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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.

Objective Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by fibroblast activation and extracellular matrix deposition. Although mechanical forces are known to influence critical processes such as tissue remodeling and cellular differentiation, the specific role of mechanosensitive genes in IPF pathogenesis remains poorly understood. Methods This study applied mechanical force–related scoring to IPF and control samples. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify IPF-specific genes associated with mechanical force–related scores, which were subsequently subjected to enrichment analysis. Core genes were screened through univariate Cox regression analysis and machine learning algorithms. Independent prognostic genes were determined using stepwise multivariate Cox regression analysis, which informed the construction of a nomogram integrating key clinicopathological variables. The core genes were further analyzed through single-cell RNA sequencing (scRNA-seq) and Connectivity Map (CMap) analyses to investigate molecular subtypes and identify potential therapeutic targets. Results IPF samples exhibited significantly higher scores related to mechanical-related genes (MRGs). Moreover, these samples demonstrated notable heterogeneity, with distinct patterns of high and low mechanical force–associated scores. Core gene analysis revealed two distinct molecular subtypes among idiopathic IPF samples. The C2 subtype was characterized by pronounced inflammatory responses, activation of mechanotransduction pathways, and more severe pathological features. CMap analysis identified nifekalant, which targets AGTR2, as a potential therapeutic agent for the C2 subtype. CD24, PPP1R14C, DSP, and CC2D2A were identified as diagnostic biomarkers, among which CD24, PPP1R14C, and CC2D2A also served as independent prognostic indicators. scRNA-seq demonstrated elevated expression of CD24 and CC2D2A in IPF samples, predominantly within ciliated cells. Pseudotime trajectory analysis revealed two distinct cell fate trajectories in IPF samples. Differentiation toward cell fate 1 was associated with enhanced protein synthesis and secretion, whereas cell fate 2 and the branching point origin region exhibited increased cell adhesion and activation of the p38 MAPK signaling pathway. Conclusion CD24, PPP1R14C, and CC2D2A were identified as prognostic genes associated with MRGs, functioning as markers for molecular subtyping in IPF. These genes may contribute to the pathogenesis of IPF by modulating mechanotransduction processes within epithelial cell subpopulations. Graphical Abstract Highlight Two IPF subtypes were identified; the C2 subtype featured strong inflammation, active mechanotransduction, and severe pathology. IPF samples showed elevated mechanical-related gene (MRG) scores with clear heterogeneity. CD24, PPP1R14C, and CC2D2A were prognostic MRG-linked biomarkers, mainly expressed in ciliated cells and involved in epithelial mechanotransduction.

Background Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis (IPF). In this analysis, treatment patterns of European patients with IPF were investigated to understand antifibrotic prescribing and identify unmet needs in IPF treatment practice. Methods Between February and March 2016, respiratory physicians from France, Germany, Italy, Spain, and the UK participated in an online questionnaire designed to collect information on IPF treatment patterns in patients under their care. Patients were categorized as treated (received approved antifibrotics) or untreated (did not receive approved antifibrotics, but may have received other unapproved therapies). Classification of IPF diagnosis (confirmed/suspected) and severity (‘mild’/‘moderate’/‘severe’) for each patient was based on the individual physician’s report. Patients’ perspectives were not recorded in this study. Results In total, 290 physicians responded to the questionnaire. Overall, 54% of patients with IPF did not receive treatment with an approved antifibrotic. More patients had a confirmed IPF diagnosis in the treated (84%) versus the untreated (51%) population. Of patients with a confirmed diagnosis, 40% did not receive treatment. The treated population was younger than the untreated population (67 vs 70 years, respectively; p  ≤ 0.01), with more frequent multidisciplinary team evaluation (83% vs 57%, respectively; p  ≤ 0.01). A higher proportion of untreated patients had forced vital capacity > 80% at diagnosis versus treated patients. Of patients with ‘mild’ IPF, 71% did not receive an approved antifibrotic versus 41% and 60% of patients with ‘moderate’ and ‘severe’ IPF, respectively. Conclusions Despite the availability of antifibrotic therapies, many European patients with confirmed IPF do not receive approved antifibrotic treatment. Importantly, there appears to be a reluctance to treat patients with ‘mild’ or ‘stable’ disease, and instead adopt a ‘watch and wait’ approach. More education is required to address diagnostic uncertainty, poor understanding of IPF and its treatments, and issues of treatment access. There is a need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity.

Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be identified on surgical lung biopsies. To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis. Data were derived from published literature and clinical experience. Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology.

The safety of pirfenidone on pulmonary fibrosis patients with other kinds of interstitial lung diseases (ILDs) in addition to idiopathic pulmonary fibrosis (IPF) is unknown. Furthermore, its effectiveness-related factors on IPF patients are not quite explored. A retrospective study, on patients prescribed pirfenidone for pulmonary fibrosis, was conducted to assess effectiveness on IPF patients and tolerability of all patients with lung fibrosis. The effectiveness of pirfenidone was tested on 110 IPF subjects receiving treatment for ≥3 months by high-resolution computed tomography (HRCT). Response-linked factors and progression-free survival (PFS) were also analyzed. The data about safety outcomes and drug dose adjustments were collected from all included subjects. A total of 176 subjects were included: 117 were IPF, 19 connective tissue disease-associated interstitial lung disease (CTD-ILD), and 40 unclassifiable ILD. Out of the 110 IPF subjects, 89 subjects were assessed as stable and 21 as progressive, out of which 10 died of acute exacerbation and 11 progressed. The effectiveness was significantly related to their baseline body mass index (BMI). IPF subjects with BMI>25kg/m2 or diffusion capacity of carbon monoxide (DLco)>30% had higher PFS rate. The most common adverse events were skin-related and gastrointestinal-related. Drug discontinuation owing to adverse events occurred similarly in these three groups. Pirfenidone was well tolerated in most of the lung fibrosis patients besides IPF, with a similar pattern of adverse events. Nearly 80% of IPF subjects were assessed as stable. More benefits were seen in IPF patients with higher BMI or mild-to-moderate disease.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrosing lung disease of unknown cause. The advent of anti-fibrotic medications known to slow disease progression has revolutionised IPF management in recent years. However, little is known about the natural history of IPF patients with mild physiological impairment. We aimed to assess the natural history of these patients using data from the Australian IPF Registry (AIPFR). Methods Using our cohort of real-world IPF patients, we compared FVC criteria for mild physiological impairment (FVC ≥ 80%) against other proposed criteria: DLco ≥ 55%; CPI ≤40 and GAP stage 1 with regards agreement in classification and relationship with disease outcomes. Within the mild cohort (FVC ≥ 80%), we also explored markers associated with poorer prognosis at 12 months. Results Of the 416 AIPFR patients (mean age 70.4 years, 70% male), 216 (52%) were classified as ‘mild’ using FVC ≥ 80%. There was only modest agreement between FVC and DLco (k = 0.30), with better agreement with GAP (k = 0.50) and CPI (k = 0.48). Patients who were mild had longer survival, regardless of how mild physiologic impairment was defined. There was, however, no difference in the annual decline in FVC% predicted between mild and moderate-severe groups (for all proposed criteria). For patients with mild impairment ( n  = 216, FVC ≥ 80%), the strongest predictor of outcomes at 12 months was oxygen desaturation on a 6 min walk test. Conclusion IPF patients with mild physiological impairment have better survival than patients with moderate-severe disease. Their overall rate of disease progression however, is comparable, suggesting that they are simply at different points in the natural history of IPF disease.

