PET to Assess Post-TB Lung Disease in TB Patients with / without HIV coinfection

Mycobacterium tuberculosis remains the second leading cause of death from a single infectious agent globally, after COVID-19. The risk of developing tuberculosis (TB) is substantially higher in human immunodeficiency virus (HIV) coinfected individuals, with TB and HIV potentiating each other, causing substantial declines in immune function. Globally in 2022, there were an estimated 1.3 million deaths and 10.6 million new cases due to TB. Importantly, it is estimated that more than 58 million patients have survived TB in this century alone. However, unlike other respiratory infections, many patients with TB have permanently damaged tissues and successful TB treatments only transition these patients from harboring a communicable infectious disease, to a syndrome of chronic pulmonary morbidity. This syndrome, commonly referred as post- TB lung disease, affects ~50% of patients with pulmonary TB, who develop chronic adverse outcomes beyond the TB treatments, including bronchiectasis, poor lung function and respiratory symptoms. Although post-TB lung disease remains poorly characterized, it is primarily mediated by M. tuberculosis-induced tissue destruction (necrosis) and subsequent adverse lung tissue remodeling and fibrosis, which in addition to causing pulmonary disease, also impairs vascular supply and reduces antibiotic access to the infected TB lesions. Currently, there are no approved treatments to prevent post-TB lung disease. We have characterized lung disease in animal models of TB to develop adjunctive treatments that prevent post-TB lung disease. Importantly, we have also developed and utilized novel, clinically translatable positron emission tomography (PET)-based imaging to longitudinally profile lesional characteristics in animal models and TB patients: 11C-rifampin (chemically identical to rifampin) PET to measure tissue antibiotic area under the curve exposures (Ordonez . . . Jain. Nat Med. 2020) and 18F-FAPI-74 PET for monitoring fibrosis. Our central hypothesis is that 18F-FAPI-74 PET could be used as a noninvasive biomarker to assess post-TB lung disease and fibrosis in TB patients. Additionally, we hypothesize that lesions with significantly reduced 11C-rifampin exposures in TB patients within 6-weeks of treatment initiation (early time-point) will develop post-TB lung disease sequelae at those sites after treatment completion. Here, we will leverage our expertise in TB pathogenesis and molecular imaging to conduct longitudinal, observational studies to visualize lesional rifampin exposures and lung fibrosis in patients with recently diagnosed pulmonary TB, with or without HIV coinfection, within 6-weeks of initiation and after completion of TB treatments. Our goals are to better characterize post-TB lung disease sequelae and identify key factors, such as lesional antibiotic exposures in TB patients that could subsequently lead to post-TB lung disease. In the future, we anticipate that these imaging approaches could be used to noninvasively characterize post TB- lung disease and evaluate novel treatments that prevent or mitigate post TB-lung disease. Project Number: 7R21AI192087-02 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Sanjay Jain | Institution: CINCINNATI CHILDRENS HOSP MED CTR, CINCINNATI, OH | Award Amount: $445,500 | Activity Code: R21 | Study Section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/7R21AI19208702