Chronic Fibrosing Interstitial Lung Disease Research Articles

Idiopathic pulmonary fibrosis : Radiological diagnosis in light of the current guidelines

Idiopathic pulmonary fibrosis (IPF) is aspecific form of chronic progressive fibrosing interstitial lung disease with a poor prognosis. High-resolution computed tomography (HRCT) plays an important role in the work-up of patients with suspected IPF. In HRCT IPF is characterized by the pattern of usual interstitial pneumonia (UIP). For a long time only supportive or immunosuppressive treatment was possible. The approval of antifibrotic agents in 2012 marked aturning point and triggered further clinical and scientific interest. Based on the recently gained knowledge the revised version of the international guidelines for the diagnosis of IPF was published in 2018, including instructions for HRCT interpretation. In this continued medical education article the relevant signs in HRCT are presented. The specifications given in the guidelines are elucidated.

Plumbagin Suppresses Pulmonary Fibrosis via Inhibition of p300 Histone Acetyltransferase Activity.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis similar to that of malignancy. The causes of IPF are not clearly known, and there is no effective therapy to date. In this study, the natural compound plumbagin, which was isolated from Plumbago rosea root extract, was screened for p300 inhibitory activity. Plumbagin specifically inhibited the activity of p300 toward histone acetyltransferases. Plumbagin treatment significantly suppressed transforming growth factor-β-induced profibrotic target-gene expression and proliferation of fibroblast cell lines. Moreover, plumbagin significantly inhibited bleomycin-induced pulmonary fibrosis in mice. Taken together, these data demonstrate the inhibitory effects of plumbagin on lung fibrosis and its promise as a therapeutic agent for IPF.

Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Boehringer Ingelheim.

The effect of emphysema on survival in patients with idiopathic pulmonary fibrosis: A retrospective study in Taiwan.

Idiopathic pulmonary fibrosis (IPF) is a rare and chronic fibrosing interstitial lung disease. However, the clinical features and outcomes of IPF in Taiwan have not been well studied. In addition, the survival difference between patients with IPF alone and combined pulmonary fibrosis and emphysema (CPFE) remains controversial. Patients diagnosed with IPF between 2006 and 2016 were retrospectively enrolled in this study. IPF was defined according to the 2011 American Thoracic Society/European Respiratory Society guideline. The clinical features, comorbidities, and outcomes of CPFE group and IPF-alone group were compared. The extents of emphysema and fibrosis were evaluated. In total, 114 patients with IPF were enrolled, and 86.8% of them were men with a mean age of 77.8 years. The median survival was 3.33 years in all patients with IPF. Moreover, 30 patients (26.3%) met the CPFE criteria. The CPFE group had a higher percentage of smokers (90% vs 50%, p < 0.001), higher forced vital capacity (82% vs 59%, p < 0.001), and lower fibrosis scores (8.5 ± 2.9 vs 10 ± 3.2, p = 0.022) than did the IPF-alone group. The baseline room air saturation and percentage of pulmonary hypertension were similar between the two groups. The survival time was not significantly different between the CPFE and IPF-alone groups (median survival, 3.58 vs 2.39 years, p = 0.163). In the multivariate analysis, higher fibrosis score, room air saturation < 90%, and lung cancer were significant factors associated with mortality. Our study showed that emphysema had no significant effect on the survival of patients with IPF. The outcome of IPF was mainly determined by the baseline disease severity and other comorbidities.

Evaluation of Cyclin D1 as a Discriminatory Immunohistochemical Biomarker for Idiopathic Pulmonary Fibrosis.

