Investigating the link between post-tuberculosis lung disease (PTLD) and circulatory biomarkers in a South African cohort
Tuberculosis (TB) is a leading cause of death from a single infectious agent, despite being preventable and curable. While global health efforts have significantly improved diagnostic and therapeutic strategies, emerging evidence demonstrates that many patients experience long-term pulmonary complications after completing TB treatment. These complications are collectively termed post-tuberculosis lung disease (PTLD). PTLD is a complex and heterogeneous disease which contributes to increased mortality in this patient population. Its pathogenesis, however, remains poorly understood. This dissertation investigates whether endothelial dysfunction and immunopathological mechanisms associate with PTLD, by examining systemic biomarkers in patients with active TB and those with a history of TB. The central hypothesis is that endothelial dysfunction and a chronic pro-inflammatory state persist beyond microbiological cure, contributing to PTLD development. Three interrelated sub-studies were conducted to explore this hypothesis. The first sub-study measured endothelial and oxidative stress biomarkers, including ADMA, VCAM-1, VEGF, angiopoietin-1, TBARS, NT-pro-BNP, and cardiac troponin-I, in patients stratified by the number of previous TB episodes and the time since the last treatment. VEGF and angiopoietin-1 were significantly elevated (up to 6500-fold above normal), with positive correlations to TB episode count. ADMA levels were 70-fold higher, though weakly negatively correlated with TB history. TBARS concentrations were low, and NT-pro-BNP and cardiac troponin-I were undetectable. The second sub-study assessed inflammatory markers IL-6, IL-8, TNF-α, CRP, and IL-1Ra in two cohorts: individuals with prior TB (>1-year post-treatment) and patients undergoing treatment for drug-sensitive TB. IL-6, TNF-α, and CRP were markedly elevated in both groups, indicating a sustained inflammatory response. IL-8 and IL-1Ra showed variable expression between cohorts, suggesting differential immune activation. The third sub-study focused on PTLD patients, measuring IL-1, IL-6, TNF-α, and CRP levels. IL-1 was elevated 83-fold, with IL-6, TNF-α, and CRP also significantly increased. Correlation analyses revealed complex relationships among biomarkers, TB history, smoking, and cardiovascular risk. Notably, IL-6 correlated positively with TB episode count, while TNF-α and CRP were interrelated. Smoking and recurrent TB episodes were moderately associated with increased inflammation. These findings challenge the conventional definition of treatment “success” in TB care, demonstrating that microbiological cure does not equate to immunological resolution. Persistent inflammation and endothelial dysfunction years after treatment completion underscore the need for long-term monitoring and host-directed therapeutic strategies. Adjunctive anti-inflammatory therapies may offer clinical benefit, but their safety must be evaluated in preclinical and pilot studies. This dissertation contributes to the understanding of PTLD by identifying key biomarkers and their associations with disease history and comorbidities. It advocates for a paradigm shift in TB management, one that integrates immune regulation and post-treatment surveillance. A deeper understanding of post-TB immune dynamics is essential to improve outcomes and inform clinical guidelines in TB-endemic settings.
Networked Digital Library of Theses and Dissertations