Inflammation and Fibrosis in Pulmonary TB: the INFIN-TB Study

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.

Grant Number: 3R01AI166988-04S1
NIH Institute/Center: NIH
Principal Investigator: Sara Auld