Immunologic and imaging signatures in post tuberculosis lung disease

Abstract

Post Tuberculosis Lung Disease (PTLD) affects millions of tuberculosis survivors and is a global health burden. The immune mechanisms that drive PTLD are complex and have historically been under investigated. Here, we discuss two immune-mediated paradigms that could drive human PTLD. We review the characteristics of a fibrotic granuloma that favors the development of PTLD via an abundance of T-helper-2 and T-regulatory cells and an upregulation of TGF-β mediated collagen deposition. Next, we discuss the post-primary tuberculosis paradigm and the complex mixture of caseous pneumonia, cavity formation and fibrosis that can also lead to PTLD. We review the delicate balance between cellular subsets and cytokines of the innate and adaptive immune system in conjunction with host-derived proteases that can perpetuate the parenchymal lung damage seen in PTLD. Next, we discuss the role of novel host directed therapies (HDT) to limit the development of PTLD and in particular, the recent repurposing of established medications such as statins, metformin and doxycycline. Finally, we review the emerging role of novel imaging techniques as a non-invasive modality for the early recognition of PTLD. While access to computed tomography imaging is unlikely to be available widely in countries with a high TB burden, its use in research settings can help phenotype PTLD. Due to a lack of disease-specific biomarkers and controlled clinical trials, there are currently no evidence-based recommendations for the management of PTLD. It is likely that an integrated antifibrotic strategy that could simultaneously target inflammatory and pro-fibrotic pathways will probably emerge as a successful way to treat this complex condition. In a disease spectrum as wide as PTLD, a single immunologic or radiographic marker may not be sufficient and a combination is more likely to be a successful surrogate that could aid in the development of successful HDTs.

Keywords: Biomarker; Granuloma; Host directed therapy; Imaging; PTLD; Radiographic signature.

Fig. 1.

Depicts the characteristics of a fibrotic granuloma (left) and a transmissive granuloma (right). Fibrotic granulomas have an abundance of Th2 and Treg cells that drive TGF-β mediated collagen deposition, thick capsule consisting of myofibroblasts and an abnormal fibrous cuff. Transmissive granulomas are rich in classically activated and foamy macrophages as well as neutrophils. These cells produce inflammatory mediators such as tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) and depending on other host modulating factors, can result in the development of active cavitary TB disease. As the figure depicts, fibrotic granulomas favor the development of PTLD and transmissive granulomas favor the development of active TB, but granulomas can undergo changes driven by host factors and surrounding milieu such that they can morph into one or the other kind. Finally, the figure also depicts that active cavitary TB can lead to PTLD in the event of aberrant healing and distortion of lung architecture.

Fig. 2.

An overview of the various HDTs that are undergoing clinical trials, such as PDE4 inhibitors, cellular and cytokine targets, repurposed drugs and RNA interference technology. Here we focus on HDTs that can potentially be used for individuals that are at high risk of developing PTLD.