Pitfalls in diagnosis and management of hypersensitivity pneumonitis

Hypersensitivity pneumonitis is a complex syndrome characterized by a combination of inflammation and fibrosis located in both the airways and the lung parenchyma. Both diagnosis and treatment are a real challenge for physicians. This review will focus on recent developments in this emerging field; furthermore, we will emphasize major gaps in the current knowledge, to stimulate further research in this field.status: publishe

Interstitial Score and Concentrations of IL-4Rα, PAR-2, and MMP-7 in Bronchoalveolar Lavage Fluid Could Be Useful Markers for Distinguishing Idiopathic Interstitial Pneumonias

Idiopathic interstitial pneumonia (IIP) entails a variable group of lung diseases of unknown etiology. Idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, interstitial lung diseases related to connective tissue disease (CTD-ILD), and hypersensitivity pneumonitis (HP) can manifest with similar clinical, radiological, and histopathological features. In a differential diagnosis, biomarkers can play a significant role. We assume that levels of specific cyto- or chemokines or their receptors can signal pathogenetic processes in the lungs. Eighty patients with different types of idiopathic interstitial pneumonia were enrolled in this study. Cell counts and concentrations of tumor necrosis factor (TNF)-α, interleukin-4 receptor α, proteinase-activated receptor (PAR)-2, matrix metalloproteinase (MMP)-7, and B cell-activating factor were measured in bronchoalveolar lavage fluid using commercial ELISA kits. High resolution computer tomography results were evaluated using alveolar and interstitial (IS) score scales. Levels of TNF-α were significantly higher in HP compared to fibrosing IIP (p < 0.0001) and CTD-ILD (p = 0.0381). Concentrations of IL-4Rα, PAR-2, and MMP-7 were positively correlated with IS (p = 0.0009; p = 0.0256; p = 0.0015, respectively). Since TNF-α plays a major role in inflammation, our results suggest that HP is predominantly an inflammatory disease. From the positive correlation with IS we believe that IL-4Rα, PAR-2, and MMP-7 could serve as fibroproliferative biomarkers in differential diagnosis of IIP

Bronchoalveolar lavage cell profiles and proteins concentrations can be used to phenotype extrinsic allergic alveolitis patients

Abstract Background Extrinsic allergic alveolitis (EAA) patients form heterogenous group with different clinical manifestation and different prognosis. We aimed to determine how to phenotype distinct EAA subgroups. Predictive role of the bronchoalveolar lavage fluid (BALF) IL-4Rα concentration at the time of diagnosis with regard to the clinical behavior in EAA patients was studied. Methods Concentrations of MMP-7, IL-4Rα, TNF-α, and PAR-2 were measured in the BALF od 71 EAA patients at the time of diagnosis. Lung functions and outcome data were assessed at 12 months after the diagnosis. Correlations between the BALF protein concentration, cell profile, lung functions and patient outcome were determined. Results We found positive correlations between BALF IL-4Rα concentration and BALF eosinophils (p = 0,006), negative correlation between IL-4Rα BALF concentration and diffusing capacity (DLco) (p = 0,003), negative correlation between IL-4Rα BALF concentration and forced vital capacity (FVC) (p = 0,004) and negative correlation between IL-4Rα concentration and BALF lymphocytes (p = 0,04). The BALF concentration of IL-4Rα was significantly higher in acute exacerbation patients (p = 0,0032) and in patients progressing despite corticosteroid treatment (p = 0,04). We observed a positive correlation between MMP-7 BALF concentration and the BALF lymphocytes (p = 0.05), negative correlation between the PAR-2 BALF concentration and DLco (p = 0.04) and a negative correlation between the BALF TNF-α concentration and DLco (p = 0.03). Conclusions Specific subgroup of EAA patients with more severe functional impact, distinct BALF cell profile and higher IL-4Rα BALF concentration can be differentiated. Correlations between the BALF concentrations of PAR-2, MMP-7 and TNF-α with clinical parameters may reflect the role of inflammation in the pathogenesis of EAA

Anticoagulant Use and Bleeding Risk in Central European Patients with Idiopathic Pulmonary Fibrosis (IPF) Treated with Antifibrotic Therapy: Real-World Data from EMPIRE

