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In patients with a progressive interstitial lung disease, 62% of whom had a CT pattern of usual interstitial pneumonia, those who received nintedanib had a lower annual rate of decline in the forced vital capacity than those who received placebo at 52 weeks.

In this randomized, placebo-controlled trial, treatment with nintedanib, an intracellular inhibitor of multiple tyrosine kinases, led to a reduced rate of loss of forced vital capacity in patients with idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. 1 A decline in forced vital capacity (FVC) is consistent with disease progression and is predictive of reduced survival time. 1 – 6 Idiopathic pulmonary fibrosis is believed to arise from an aberrant proliferation of fibrous tissue and tissue remodeling due to the abnormal function and signaling of alveolar epithelial cells and interstitial fibroblasts. 7 The activation of cell-signaling pathways through tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of . . .

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) causes considerable global morbidity and mortality, and its mechanisms of disease progression are poorly understood. Recent observational studies have reported associations between lung dysbiosis, mortality, and altered host defense gene expression, supporting a role for lung microbiota in IPF. However, the causal significance of altered lung microbiota in disease progression is undetermined. To examine the effect of microbiota on local alveolar inflammation and disease progression using both animal models and human subjects with IPF. For human studies, we characterized lung microbiota in BAL fluid from 68 patients with IPF. For animal modeling, we used a murine model of pulmonary fibrosis in conventional and germ-free mice. Lung bacteria were characterized using 16S rRNA gene sequencing with novel techniques optimized for low-biomass sample load. Microbiota were correlated with alveolar inflammation, measures of pulmonary fibrosis, and disease progression. Disruption of the lung microbiome predicts disease progression, correlates with local host inflammation, and participates in disease progression. In patients with IPF, lung bacterial burden predicts fibrosis progression, and microbiota diversity and composition correlate with increased alveolar profibrotic cytokines. In murine models of fibrosis, lung dysbiosis precedes peak lung injury and is persistent. In germ-free animals, the absence of a microbiome protects against mortality. Our results demonstrate that lung microbiota contribute to the progression of IPF. We provide biological plausibility for the hypothesis that lung dysbiosis promotes alveolar inflammation and aberrant repair. Manipulation of lung microbiota may represent a novel target for the treatment of IPF.

A prospective study using consistent HRCT findings plus BAL lymphocytosis greater than 30% (or 20% for current smokers) as the \"gold standard\" criteria for HP developed a prediction rule for identifying \"active\" HP; however, the proportion of patients with radiologic/histopathologic fibrosis is not reported in this study, making use of this rule less applicable to fibrotic HP (40). The most difficult cases offibrotic lung disease to diagnose involve two scenarios: (1) there is a plausible exposure (i.e., longstanding exposure to domestic birds) but HP-associated HRCT and histopathologic findings are absent, and (2) a patient meets most of the criteria for an idiopathic interstitial pneumonia, but HRCT or biopsy shows nonspecific features sometimes associated with HP, such as mild air-trapping/mosaic attenuation on HRCT or biopsy showing rare giant cells, minor lymphocytic bronchiolitis, or airway-centered fibrosis (3). IPF is understood as a disease of aberrant wound healing after repetitive injury with upregulation of proliferation, remodeling, and myofibroblast genes, whereas inhaled antigens lead to T-cell activation and increased expression of immune response genes in HP (64-66). An animal model of pulmonary fibrosis indicates that infection with Streptococcus pneumoniae may trigger fibrosis progression, mimicking an acute disease exacerbation, with antibiotic treatment or vaccination attenuating this effect (88, 89). [...]in patients with fibrotic HP and acute disease worsening, the possibility of infection should be thoroughly evaluated and treated with appropriate antibiotics.

Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis. In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC. This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy. The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks. This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.

In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. To investigate the potential impact of diagnostic subgroups on the progression of IPF and the effect of nintedanib. We conducted a post hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS trials. Seven hundred twenty-three (68.1%) patients had honeycombing and/or biopsy, and 338 (31.9%) patients had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in FVC in patients treated with placebo was -225.7 and -221.0 ml/yr, and the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 117.0 ml/yr (95% confidence interval, 76.3-157.8) and 98.9 ml/yr (95% confidence interval, 36.4-161.5). There was no significant treatment-by-subgroup interaction (P = 0.8139). Adverse events were similar between the subgroups. Patients with IPF diagnosed in clinical practice who had possible UIP with traction bronchiectasis on HRCT and had not undergone surgical lung biopsy had disease that progressed in a similar way, and responded similarly to nintedanib, to that of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.

Idiopathic pulmonary fibrosis is characterized by rapid loss of vital capacity, disability, and death. There are no effective treatments. Although this study failed to meets its primary end point, the data show therapeutic efficacy at a cost of substantial GI toxicity. Idiopathic pulmonary fibrosis is a debilitating disease characterized by destruction of the gas-exchanging regions of the lung. 1 Its pathogenesis is thought to involve aberrant wound healing mediated by multiple signaling pathways, resulting in progressive lung injury and scarring. 1 Symptoms, including cough and dyspnea, limit physical activity and reduce the patient's quality of life and independence. 2 The course of the disease is difficult to predict, but it generally involves progressive deterioration, with a median survival time of 2.5 to 3.5 years after diagnosis. 3 Unpredictable acute exacerbations occur in some patients and are often fatal. 3 , 4 BIBF 1120 is a potent intracellular . . .

[...]there is frequent reluctance to perform surgical lung biopsy in patients with clinically unclassifiable ILD due to safety concerns. [...]it should accommodate all forms of fibrotic ILD and different types of diagnostic criteria (e.g., criteria based vs. consensus based). [...]it should be agnostic to changes in existing diagnostic criteria or the creation of new diagnostic criteria. [...]it should balance diagnostic certainty with clinical practicality, a balance that may differ in clinical vs. research settings.