Pathogenesis of Post-Tuberculosis Lung Disease: Defining Knowledge Gaps and Research Priorities at the Second International Post-Tuberculosis Symposium

Abstract

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed.

Keywords: fibrosis; matrix metalloproteinases; neutrophils; post-tuberculosis lung disease; tuberculosis.

Figure 1.

Consensus key areas of importance in post-tuberculosis lung disease pathogenesis. Created with BioRender.com. ECM = extracellular matrix; MMPs = matrix metalloproteinases; Mtb = Mycobacterium tuberculosis; TB = tuberculosis.

Figure 2.

Proposed relationship between Mycobacterium tuberculosis (Mtb) bacterial burden, extracellular matrix (ECM) remodeling, and risk of post-tuberculosis lung disease (PTLD). Disseminated tuberculosis (TB) disease often occurs in the setting of immunodeficiency (e.g., advanced HIV) or a less developed immune system (e.g., infants) and is characterized by less clinically evident ECM damage and remodeling. In disseminated disease, sputum Mtb burden may be low because of a lack of cavitation, but there is a high Mtb burden in tissues on histopathological analysis and/or postmortem findings, and mortality is typically high. In patients with minimal pulmonary disease, there is typically a low Mtb burden with moderate pulmonary immune responses and accompanying ECM damage remodeling, in addition to a relatively lower risk of PTLD. In advanced pulmonary disease, including classical post-primary TB with upper lobe cavitation, there is a high Mtb burden, often with accompanying sputum smear acid-fast bacilli positivity, and more extensive ECM damage and remodeling, with a greatly increased risk of PTLD.