Pulmonary fibrosis in sarcoidosis

Abstract

Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern surrounding the granulomas. Th1 to Th2 shift in environment along with angiogenesis is implicated in exuberant fibrosis. Clinical features include dyspnea, cough, and frequently with pulmonary function tests showing a mixed ventilatory defect with severely decreased diffusion capacity of carbon monoxide. Serologic markers including soluble interleukin 2 receptor, chitotriosidase and kern von den lunges 6, and chemokine ligand 18 are elevated and implicated in progression of disease. CT imaging shows fibrosis along bronchovascular bundles with reticulations, traction bronchiectasis and honeycombing predominantly in the upper and central distribution. Complications include sarcoidosis-associated pulmonary hypertension (SAPH) and chronic pulmonary aspergillosis. Treatment involves glucocorticoids and steroid-sparing agents in the presence of active granulomas. Anti-fibrotic agents such as pirfenidone and nintedanib have been shown to slow down pulmonary function decline in randomized clinical trials involving sarcoidosis-associated pulmonary fibrosis. Transplant workup is indicated in New York Heart Association class III or IV with similar success rates as in other lung transplant patients.

Fig. 1.

Non-caseating granuloma with surrounding myofibroblasts and dense collagen tissue in fibrotic disease in sarcoidosis.

Fig. 2.

Antigen presentation via antigen presenting cells (APC) activates Th0 helper cells that in the presence of specific cytokines, differentiates into Th1, Th17.1, Th17 or T_reg cells. IFN-γ activates macrophages that secrete tumor necrosis factor TNF and subsequently transition to epithelioid giant cells. IFN-γ mediates activation of Tbx2 gene activates transcription factor (TF) Tbet that inhibits TF Gata3. Gata3 is implicated in activation of T_reg cells to produce IL 10 and TGF-β and activation of Th2 cells that produce IL4 and IL 13 with downstream activation of collagen production and fibrosis.

Fig. 3.

Th2 cytokines mediated stimulation of M2 macrophages by collagen to produce CCL18. CCL18 in turn stimulates collagen production by fibroblasts starting a positive feedback loop leading to pulmonary fibrosis.

Fig. 4.

Kaplan Meier Survival analysis for sarcoidosis with fibrosis as compared to general population. Figure reproduced with permission from European Respiratory Journal (2).

Fig. 5.

Kaplan Meier Survival analysis for sarcoidosis patients with chronic pulmonary aspergillosis. Figure reproduced with permission from European Respiratory Journal (1).