Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1^-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.

Background: There is growing interest in identifying early stages of interstitial lung disease (ILD) to improve patient outcomes. This document reviews updated evidence on interstitial lung abnormalities (ILAs); provides suggestions for screening, evaluation, and management; proposes criteria for distinguishing ILAs from ILD; and identifies research priorities. Methods: A committee of clinical and methodology experts met by video conference to define ILAs and ILD by consensus and voted on 11 prespecified questions after reviewing synthesized evidence from a systematic literature search. Agreement of ≥70% was required to approve each suggestion. Results: ILA is defined as nondependent bilateral parenchymal abnormalities on computed tomography, including ground-glass opacities or reticulations, lung distortion, traction bronchiectasis, and/or honeycombing involving ≥5% of a lung zone. The updated definition removes the prior exclusion of high-risk populations. ILD is distinguished from ILAs by symptoms (dyspnea/cough) attributable to an interstitial process, abnormal or declining lung function, fibrotic (honeycombing and/or reticulation with traction bronchiectasis involving ≥5% of total lung volume) or progressive imaging abnormalities, and/or specific fibrotic ILD patterns on imaging or pathology. Suggestions include ILA/ILD assessment on imaging acquired for lung cancer screening, screening adults with connective tissue disease and first-degree relatives of patients with familial pulmonary fibrosis, assessing baseline symptoms and pulmonary function among those with ILAs, and monitoring ILAs with chest computed tomography every 2–3 years. Conclusions: This document presents a comprehensive literature review of ILAs with updates to the Fleischner Society ILA definition, establishes a working ILD definition, and provides evidence-based suggestions for ILA evaluation and management.

The prevalence and incidence of sarcoidosis varies worldwide. We estimated the prevalence and incidence of sarcoidosis in Korea using nationwide claims data from the Korean Health Insurance Review and Assessment Service. Cases of sarcoidosis were identified for any visit between 2007 to 2016 that listed the Korean Classification of Disease, 7th edition code of sarcoidosis and rare incurable disease exempted calculation code. A narrow case definition was used as follows: 1) ≥ two sarcoidosis-coded visits within 1 year of the first claim, 2) no claims for other diseases that could form granuloma. A total of 4791 patients (narrow, n = 2388) visited medical institutions for sarcoidosis during the study period; 2999 patients (narrow, n = 1696) were newly identified between 2009 and 2015. The sarcoidosis prevalence was 9.37 per 105 people (narrow, 4.69) and was highest between ages 60–69 years. The incidence rate was 0.85 per 105 population at risk (narrow, 0.48), with the highest incidence rate between ages 50–59 years. For incident cases (mean age: 48.5 year), the age distribution in whole population and females showed monophasic patterns peaking at aged 50–59 years, while males had biphasic incidence peak at aged 30–39 years and 60–69 years. The annual incidence rates showed increasing trends from 0.85 per 105 population at risk in 2009 to 0.97 per 105 population at risk in 2015. In comparison with previous reports, the prevalence and incidence of sarcoidosis in Korea have increased and middle-aged women showed the highest risk.

Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) has a variable clinical course for which predicting prognosis is difficult. However, the role of blood biomarkers in RA-ILD is ill-defined. The aim of this study was to investigate the prognostic value of Krebs von den Lungen-6 (KL-6) levels in RA-ILD patients. The medical records of 84 patients with RA-ILD were retrospectively reviewed. Plasma KL-6 levels were measured by Nanopia KL-6 assay (SEKISUI MEDICAL, Tokyo), using latex-enhanced immunoturbidimetric assay. The median follow-up period was 61 months. Mean age was 61.4 years, 45.2% were men, 44.0% were ever-smokers, and 35.7% showed a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography. The median KL-6 level at baseline was 741.2 U/mL (interquartile range, 439.7–1308.9 U/mL). On multivariate logistic regression analysis, a high KL-6 level (≥ 640 U/mL) was an independently associated with a UIP pattern (odds ratio [OR], 5.173; P = 0.005) with old age (OR, 1.104, P = 0.005). On multivariate Cox analysis, a high KL-6 level (≥ 685 U/mL) was an independent prognostic factor for the mortality (hazard ratio [HR], 2.984; P = 0.016) with a older age (HR, 1.061; P = 0.030), male sex (HR, 3.610; P = 0.001), lower forced vital capacity (HR, 0.957; P = 0.002), and a UIP pattern (HR, 4.034; P = 0.002). Our results suggest that high KL-6 levels might be useful as a biomarker for the presence of a UIP pattern and prognosis in patients with RA-ILD.

Background: The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. Methods: Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. Results: The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DL_CO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. Conclusions: Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

Phase 3 trials have shown that nintedanib reduces the decline in forced vital capacity (FVC) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) with acceptable safety profiles; however, its effects on advanced IPF are unclear. We investigated the efficacy and safety of nintedanib in patients with advanced IPF. Prospective data were obtained from 108 IPF patients administered at least one dose of nintedanib. Of these patients, 47.2% had advanced IPF (FVC < 50% predicted, or diffusing capacity < 30% predicted). The median treatment duration was 42.2 weeks. Nintedanib significantly reduced the decline rate in both FVC (− 0.55% [before] vs. -0.32% [after] predicted/month, p = 0.020) and total lung capacity (TLC) (− 0.35% vs. -0.06% predicted/month, p < 0.001) in all patients. A significant improvement in FVC decline rate after treatment was also observed in the advanced group (− 0.77% vs. -0.22% predicted/month, p = 0.003), but not in the non-advanced group (− 0.41% vs. -0.33% predicted/month, p = 0.564). Adverse events occurred in 97.2% of the cohort, including diarrhoea (50.0%) and anorexia (45.4%). Following adjustment for treatment duration, no inter-group difference in odds ratio was observed for the occurrence of adverse events. However, the advanced group showed a higher frequency of treatment interruption (68.0% vs. 40.0%), mainly as a result of disease progression (47.1% vs. 36.4%). The efficacy and safety profiles of nintedanib in the advanced group were comparable to those in the non-advanced group except for a higher frequency of discontinuation, which may be due to the advanced status itself.