To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.
Increasing use of molecular targeting agents and immune checkpoint inhibitors has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. In this position paper from the Fleischner Society, the authors provide diagnostic criteria and management recommendations of drug-related pneumonitis for radiologists, clinicians, clinical trialists, and trial sponsors.
Background: Although the third most frequent interstitial lung disease, hypersensitivity pneumonitis (HP) remains an enigmatic disease without clear diagnostic and therapeutic guidelines. We assessed the effect of the commonly used therapeutic interventions (i.e. exposure avoidance and corticosteroid treatment) in an HP cohort. Methods: We collected clinical data of all HP patients followed at our centre between January 1, 2005, and December 31, 2016. HP patients were stratified according to the presence of fibrosis on chest CT. Survival was analysed using the multivariate Cox proportional hazards model. Forced vital capacity (percent predicted, FVC%) and diffusing capacity of the lung for carbon monoxide (percent predicted, DLCO%) evolution were analysed using linear mixed-effect models. Results: Two hundred and two HP patients were identified: 93 non-fibrotic HP (nfHP) and 109 fibrotic HP (fHP), experiencing a monthly FVC% decline before treatment of 0.93% and 0.56%, respectively. While nfHP had an excellent survival, fHP patients experienced a median survival of 9.2 years. Corticosteroid treatment and exposure avoidance did not result in survival differences. Although nfHP patients showed FVC% and DLCO% increase after corticosteroid initiation, no therapeutic effect was seen in fHP patients. FVC% and DLCO% increased in nfHP patients after exposure avoidance, while a positive numerical trend was seen for FVC% after exposure avoidance in fHP patients (p = 0.15). Conclusions: nfHP patients experienced an excellent survival with good therapeutic effect on pulmonary function tests with both corticosteroid initiation as well as antigen avoidance. In contrast, fHP patients experienced a dismal prognosis (median survival of 9.2 years) without any therapeutic effect of corticosteroid treatment. Whether antigen avoidance is useful in fHP patients is still unclear.
To investigate the use of diffusion-weighted (DW) imaging for differentiating benign lesions from malignant pleural disease (MPD) and to retrospectively assess dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging acquisitions to find out whether combining these measurements with DW imaging could improve the diagnostic value of DW imaging. This study was approved by the local ethics committee, and all patients provided written informed consent. Thirty-one consecutive patients with pleural abnormalities suspicious for MPD underwent whole-body positron emission tomography (PET)/computed tomography (CT) and thorax MR examinations. Diagnostic thoracoscopy with histopathologic analysis of pleural biopsies served as the reference standard. First-line evaluation of each suspicious lesion was performed by using the apparent diffusion coefficient (ADC) calculated from the DW image, and the optimal cutoff value was found by using receiver operating characteristic curve analysis. Afterward, DCE MR imaging data were used to improve the diagnosis in the range of ADCs where DW imaging results were equivocal. Sensitivity, specificity, and accuracy of PET/CT for diagnosis of MPD were 100%, 35.3%, and 64.5%. The optimal ADC threshold to differentiate benign lesions from MPD with DW MR imaging was 1.52 × 10(-3) mm(2)/sec, with sensitivity, specificity, and accuracy of 71.4%, 100%, and 87.1%, respectively. This result could be improved to 92.8%, 94.1%, and 93.5%, respectively, when DCE MR imaging data were included in those cases where ADC was between 1.52 and 2.00 × 10(-3) mm(2)/sec. A total of 20 patients had disease diagnosed correctly, nine had disease diagnosed incorrectly, and two cases were undetermined with PET/CT. DW imaging helped stage disease correctly in 27 patients and incorrectly in four. The undetermined cases at PET/CT were correctly diagnosed at MR imaging. DW imaging is a promising tool for differentiating MPD from benign lesions, with high accuracy, and supplementation with DCE MR imaging seems to further improve sensitivity.
There are elements in this study that suggest the presence of alveolar collapse in an early stage when there is only little fibrosis, supporting the theory that alveolar collapse might be the initi... PurposeTo elucidate the underlying lung changes responsible for the computed tomographic (CT) features of idiopathic pulmonary fibrosis (IPF) and to gain insight into the way IPF proceeds through t...