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Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6-32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data., Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD., Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described., Conclusions: Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients., Trial Registration: www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

The German Society of Pneumology initiated the AWMFS1 guideline Post-COVID/Long-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendation describes current post-COVID/long-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an expilcit practical claim and will be continuously developed and adapted by the author team based on the current increase in knowledge., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-027., (Thieme. All rights reserved.)

Introduction: Massive haemoptysis is a life-threatening event in advanced cystic fibrosis (CF) lung disease with bronchial artery embolisation (BAE) as standard of care treatment. The aim of our study was to scrutinise short-term and long-term outcomes of patients with CF and haemoptysis after BAE using coils., Methods: We carried out a retrospective cohort study of 34 adult patients treated for massive haemoptysis with super selective bronchial artery coil embolisation (ssBACE) between January 2008 and February 2015. Embolisation protocol was restricted to the culprit vessel(s) and three lobes maximum. Demographic data, functional end-expiratory volume in 1 s in % predicted (FEV1% pred.) and body mass index before and after ssBACE, sputum colonisation, procedural data, time to transplant and time to death were documented., Results: Patients treated with ssBACE showed significant improvement of FEV 1 % pred. after embolisation (p=0.004) with 72.8% alive 5 years post-ssBACE. Mean age of the patients was 29.9 years (±7.7). Mean FEV 1 % pred. was 45.7% (±20.1). Median survival to follow-up was 75 months (0-125). Severe complication rate was 0%, recanalisation rate 8.8% and 5-year-reintervention rate 58.8%. Chronic infection with Pseudomonas aeruginosa was found in 79.4%, Staphylococcus areus in 50% and Aspergillus fumigatus in 47.1%., Discussion: ssBACE is a safe and effective treatment for massive haemoptysis in patients with CF with good results for controlling haemostasis and excellent short-term and long-term survival, especially in severely affected patients with FEV<40% pred. We think the data of our study support the use of coils and a protocol of careful and prudent embolisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs., Methods: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting., Findings: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed., Interpretation: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC., Funding: German Center for Lung Research, Roche Pharma., Competing Interests: Declaration of interests JB reports personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Biogen, Galapagos, Promedior, Roche, and the German Center for Lung Research (DZL). SB reports personal fees and non-financial support from Roche, Bayer, Novartis, and Boehringer Ingelheim; personal fees from Merck Serono; and non-financial support from Teva, Gilead, Lucane Pharma, Actelion, CSL Behring, and Vertex. FB reports personal fees for consultancy, lecturing, and travel support from Boehringer Ingelheim and Roche. MC reports grants from DZL. JHF reports personal fees, grants, and non-financial support from Roche; and personal fees and non-financial support from Boehringer Ingelheim. AG reports grants from DZL, Boehringer Ingelheim, and Roche. MH reports grants from Actelion; honoraria for lectures from Actelion, Bayer Healthcare, Berlin Chemie, Boehringer Ingelheim, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Novartis, OMT, Pfizer, and Roche; honoraria for advisory boards from Actelion, Bayer, Boehringer Ingelheim, GSK, MSD, and Roche; and honoraria for clinical trials from Actelion, Bayer, GSK, Pfizer, and United Therapeutics. NKn reports personal fees from Roche. DK reports personal fees from Roche; and personal fees and non-financial support from Boehringer Ingelheim. MK reports grants from DZL; and grants and personal fees from Boehringer Ingelheim and Roche. AP reports grants from DZL; grants, personal fees, and non-financial support from Boehringer Ingelheim and AstraZeneca; personal fees and non-financial support from Roche, Pliant, Chiesi Pharmaceuticals, and Nitto Denko; personal fees from Amgen; and non-financial support from Galapagos. KFR reports grants and personal fees from Boehringer Ingelheim and AstraZeneca; and personal fees from Novartis, Sanofi, Regeneron, Roche, and Chiesi Pharmaceuticals. TW reports grants from Roche; and personal fees from Boehringer Ingelheim, Roche, and Novartis. HWil reports personal fees for lectures or consultations from Actelion–Janssen, Bayer, Biotest, Boehringer Ingelheim, GSK, Pfizer, and Roche. HWir reports lecture fees from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice., Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms., Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2])., Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice., Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms., Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years., Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: An association between idiopathic pulmonary fibrosis (IPF) and advancing age is suspected since IPF occurs primarily in patients over 60 years of age. Though, little is known about the disease in the elderly. The aim of this study was to characterize elderly IPF patients using data from the longitudinal, German-wide INSIGHTS-IPF registry. Methods: Patients were grouped into elderly (≥75 years) and nonelderly IPF (<75 years) at the time of enrollment into the study. Baseline clinical characteristics, comorbidities, health related quality of life (HRQoL), medical therapy and survival were compared between age groups. Effects of antifibrotic therapy on forced vital capacity (FVC) were analyzed over 24 months. Results: Of 1,009 patients, 350 (34.7%) were ≥75 years old. Elderly IPF patients compared to younger patients had a higher number of comorbidities (3.6 ± 2.5 vs. 2.8 ± 2.3; p < 0.001). The mean ± SD EQ-5D score (0.64 ± 0.21 vs. 0.69 ± 0.21; p = 0.005), and the overall WHO-5 score (13.1 ± 5.9 vs. 14.3 ± 6.0; p = 0.015) were significantly lower while the UCSD-SOBQ (52.6 ± 31.2 vs. 45.5 ± 31.2; p = 0.030) was significantly higher in elderly patients, indicating a more impaired HRQoL and more breathlessness. At baseline, 55.4% of elderly and 56.8% of nonelderly patients with IPF were treated with antifibrotic therapy ( p = 0.687). For FVC decline after initiation of antifibrotic therapy, there was neither a significant difference between age groups at the different time points over 24 months (beta: 0.41; 95%-CI: -0.98 to 1.81; p = 0.563) nor over the whole course of time (beta: -0.05; 95%-CI: -0.20 to 0.09; p = 0.478). All-cause mortality was higher in elderly patients (49.1 vs. 37.9%; HR 1.65; 95%-CI 1.36-2.00; p < 0.001). Antifibrotic therapy was associated with improved survival in IPF patients, independent from age (<75 years: beta 0.76; 95%-CI: 0.59-0.99; p = 0.049; ≥75 years: beta 0.71; 95%-CI: 0.51-0.98; p = 0.043). Conclusion: In real life, a significant proportion of IPF patients are ≥75 years old, characterized by higher number of comorbidities and global reduced HRQoL. However, the effect of an antifibrotic therapy was similar between age groups and associated with a survival benefit emphasizing the importance for an early antifibrotic therapy in IPF, independent from age., (Copyright © 2020 Leuschner, Klotsche, Kreuter, Prasse, Wirtz, Pittrow, Frankenberger, Behr, Kneidinger and the INSIGHTS-IPF Registry Group.)

