Causality of Post-TB Lung Disease: Population-Level Evidence from Rural Uganda

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading single-agent cause of infectious mortality worldwide, including among people with HIV (PWH). TB survivors also continue to experience sequelae including post-TB lung disease (PTLD) and higher mortality. It remains uncertain, however, how much of these post-TB sequelae reflect TB itself versus underlying pre-TB risk factors and lung disease. For example, if a substantial burden of PTLD reflects pre-existing lung damage due to smoking – itself a risk factor for TB – then preventing TB may have minimal effect on this burden, and we should prioritize efforts to augment smoking cessation (including among people at risk for TB). By contrast, if PTLD development instead reflects lung damage incurred while TB diagnosis was delayed (e.g., because people who smoke may delay seeking care for a cough), then efforts to detect TB more rapidly – or prevent TB in the first place – are even more essential. Such questions can only be answered by evaluating lung function and respiratory symptoms both before and after people develop TB. Performing such a study is challenging, however, because typically no more than 1 in 500 people develop TB each year. Thus, a large population must be followed after an initial lung function evaluation to obtain a sufficient sample size for analysis. This proposal leverages a unique opportunity to create such a prospective cohort, as 9,000 people from a district in rural southwestern Uganda (Rakai district) are already being recruited into a cohort study involving lung function testing. These participants can be followed for TB and paired with an additional 20,000 people from an ongoing decades-long community-based cohort study in the same area (the Rakai Community Cohort Study) to create a novel prospective population-based cohort for evaluating pre-TB and post-TB lung function in an HIV-endemic African setting. In Specific Aim 1, we will characterize trajectories of lung function before and after the development of TB disease, including among key subgroups (e.g., PWH). This aim will enable us to infer the fraction of post-TB lung function deficits that are attributable to TB itself versus reflective of underlying lung vulnerability. In Specific Aim 2, we will identify pre-TB characteristics and biomarkers that are associated with a higher burden of future PTLD – both through higher risk of developing TB and higher risk of experiencing PTLD if TB develops. This aim will enhance our understanding of PTLD pathophysiology and identify key subpopulations that might benefit from interventions to prevent TB or mitigate its consequences. In Specific Aim 3, we will use population modeling techniques to project the likely long-term impacts of different interventions on the population burden of post-TB illness. These results will enable policymakers to better prioritize those interventions most likely to have the greatest impact when delivered to specific key populations. In summary, the proposed study will make use of a novel “window of opportunity” to better understand lung function in TB survivors – before they develop TB in the first place. This understanding will facilitate a more effective response to averting and/or mitigating the tremendous burden of post-TB illness worldwide.