Although only recently introduced in the ILD community, the concept of progressive fibrosing interstitial lung disease (PF-ILD) has rapidly acquired an important place in the management of non-idiopathic pulmonary fibrosis fibrosing ILD (nonIPF fILD) patients. It confirms a clinical gut feeling that an important subgroup of nonIPF fILD portends a dismal prognosis despite therapeutically addressing the alleged triggering event. Due to several recently published landmark papers showing a treatment benefit with currently available antifibrotic drugs in PF-ILD patients, endorsing a PF-ILD phenotype has vital therapeutic consequences. Importantly, defining progressiveness is based on former progression, which has proven to be a rather moderate predictor of future progression. As fibrosis extent >20% and the presence of honeycombing have superior predictive properties regarding future progression, we advocate immediate initiation of antifibrotic treatment in the presence of these risk factors. In this perspective, we describe the historical context wherein PF-ILD has emerged, determine the currently employed PF-ILD criteria and their inherent limitations and propose new directions to mature its definition. Finally, while ascertaining progression in a nonIPF fILD patient clearly demonstrates the need for (additional) therapy, in the future, therapeutic decisions should be taken after assessing which pathway is ultimately driving the progression. Although not readily available, pathophysiological insight and diagnostic means are emergent to go full steam ahead in this novel direction.

Scientific Knowledge on the Subject: The transcriptome landscape of pulmonary fibrosis has been studied almost univariably in the context of idiopathic pulmonary fibrosis (IPF). In fibrotic hypersensitivity pneumonitis (fHP), T cell activation has been shown, but it remains unclear what the most prevailing molecular traits are in fHP. What This Study Adds to the Field: In this explant lung study, we characterised the six most prevailing molecular traits including extracellular matrix, antigen presentation/sensitization, honeycombing, B-cell activation, endothelial dysfunction and progressive disruption in normal cellular homeostatic processes. The molecular traits differently associated with disease progression dynamics and correlated with in vivo disease behaviour in a separate clinical fHP cohort. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent, rather than diagnosis alone.

Bronchiolitis obliterans syndrome (BOS) is considered an airway-centered disease, with bronchiolitis obliterans (BO) as pathologic hallmark. However, the histologic spectrum of pure clinical BOS remains poorly characterized. We provide the first in-depth histopathologic description of well-characterized BOS patients and patients without chronic lung allograft dysfunction (CLAD), defined according to the recent consensus guidelines. Explant lung tissue from 52 clinically-defined BOS and 26 non-CLAD patients (collected 1993–2018) was analyzed for histologic parameters, including but not limited to airway lesions, vasculopathy and fibrosis. In BOS, BO lesions were evident in 38 (73%) patients and varied from concentric sub-epithelial fibrotic BO to inflammatory BO, while 10/14 patients without BO displayed ‘vanishing airways’, defined by a discordance between arteries and airways. Chronic vascular abnormalities were detected in 22 (42%) patients. Ashcroft fibrosis scores revealed a median of 43% (IQR: 23–69) of normal lung parenchyma per patient; 26% (IQR: 18–37) of minimal alveolar fibrous thickening; and 11% (IQR: 4–18) of moderate alveolar thickening without architectural damage. Patchy areas of definite fibrotic damage to the lung structure (i.e., Ashcroft score ≥ 5) were present in 28 (54%) patients. Fibrosis was classified as bronchocentric (n = 21/28, 75%), paraseptal (n = 17/28, 61%) and subpleural (n = 15/28, 54%). In non-CLAD patients, BO lesions were absent, chronic vascular abnormalities present in 1 (4%) patient and mean Ashcroft scores were significantly lower compared to BOS (p = 0.0038) with 78% (IQR:64–88) normally preserved lung parenchyma. BOS explant lungs revealed evidence of various histopathologic findings, including vasculopathy and fibrotic changes, which may contribute to the pathophysiology of BOS.

A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness of idiopathic pulmonary fibrosis (IPF). Common pathophysiological mechanisms such as a shared genetic susceptibility and a common downstream pathway—self-sustaining fibroproliferation—support the concept of a progressive fibrosing phenotype, which is applicable to a broad range of non-IPF ILDs. While antifibrotic drugs became the standard of care in IPF, immunosuppressive agents are still the mainstay of treatment in non-IPF fibrosing ILD (F-ILD). However, recently, randomized placebo-controlled trials have demonstrated the efficacy and safety of antifibrotic treatment in systemic sclerosis-associated F-ILD and a broad range of F-ILDs with a progressive phenotype. This review summarizes the current pharmacological management and highlights the unmet needs in patients with non-IPF ILD.

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