Phenotype, Progression and Immune Correlates of Post-Tuberculosis Lung Disease

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PROJECT ABSTRACT Pulmonary tuberculosis (PTB) is associated with lung injury which can persist despite successful therapy. Lung sequelae of treated PTB are increasingly recognized as an independent risk factor for chronic obstructive pulmonary disease (COPD) and, an important contributor of excess morbidity and mortality. Our prior work measuring lung function in a cohort of young and predominantly never-smoking adults with PTB who successfully completed TB therapy found 14% had COPD, an additional 10% had airflow obstruction which responded to bronchodilator therapy, and nearly 50% had a restrictive spirometry pattern. These data suggest that the predominant phenotype of post-PTB chronic lung disease (CLD) may differ from that seen in smoking-associated COPD. Post-PTB CLD may have distinct natural history, prognosis and therapeutic strategies which, till date, have not been investigated. Our prior work also found that post-PTB CLD was associated with the duration of illness prior to initiating TB therapy and high levels of slow-to-resolve pro-fibrotic cytokines during late TB therapy. Together, these data suggest that the vast majority of acute lung injury associated with PTB likely occurs prior to and shortly after initiating TB therapy, and that elevated or persistent levels of key immune markers may be detrimental through their impact on lung tissue remodeling. However, few studies have prospectively characterized immune markers associated with long-term functional outcomes in PTB. This is an important knowledge gap preventing the identification of potentially modifiable immune pathways for targeted host-directed therapies, and the optimal timing of intervention with these therapies, to prevent post-PTB CLD. To address these knowledge gaps, we will nest a prospective cohort study within the RePORT-India TB Research Consortium to 1) characterize the early natural history of post-PTB CLD and provide rationale for long-term monitoring and bronchodilator therapy in affected cases, 2) characterize the functional and morphological phenotype of post-PTB CLD by serial pulmonary function testing and multi-detector computed tomography, 3) identify immune profiles measured during early, late and post-therapy associated with post-PTB CLD. Through this K99/R00 award, Dr. Gupte will complement his prior training in infectious disease epidemiology by obtaining mentorship in the identification, measurement and interpretation of 1) clinically relevant lung function and imaging outcomes for CLD research; 2) potentially modifiable immune markers of chronic lung injury for future therapeutic trials; and 3) advanced statistical methods for the integrated analysis of lung function, imaging and immunological data. This K99/R00 award will help Dr. Gupte develop into an independent investigator conducting impactful clinical research at the intersection of infectious and chronic lung diseases globally, while also building site capacity and generating novel data to support subsequent R01 applications aimed at identifying diagnostic, prognostic and therapeutic strategies for CLD in treated PTB.