Distinction of idiopathic pulmonary fibrosis (IPF) from other chronic fibrosing interstitial pneumonitides, such as hypersensitivity pneumonitis (HP) and connective tissue diseases, is critical due to varied biological and clinical outcomes. However, their histologic overlaps often pose diagnostic challenges. A recent study suggested an association of herpesvirus saimiri infection with IPF. Productive viral infection is associated with coexpression of pirated mammalian protein cyclin D1, shown to be overexpressed by immunohistochemistry (IHC) in the regenerating alveolar epithelium in IPF but not in normal lungs. We evaluated the diagnostic utility of cyclin D1 to discriminate between IPF and other fibrosing interstitial lung diseases. A retrospective study of cyclin D1 IHC expression in 27 consecutive cases of chronic fibrosing interstitial lung diseases from 2011 to 2017: 12 usual interstitial pneumonia (UIP) pattern; 5 nonspecific interstitial pneumonia pattern; 3 HP pattern; 7 unclassifiable was performed. Five cases of normal lung obtained from lobectomy specimen for malignancy are included as control. Immunoreactivity was graded semiquantitatively on a scale of 0 to 3. Cyclin D1 staining was uniformly strongly positive in all cases evaluated in the study, particularly in proliferating type II pneumocytes in the region of fibrosing areas. There was no statistical difference in the extent of cyclin D1 expression between UIP and non-UIP groups (2.7 vs. 2.5) and IPF versus non-IPF groups (2.7 vs. 2.4). Cyclin D1 expression is lower in control group compared with UIP groups (1.2 vs. 2.7). Cyclin D1 is not a specific marker of UIP pattern/IPF. The high expression of cyclin D1 in lung tissue of fibrosing interstitial pneumonitides regardless of etiology most likely correlates with proliferation in type II pneumocytes.

Association between Pepsin in Bronchoalveolar Lavage Fluid and Prognosis of Chronic Fibrosing Interstitial Lung Disease.

Chronic fibrosing interstitial lung disease (ILD)s are characterized by chronic progressive fibrosis of lung which include idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), and connective tissue disease-associated interstitial lung disease (CTD-ILD). IPF is an irreversible fibrotic lung disease which results in respiratory failure. Although NSIP and CTD-ILD can be improved or stable by treatment with corticosteroid or immunosuppressant, some of them progress to fibrotic lung diseases. Aspiration of gastric contents is suggested as an aggravating factor of ILDs. We measured pepsin, a marker of gastric aspiration, in bronchoalveolar lavage (BAL) fluid of chronic fibrosing ILD patients to evaluate the association between BAL fluid pepsin and prognosis of chronic fibrosing ILDs. Patients with chronic fibrosing ILDs, who underwent bronchoscopy between December 2010 and April 2015 were prospectively enrolled. Pepsin levels were measured using a commercial ELISA kit. Clinical characteristics, lung function data, and mortality were analyzed. Fifty-one patients with chronic fibrosing ILDs were enrolled (26 with IPF, 15 with NSIP, and 10 with CTD-ILD). Pepsin levels in BAL fluid were 69.87 ± 74.16 ng/mL in IPF, 110.68 ± 94.93 ng/mL in NSIP, and 101.87 ± 88.44 ng/mL in CTD-ILDs. There were no statistically significant differences in BAL fluid pepsin levels among patients with the different chronic fibrosing ILDs. In multivariate regression analysis, higher BAL pepsin levels were associated with higher mortality (adjusted odds ratio [aOR] = 1.021, p = 0.025). BAL fluid pepsin may be used as a prognostic marker for predicting mortality in chronic fibrosing ILD patients.

Usual interstitial pneumonia: typical, possible, and "inconsistent" patterns.

ABSTRACTIdiopathic pulmonary fibrosis is a severe and progressive chronic fibrosing interstitial lung disease, a definitive diagnosis being established by specific combinations of clinical, radiological, and pathological findings. According to current international guidelines, HRCT plays a key role in establishing a diagnosis of usual interstitial pneumonia (UIP). Current guidelines describe three UIP patterns based on HRCT findings: a typical UIP pattern; a pattern designated “possible UIP”; and a pattern designated “inconsistent with UIP”, each pattern having important diagnostic implications. A typical UIP pattern on HRCT is highly accurate for the presence of histopathological UIP, being currently considered to be diagnostic of UIP. The remaining patterns require further diagnostic investigation. Other known causes of a UIP pattern include drug-induced interstitial lung disease, chronic hypersensitivity pneumonitis, occupational diseases (e.g., asbestosis), and connective tissue diseases, all of which should be included in the clinical differential diagnosis. Given the importance of CT studies in establishing a diagnosis and the possibility of interobserver variability, the objective of this pictorial essay was to illustrate all three UIP patterns on HRCT.

