Fibroblast activating protein PET-CT imaging of TB-associated fibrosis

ABSTRACT
Although most of the world's annual 11 million TB patients survive their infection, up to half of those cured of
pulmonary TB develop permanent lung damage, manifesting as chronic cough, breathlessness, and decreased
functional capacity. With an estimated 155 million TB survivors alive in 2020, post-TB lung disease (PTLD)
is a substantial contributor to the global burden of chronic respiratory disease which is, in turn, the third
most important cause of mortality worldwide. Lung fibrosis is a major feature of most PTLD pathologies, yet
mechanisms of profibrotic activity in these individuals are unclear and there are currently no approved
medications available for treatment or prevention of this syndrome. Considering the global burden of PTLD
exceeds that of all other interstitial lung diseases combined, this is a major research gap in urgent need
of attention. In this proposal we aim to evaluate a novel and potentially transformative approach capable of
directly characterizing profibrotic activity in the lungs of adult pulmonary TB patients using fibroblast activation
protein (FAP) positron emission computed tomography (FAP PET/CT). FAP is a cell surface serine protease that
is selectively upregulated on lung fibroblasts in conditions associated with extracellular matrix remodeling,
including idiopathic pulmonary fibrosis, wound healing, and cancer. Importantly, emerging preclinical studies
have shown reversal of fibrosis in preclinical models using FAP inhibition. In this proposal, we will pursue two
aims using a longitudinal cohort study design: Aim 1: To determine the relationship between change in FAP
radiographic signals in lungs during TB treatment and change in lung structural damage in adult patients
treated for pulmonary TB. Greater radiographic lung structural damage in TB, a hallmark of PTLD, is inversely
associated with lung function and has repeatedly been associated with reduced survival in TB. In this longitudinal
study, we will perform FAP PET/CT and high-resolution CT (HRCT) within 6 weeks of TB treatment initiation and
again within 6 months after TB cure. We expect patients with less decrease in FAP lung signals will have less
improvement in lung structural damage despite curative TB treatment. Aim 2: To characterize the association
between FAP PET/CT signals early after TB diagnosis and persistent lung structural damage after cure.
We will use the longitudinal data from FAP PET/CT and HRCT above to evaluate the hypothesis that higher
levels of total FAP signal in the lungs near the time of TB treatment initiation will be associated with
higher overall levels of residual structural lung damage on HRCT after TB cure. Currently very little is
known about how to treat, predict, or prevent PTLD, and therapeutic and diagnostic targets are urgently needed.
These aims will substantially advance the field via use of an innovative approach to characterize a biomarker for
interventions designed to decrease the patient and public health burden of this globally important and historically
neglected disease.

Grant Number: 1R21AI179016-01A1
NIH Institute/Center: NIH
Principal Investigator: GREGORY BISSON