Objective: There is a paucity of observational data on antifibrotic therapy for idiopathic pulmonary fibrosis (IPF). We aimed to assess the course of disease of IPF patients with and without antifibrotic therapy under real-life conditions., Methods: We analysed data from a non-interventional, prospective cohort study of consecutively enrolled IPF patients from 20 interstitial lung disease expert centres in Germany. Data quality was ensured by automated plausibility checks, on-site monitoring, and source data verification. Propensity scores were applied to account for known differences in baseline characteristics between patients with and without antifibrotic therapy., Results: Among the 588 patients suitable for analysis, the mean±sd age was 69.8±9.1 years, and 81.0% were male. The mean±sd duration of disease since diagnosis was 1.8±3.4 years. The mean±sd value at baseline for forced vital capacity (FVC) and diffusion capacity ( D LCO ) were 68.6±18.8% predicted and 37.8±18.5% predicted, respectively. During a mean±sd follow-up of 1.2±0.7 years, 194 (33.0%) patients died. The 1-year and 2-year survival rates were 87% versus 46% and 62% versus 21%, respectively, for patients with versus without antifibrotic therapy. The risk of death was 37% lower in patients with antifibrotic therapy (hazard ratio 0.63, 95% CI 0.45; 0.87; p=0.005). The results were robust (and remained statistically significant) on multivariable analysis. Overall decline of FVC and D LCO was slow and did not differ significantly between patients with or without antifibrotic therapy., Conclusions: Survival was significantly higher in IPF patients with antifibrotic therapy, but the course of lung function parameters was similar in patients with and without antifibrotic therapy. This suggests that in clinical practice, premature mortality of IPF patients eventually occurs despite stable measurements for FVC and D LCO ., Competing Interests: Conflict of interest: J. Behr reports grants and personal fees from Boehriger Ingelheim, personal fees from Actelion, Roche, Galapagos, Promedior, BMS and MSD, during the conduct of the study. Conflict of interest: A. Prasse reports grants and personal fees from Roche/InterMune and Boehringer Ingelheim, outside the submitted work. Conflict of interest: H. Wirtz reports personal fees from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Koschel has nothing to disclose. Conflict of interest: D. Pittrow reports personal fees from Actelion, Bayer, Boehringer Ingelheim, Sanofi, Biogen, Shield and MSD, outside the submitted work. Conflict of interest: M. Held has nothing to disclose. Conflict of interest: J. Klotsche has nothing to disclose. Conflict of interest: S. Andreas reports grants and personal fees from Boehringer Ingelheim, personal fees from Roche, outside the submitted work. Conflict of interest: M. Claussen reports personal fees from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: C. Grohé has nothing to disclose. Conflict of interest: H. Wilkens reports personal fees from Boehringer Ingelheim, Roche, Actelion, Biotest, GSK, Pfizer and Bayer, outside the submitted work. Conflict of interest: L. Hagmeyer has nothing to disclose. Conflict of interest: D. Skowasch reports personal fees from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: J.F. Meyer reports personal fees for lectures from Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: J. Kirschner has nothing to disclose. Conflict of interest: S. Gläser reports grants and personal fees from Boehringer Ingelheim and Novartis, personal fees from Roche, Actelion, Berlin Chemie and Astra, outside the submitted work. Conflict of interest: N. Kahn has nothing to disclose. Conflict of interest: T. Welte reports grants and personal fees from Boehringer Ingelheim, grants from Roche, outside the submitted work. Conflict of interest: C. Neurohr reports personal fees from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: M. Schwaiblmair has nothing to disclose. Conflict of interest: T. Bahmer reports grants from German Center of Lung Research (DZL), personal fees from Roche, AstraZeneca, Chiesi, GSK and Novartis, outside the submitted work. Conflict of interest: T. Oqueka has nothing to disclose. Conflict of interest: M. Frankenberger has nothing to disclose. Conflict of interest: M. Kreuter reports grants and personal fees from Roche/InterMune and Boehringer Ingelheim, outside the submitted work., (Copyright ©ERS 2020.)