Drug Treatment of Idiopathic Pulmonary Fibrosis: Systematic Review and Network Meta-Analysis.

Idiopathic pulmonary fibrosis (IPF) is a form of chronic progressive fibrosing interstitial lung disease of unknown origin. Recently, nintedanib and pirfenidone demonstrated efficacy in slowing disease progression and were approved by the US Food and Drug Administration. Although numerous treatments have been evaluated in IPF, none have shown significant decreases in mortality. The objective of this study was to identify all pharmacologic treatments evaluated for IPF and analyze their efficacy via Bayesian network meta-analysis and pairwise indirect treatment comparisons. This review did not evaluate the effect of steroid therapy. We searched MEDLINE, Embase, and the Cochrane Library for studies published on or before August 2014. Studies were required to contain a randomized evaluation of nonsteroidal drug therapy for treatment of IPF and be published in English. Key outcomes of interest for this analysis were pulmonary function as measured by FVC as well as all-cause and respiratory-specific death. All outcomes were analyzed via a Bayesian framework. Our review identified 30 eligible studies that evaluated 16 unique treatments. Under both the fixed-effect and random-effect models for respiratory-specific mortality, no treatments performed better than placebo. For all-cause mortality, pirfenidone and nintedanib had effects approaching significance with credible intervals slightly crossing the null under a fixed-effect model. Notably, for respiratory-specific mortality, all-cause mortality, and decline in percent predicted FVC, nintedanib and pirfenidone were virtually indistinguishable and no clear advantage was detected. Although two treatments have been approved for IPF on the basis of reduced decline in pulmonary function, neither one has a clear advantage on mortality outcomes.

Biomarkers for Staging and Evaluating the Therapy for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a form of chronic fibrosing interstitial lung disease of unknown etiology and poor prognosis. The clinical course of IPF varies considerably in the severity and the rate of progression. Potential prognostic biomarkers have been suggested as markers of severity

Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease of unknown etiology that is currently untreatable. In this study we aim to characterize the potential of extracellular/circulating microRNAs (miRNAs) in serum as biomarkers for IPF. MethodsTotal serum RNAs were isolated from serum from healthy control subjects (n=12), rapid progressive (n=12) and slowly progressive IPF patients (n=12). Serum RNA was analyzed by using TaqMan microRNA assays containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis on the significant differential miRNAs were performed using DIANA-mirPath. ResultsWe found 47 significantly differentially expressed serum miRNAs (p<0.05) in rapid progressive or slowly progressive IPF patients compared to healthy controls, including 21 up-regulated miRNAs and 26 down-regulated miRNAs. Bioinformatic analysis by DIANA-mirPath demonstrated that 53 KEGG biological processes were significantly enriched (p<0.05, FDR corrected) among differentially expressed serum miRNAs, including TGF-beta signaling pathway (p<0.0001), MAPK signaling pathway (p<0.0001), PI3K–Akt signaling pathway (p<0.0001), Wnt signaling pathway (p<0.0001), HIF-1 signaling pathway (p<0.0001), Regulation of actin cytoskeleton (p<0.0001), Jak–STAT signaling pathway (p<0.0001), Notch signaling pathway (p<0.0001), and Cytokine–cytokine receptor interaction (p=0.0062). We further validated six miRNAs (miR-21, miR-199a-5p, miR-200c, miR-31, let-7a, and let-7d) for further validation using an independent cohort of 20 rapid progressive IPF, 24 slowly progressive IPF patients and 20 healthy controls. In agreement with the preliminary data from miRNA assay, miR-21, miR-199a-5p, and miR-200c were significantly increased in serums of IPF patients while miR-31, let-7a, and let-7d were significantly under expressed in serums of IPF patients compared to healthy controls. ConclusionsThese studies demonstrated that extracellular/circulating miRNAs in serum could be potentially served as novel regulators influencing disease progression of IPF.