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with very high mortality. Objective: We sought to characterize serial changes in pulmonary artery pressures (PAP) in patients with advanced IPF who survive to transplant. Methods: Retrospective analysis of IPF patients comparing mean PAP at the time of initial evaluation for transplan- tation (mPAP baseline ) with mPAP at the time of transplant (mPAP follow-up ). The measurements were correlated with New York Heart Association (NYHA) functional class and oxygen requirements. Results: The final cohort consisted of 44 patients with serial right heart catheterization data. The mean mPAP baseline and mPAP follow-up were 22.5 and 32.7 mm Hg, respectively. 38.6% (17/44) of the patients had pulmonary hypertension (PH) at baseline. The majority of the non-PH patients developed PH during the serial time interval with a subsequent incidence of 77.8%. At the time of transplant, 86.4% of the patients had PH. There was a significant association between transplant NYHA class, severity of PH and oxygen requirements. Transplant NYHA class IV patients had a higher rate of mPAP change. The severity of PH at the time of transplant did not affect transplant outcomes. Conclusion: PH is common and progressive in patients with advanced IPF who are transplant candidates. Serial change and severity of PAP elevations have a significant association with oxygen requirements and functional status, but not transplant outcomes. Whether or not progressive PH has a significant impact on outcomes without transplantation requires further study.

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is defined as a sudden acceleration of the disease with the appearance of pulmonary infiltrates superimposed on the characteristic pattern of IPF that leads to a significant decline in lung function. It has high in-hospital mortality rates, despite medical treatment with systematic steroids. We sought to investigate whether there were in-hospital mortality differences according to clinical stratification (AE, suspected AE, or AE of known cause) and/or treatment with systemic steroids. We reviewed the clinical characteristics and outcomes of patients with IPF admitted to our hospital during the years 2003–2014 due to a worsening of their clinical status. We identified 50 IPF patients, 9 with AE (18%), 12 with suspected exacerbation (24%), and 29 with AE of known cause (58%), mostly respiratory infections. In-hospital mortality was similar in the three groups (33% vs. 17% vs. 34%, respectively). Likewise, we did not find differences between them with respect to the use of systemic steroids (length of treatment duration or total dose). Nevertheless, there was an independent association between in-hospital mortality and high average daily steroid dose. We did not observe significant differences in prognosis or use of systemic steroids according to current diagnostic stratification groups in patients hospitalized because of an exacerbation of IPF.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia with an unpredictable course. The aims of this study were to retrospectively re-evaluate a cohort of patients with IPF according to the 2011 international IPF guidelines and 1) to characterize the subgroups of patients when classified according to their observed survival times and 2) to evaluate whether Composite Physiologic Index (CPI), Gender-Age-Physiology (GAP) Index or clinical variables could predict mortality. Methods Retrospective data was collected and patients were classified into subgroups according to their observed lifespans. Differences in clinical variables, CPI and GAP stages as well as in comorbidities were investigated between the subgroups. Predictors of mortality were identified by COX proportional hazard analyses. Results A total of 132 patients were included in this study. The disease course was rapid (≤ 2 years) in 30.0%, moderate (2–5 years) in 28.0% and slow (≥ 5 years) in 29.0% of the patients. Pulmonary function tests (PFT) and CPI at baseline differentiated significantly between the rapid disease course group and those patients with longer survival times. However, the predictive accuracy of the investigated clinical variables was mainly less than 0.80. The proportions of patients with comorbidities did not differ between the subgroups, but more patients with a rapid disease course were diagnosed with heart failure after the diagnosis of IPF. Most patients with a rapid disease course were categorized in GAP stages I and II, but all patients in GAP stage III had a rapid disease course. The best predictive multivariable model included age, gender and CPI. GAP staging had slightly better accuracy (0.67) than CPI (0.64) in predicting 2-year mortality. Conclusions Although the patients with a rapid disease course could be differentiated at baseline in terms of PFT and CPI, the predictive accuracy of any single clinical variable as well as CPI and GAP remained low. GAP staging was unable to identify the majority of patients with a rapid disease progression. It is challenging to predict disease progression and mortality in IPF even with risk prediction models.

Background Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series. Methods Five consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied. Results There were four males and one female, aged 70±2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6±13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically. Conclusions IPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.