From granuloma to fibrosis: sarcoidosis associated pulmonary fibrosis

Abstract

Purpose of review: Up to twenty percent of patients with sarcoidosis develop pulmonary fibrosis, transforming an often benign disease into a highly morbid and potentially fatal one. We highlight the fibrotic pulmonary sarcoidosis phenotype as an area of intense clinical and translational investigation, review recent developments in treatment, and provide a roadmap for future research in sarcoidosis associated pulmonary fibrosis.

Recent findings: Granulomatous inflammation in a lymphatic distribution is the hallmark finding of pulmonary sarcoidosis and the nidus for fibrosis. Recent research demonstrates that fibrotic sarcoidosis begins in the setting of persistent, uncontrolled inflammation, and is aided by pro-fibrotic genetic features and immune responses. Comparison to other fibrotic lung diseases also reveals key features that inform our understanding of common pathways in fibrosis.

Summary: Understanding the mechanisms of fibrotic transformation in sarcoidosis enhances clinical care and facilitates development of novel therapeutic options. The impact of these findings in fibrotic sarcoidosis may be amplified through application to other interstitial lung diseases marked by inflammatory to fibrotic transformation. Important aspects of clinical management of fibrotic sarcoidosis include surveillance for co-morbidities, such as pulmonary hypertension, airway disease, and infection, and assessment for pulmonary disease activity that may benefit from immunosuppression.

Figure 1

Multiple non-caseating granulomas distributed along the airway (arrowheads). Image courtesy of Aliya Husain MD.

Figure 2

Granulomatous inflammation transitions to fibrosis. The pathophysiology of sarcoidosis begins with exposure to putative inhaled antigen(s) that in the appropriate genetic and epigenetic context initiate an immune cascade via activation of interstitial dendritic cells (DC), alveolar macrophages (Mφ), and type 2 alveolar epithelial cells (AEC-II) (a). Antigen is presented by cells such as DC and recognized by CD4+ T cells (b). The engagement of CD4+ cells leads to their activation and proliferation, and release of an array of pro-inflammatory cytokines (c). Antigen features, Th1 polarization of CD4+ lymphocytes, and the cytokine milieu all likely contribute to the recruitment and organization of macrophages into granulomas within lymphatic tracks (d). In some cases, fibrosis begins at the periphery of sarcoid granulomas (e), which serves to contain if not break up active granulomas. As it extends over time, this deposition of collagen results in mature fibrosis which obliterates parenchymal tissue, resulting in “end-stage” sarcoidosis (f).

Figure 3

Chest CT of a patient with fibrotic pulmonary sarcoidosis and pulmonary hypertension (axial view at level of carina).