Fibrotic hypersensitivity pneumonitis

Fibrotic hypersensitivity pneumonitis (FHP) is a specific form of HP defined by chest imaging evidence or pathologic evidence of fibrosis or scarring. Fibrotic HP appears to be irreversible, is often progressive and frequently indistinguishable from other forms of chronic fibrosing interstitial lung diseases (ILD), in particular idiopathic pulmonary fibrosis (IPF). Accurate diagnosis is a challenge given the diverse and often nonspecific clinicoradiologic patterns, heterogenous clinical course, and a frequent lack of a readily recognizable temporal relationship between exposure to an inciting antigen (IA) and symptoms in more than half of the patients. This chapter focuses on the clinical features, diagnostic evaluation and management of FHP.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive, chronic fibrosing interstitial lung disease occurring primarily in older adults and limited to the lungs. The prognosis is dire, with half of all patients progressing to death from respiratory failure within 3 to 5 years from initial diagnosis. The pathogenesis of IPF is complex and incompletely understood, and the natural history of this disease is variable and unpredictable. There is no widely accepted treatment for IPF, except for lung transplantation. Nevertheless, these are important and exciting times for the diagnosis and management of patients with IPF. Novel diagnostic approaches (e.g., biomarker-based), improved prognostic models, and clinical trials of novel drug agents may alter disease management substantially over the next few years. For now, clinicians should practice comprehensive management, including symptom-based management, aggressive management of comorbidities, and patient education and support.

Paclitaxel induced chronic fibrosing interstitial pneumonitis: a case report and review of the literature

Pulmonary toxicity is rarely associated with paclitaxel chemotherapy and its mechanism is not well known. This report describes one patient with pancreatic adenocarcinoma, metastatic neuroendocrine low-grade pancreatic tumor, and a concomitant stage I non-small cell lung cancer (NSCLC), who also developed life-threatening paclitaxel-induced chronic fibrosing interstitial pneumonitis. Giving the gravity of the condition and the not-wellestablished treatment, physicians should be aware of the possibility of chronic fibrosing interstitial lung disease during the course of paclitaxel containing regimens in patients who present with respiratory symptoms.

Paclitaxel induced chronic fibrosing interstitial pneumonitis: a case report and review of the literature

Pulmonary toxicity is rarely associated with paclitaxel chemotherapy and its mechanism is not well known. This report describes one patient with pancreatic adenocarcinoma, metastatic neuroendocrine low-grade pancreatic tumor, and a concomitant stage I non-small cell lung cancer (NSCLC), who also developed life-threatening paclitaxel-induced chronic fibrosing interstitial pneumonitis. Giving the gravity of the condition and the not-well-established treatment, physicians should be aware of the possibility of chronic fibrosing interstitial lung disease during the course of paclitaxel containing regimens in patients who present with respiratory symptoms.

Alveolar Oxidative Stress is Associated with Elevated Levels of Nonenzymatic Low-Molecular-Weight Antioxidants in Patients with Different Forms of Chronic Fibrosing Interstitial Lung Diseases

Increasing evidence indicates that disequilibrium of the alveolar oxidant-antioxidant balance may play a role in the pathogenesis of chronic fibrosing lung diseases. Excessive production of oxidants and a differential regulation of antioxidant enzymes have been described under these conditions. We characterized for the first time numerous nonenzymatic low-molecular-weight antioxidants in bronchoalveolar lavage fluids from patients with different forms of lung fibrosis initiated either by injury to the alveolar epithelium (idiopathic pulmonary fibrosis, IPF) or by inflammation (chronic sarcoidosis/hypersensitivity pneumonitis). Footprints of oxidative stress accompanied by an increase in the majority of antioxidants assessed were observed in all patient groups: elevated levels of uric acid, ascorbic acid, retinol, and alpha-tocopherol were noted, whereas glutathione levels were unchanged. The expression of Nrf2, an important redox-sensitive transcriptional regulator of antioxidants, was increased in IPF lungs. Our findings were corroborated in the bleomycin model of lung fibrosis where--aside from uric acid--nonenzymatic antioxidants were elevated during the fibrotic phase. In conclusion, alveolar levels of nonenzymatic antioxidants are elevated in fibrosing lung diseases, but are incapable of restoring oxidative balance. This increase may be part of an adaptive response to oxidative stress. However, a leakage from the blood may also contribute to our findings.