” however, recent studies by our group and others suggest an alternative paradigm where much of PTLD can be prevented by giving host-directed therapies during TB treatment. Defining the biological pathways that drive PTLD and the populations at risk will provide a rare opportunity to address one of the most common global causes of chronic lung disease in people with and without HIV. In the Inflammation and Fibrosis in Pulmonary TB (INFIN-TB) study, we will test the hypothesis that pulmonary neutrophilic inflammation (Aim 1) and profibrotic activity (Aim 2) occurring early during TB treatment increase the risk of PTLD. We will enroll a prospective cohort of 250 people, 125 with HIV and 125 without HIV, with newly diagnosed, drug-susceptible pulmonary TB and will follow them for 12 months, from the time of TB diagnosis and treatment initiation until 6 months after completion of TB treatment. To ascertain relevant pathophysiology from the site of disease, we will collect airway samples at multiple time points in addition to comprehensive measurements of lung function and high-resolution CT scans. For Aim 1, we will determine the association between sputum levels of matrix metalloproteinase (MMP)-8, a matrix-degrading enzyme released by neutrophils, and the risk of PTLD, as measured by formal lung function testing. For Aim 2, we will determine the association between sputum levels of transforming growth factor (TGF)-β, a master regulator of fibrosis, and PTLD. Secondary analyses will determine whether HIV modifies the relationship between neutrophilic or profibrotic activity and PTLD, and will include additional biomarkers of neutrophil and profibrotic activity in both sputum and exhaled breath condensate, in addition to direct assessment of collagen deposition in the lungs using a novel collagen-binding PET probe. By focusing on the complementary pathways of neutrophil-mediated lung damage and profibrotic repair and remodeling, and then connecting activity in those biological pathways to clinically significant impairments in lung function among TB survivors, this study will be the most comprehensive study of PTLD to date. The knowledge gained from this study will directly inform future mechanistic and therapeutic studies with the goal of reducing rates and severity of PTLD and improving long-term outcomes for millions of TB survivors each year.

PROJECT NARRATIVE Despite being cured of their tuberculosis (TB), millions of TB survivors each year suffer from chronic lung damage. Unfortunately, the nature of this lung damage is not well understood, which limits our ability to care for patients suffering from chronic lung disease after TB. By characterizing the role of neutrophilic and profibrotic activity as risk factors for post-TB lung damage, this study will inform future treatment strategies to prevent or reduce this devastating complication of TB.