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

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

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.