WOS: 000554054500001PubMed: 32734423Introduction Nintedanib, a tyrosine kinase receptor inhibitor, may be associated with increased bleeding risk. Thus, patients with an inherited predisposition to bleeding, or those receiving therapeutic doses of anticoagulants or high-dose antiplatelet therapy, have been excluded from clinical trials of nintedanib in idiopathic pulmonary fibrosis (IPF). Objective Our objective was to examine real-world bleeding events in patients with IPF treated with antifibrotics, including those receiving anticoagulants and/or antiplatelet therapy. Methods the European MultiPartner IPF Registry (EMPIRE) enrolled 2794 patients with IPF: group A (1828: no anticoagulant or antiplatelet treatment), group B (227: anticoagulant treatment), group C (659: antiplatelet treatment), and group D (80: anticoagulant and antiplatelet treatment). Overall, 673 (24.1%) received nintedanib and 933 (33.4%) received pirfenidone. Bleeding events and their relationship to antifibrotic and anticoagulation treatment were characterized. Results Group A patients, versus those in groups B, C, and D, were typically younger and generally had the lowest comorbidity rates. A higher proportion of patients in groups A and C, versus group B, received nintedanib. Pirfenidone, most common in group D, was more evenly balanced across groups. in patients with reported bleeding events, seven of eight received nintedanib (groups A, C, and D). Bleeding incidence was 3.0, 0, 1.3, and 18.1 per 10,000 patient-years (groups A, B, C, and D, respectively). Conclusion Real-world data from EMPIRE showed that patients on anticoagulant medications received nintedanib less frequently, perhaps based on its mechanism of action. Overall, bleeding incidence was low (0.29%: nintedanib 0.25%; pirfenidone 0.04%) and irrespective of anticoagulant or antiplatelet therapy received (P = 0.072).Boehringer Ingelheim International GmbH (BI)Boehringer Ingelheim; Boehringer Ingelheim International GmbHBoehringer IngelheimThis study was supported by Boehringer Ingelheim International GmbH (BI). Medical writing assistance was provided by Islay Steele, PhD, of Nucleus Global, which was contracted and funded by Boehringer Ingelheim International GmbH. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations

Survival and lung function decline in patients with definite, probable and possible idiopathic pulmonary fibrosis treated with pirfenidone

Background There is no clear evidence whether pirfenidone has a benefit in patients with probable or possible UIP, i.e. when idiopathic pulmonary fibrosis (IPF) is diagnosed with a lower degree of diagnostic certainty. We report on outcomes of treatment with pirfenidone in IPF patients diagnosed with various degrees of certainty. Methods and findings We followed patients in the multi-national European MultiPartner IPF Registry (EMPIRE) first seen between 2015 and 2018. Patients were assessed with HRCT, histopathology and received a multi-disciplinary team (MDT) IPF diagnosis. Endpoints of interest were overall survival (OS), progression-free survival (PFS) and lung function decline. Results A total of 1626 patients were analysed, treated with either pirfenidone (N = 808) or receiving no antifibrotic treatment (N = 818). When patients treated with pirfenidone were compared to patients not receiving antifibrotic treatment, OS (one-, two- and three-year probability of survival 0.871 vs 0.798; 0.728 vs 0.632; 0.579 vs 0.556, P = 0.002), and PFS (one-, two- and three-year probability of survival 0.597 vs 0.536; 0.309 vs 0.281; 0.158 vs 0.148, P = 0.043) was higher, and FVC decline smaller (-0.073 l/yr vs -0.169 l/yr, P = 0.017). The benefit of pirfenidone on OS and PFS was also seen in patients with probable or possible IPF. Conclusions This EMPIRE analysis confirms the favourable outcomes observed for pirfenidone treatment in patients with definitive IPF and indicates benefits also for patients with probable or possible IPF.F. Hofmann-La Roche; Boehringer IngelheimThis study was supported by F. Hofmann-La Roche. The EMPIRE registry is supported by Boehringer Ingelheim and F. Hofmann-La Roche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Comorbidity burden and survival in patients with idiopathic pulmonary fibrosis: the EMPIRE registry study

Background Patients with idiopathic pulmonary fibrosis (IPF) frequently have multiple comorbidities, which may influence survival but go under-recognised in clinical practice. We therefore report comorbidity, antifibrotic treatment use and survival of patients with IPF observed in the multi-national EMPIRE registry. Methods For this prospective IPF cohort, demographics, comorbidities, survival and causes of death were analysed. Comorbidities were noted by the treating physician based on the patient's past medical history or as reported during follow-up. Comorbidities were defined as prevalent when noted at enrolment, or as incident when recorded during follow-up. Survival was analysed by Kaplan-Meier estimates, log-rank test, and Cox proportional hazards models. Hazard ratios (HR) were adjusted for gender, age, smoking status and FVC at enrolment. Results A population of 3,580 patients with IPF from 11 Central and Eastern European countries was followed every 6 months for up to 6 years. At enrolment, 91.3% of patients reported at least one comorbidity, whereas more than one-third (37.8%) reported four or more comorbidities. Five-year survival was 53.7% in patients with no prevalent comorbidities, whereas it was 48.4%, 47.0%, 43.8% and 41.1% in patients with 1, 2, 3 and >= 4 comorbidities, respectively. The presence of multiple comorbidities at enrolment was associated with significantly worse survival (log-rank test P = 0.007). Adjusted HRs indicate that risk of death was increased by 44% in patients with IPF reporting >= 4 comorbidities at baseline compared with no comorbidity (P = 0.021). The relationship between number of comorbidities and decreased survival was also seen in patients receiving antifibrotic treatment (63% of all patients; log-rank test P 0.001). Comorbidity as cause of death was identified in at least 26.1% of deaths. Conclusions The majority of patients with IPF demonstrate comorbidities, and many have comorbidity-related deaths. Increasing numbers of comorbidities are associated with worse survival; and this pattern is also present in patients receiving antifibrotic therapy.The EMPIRE registry is supported in part by Boehringer Ingelheim and Roche. The authors did not receive payment for the development of the manuscript.Boehringer Ingelheim; Roch