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension., Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data., Methods and Results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy ( n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status., Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy., Competing Interests: COMPERA is supported by an educational grant from Bayer, GSK, OMT and Actelion. The authors declare no conflicts of interest in relation to the study.

Purpose: Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services., Methods: We performed a multicenter (n = 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression., Results: We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32-2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98-0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93-0.97)., Conclusions/implications: The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.

Background: Despite the encouraging results of noninvasive ventilation (NIV) in chronic hypercapnic COPD patients, it is also evident that some patients do not tolerate NIV or do not benefit from it. We conducted a study in which COPD patients with stable, chronic hypercapnia were treated with NIV and nasal high-flow (NHF) to compare effectiveness., Methods: In a multi-centered, randomized, controlled, cross-over design, patients received 6 weeks of NHF ventilation followed by 6 weeks of NIV ventilation or vice-versa (TIBICO) between 2011 and 2016. COPD patients with stable daytime hypercapnia (pCO 2 ≥50 mmHg) were recruited from 13 German centers. The primary endpoint was pCO 2 changes from baseline blood gas, lung function, quality of life (QoL), the 6 min walking test, and duration of device use were secondary endpoints., Results: A total of 102 patients (mean±SD) age 65.3±9.3 years, 61% females, body mass index 23.1±4.8 kg/m 2 , 90% GOLD D, pCO 2 56.5±5.4 mmHg were randomized. PCO 2 levels decreased by 4.7% (n=94; full analysis set; 95% CI 1.8-7.5, P =0.002) using NHF and 7.1% (95% CI 4.1-10.1, P <0.001) from baseline using NIV (indistinguishable to intention-to-treat analysis). The difference of pCO 2 changes between the two devices was -1.4 mmHg (95% CI -3.1-0.4, P =0.12). Both devices had positive impact on blood gases and respiratory scores (St. George's Respiratory Questionnaire, Severe Respiratory Insufficiency Questionnaire)., Conclusions: NHF may constitute an alternative to NIV in COPD patients with stable chronic hypercapnia, eg, those not tolerating or rejecting NIV with respect to pCO 2 reduction and improvement in QoL., Competing Interests: Dr. Bräunlich reports grants and non-financial support from TNI Medical AG during the conduct of the study; and grants, personal fees and non-financial support from TNI Medical AG and personal fees from Fisher&Paykel, outside the submitted work. Prof. Kähler reports non-financial support from TNI Medical AG. Prof. Randerath reports grants from Heinen und Löwenstein, Weinmann, Philips Respironics, and Inspire, outside the submitted work. Prof. Wirtz reports personal fees and non-financial support from TNI Medical AG, during the conduct of the study. All other authors have nothing to disclose.

Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus-based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open-label, 12-month multicenter trial was conducted at 8 German sites. Patients 3-18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3-5 ng/mL) with reduced CNI (tacrolimus 3-5 ng/mL or cyclosporine 25-75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy-proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: The objective was to assess quality of life (QoL) in lung cancer survivors, compare it to the general population, and identify factors associated with global QoL, physical functioning, emotional functioning, fatigue, pain, and dyspnea., Methods: Data from NSCLC patients who had survived 1 year or longer after diagnosis were collected cross-sectionally in a multicenter study. QoL was assessed with the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the lung cancer module QLQ-LC13 across different clinical subgroups and compared to age- and sex-standardized general population reference values. Multivariable linear regression analyses were performed to test the associations of patient-, tumor-, and treatment-related factors with the six primary QoL scales., Results: Six hundred fifty-seven NSCLC patients participated in the study with a median time since diagnosis of 3.7 years (range, 1.0-21.2 years). Compared to the age- and sex-standardized general population, clinically meaningful differences in the QoL detriment were found on almost all domains: lung cancer survivors had clinically relevant poorer global QoL (10 points, p < 0.001). Whereas in 12 months or longer treatment-free patients this detriment was small (8.3), it was higher in patients currently in treatment (16.0). Regarding functioning and symptom scales, respective detriments were largest for dyspnea (41 points), role function (33 points), fatigue (27 points), social function (27 points), physical function (24 points), and insomnia (21 points) observed across all subgroups. The main factor associated with poorer QoL in all primary QoL scales was mental distress (β |19-31|, all p < 0.001). Detriments in QoL across multiple primary QoL scales were also observed with current treatment (β |8-12|, p < 0.01), respiratory comorbidity (β |4-5|, p < 0.01), and living on a disability pension (β |10-11|, p < 0.01). The main factor associated with better QoL in almost all primary QoL scales was higher physical activity (β |10-20|, p < 0.001). Better QoL was also observed in patients with high income (β |10-14|, p < 0.01)., Conclusions: Lung cancer survivors experience both functional restrictions and symptoms that persist long term after active treatment ends. This substantiates the importance of providing long-term supportive care., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities., Methods: We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease-specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations., Results: Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations., Conclusions: These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non-responders to therapy who have high symptoms and/or exacerbation rates., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nasal High Flow (NHF) provides a warmed and humidified air stream. In pediatrics, this method is already in widespread use and is increasingly replacing the CPAP. New studies show success in treating adults. Currently the acute hypoxemic insufficiency cause of pneumoniae is a secured area of use. NHF is not inferior in comparison to other oxygen delivery systems. At this juncture effectiveness of this easy to use method is not clear. Preliminary reports describe an improvement in ventilation by the NHF. Here, a wash-out of the airways and improved alveolar ventilation seem to be the main operating principles., (© Georg Thieme Verlag KG Stuttgart · New York.)

With the increase of the proportion of the elderly in the total population more cases of pulmonary and extrapulmonary tuberculosis (TB) are observed in this age group as well. Symptoms of TB are unspecific, often less apparent in the elderly, and may therefore cause a delay in the diagnostic process. A history of TB and comorbidities are more common in elder as compared to younger TB patients. The tuberculin skin test is less frequently positive. The interferon-gamma-release assay is complementary and together with clinical, radiologic, and bacteriologic test results helpful for the diagnosis or the exclusion of an active or latent TB infection. Medical treatment of TB in the elderly follows the established guidelines in the same way as for younger patients. The likelihood of drug-induced side effects and interactions with concomitant medications, however, is increased. Comorbidity and age-related immunosuppression may lead to a delay in the healing process. Higher age, comorbidity, and immunosuppression are predictors of an increased TB mortality. Even in a low-incidence country like Germany, TB should be recognized as an explanation for clinical symptoms particularly in the elderly patient group in order to allow an early diagnosis and therapy and thus a reduction of mortality and prevention of a further spread of this disease.

Background: Although the incidence of 6.6 newly diagnosed tuberculosis (TB) cases per 100,000 inhabitants is in decline in Germany, TB remains a disease of significant epidemiologic importance., Patients and Methods: From 04/2001 to 07/2008, a total of 75 TB patients of an internal-pulmonary outpatient clinic had been treated (0.5% of all patients). 58 (77.3%) patients fulfilled the criteria of an active TB, 17 (22.7%) of latent tuberculous infection (LTBI). 68.0% were male (average age men 39.3 +/- 16.9 years [mean +/- standard deviation], women 46.8 +/- 21.5 years; p = not significant). 69.3% of the patients were born in Germany, 30.7% abroad. 84.5% patients had isolated pulmonary, 8.6% additional organ involvement, and 6.9% isolated extrapulmonary TB. 62.1% of active TB cases were microbiologically proven (51.7% microscopically, 43.1% in addition culturally, 6.9% exclusively culturally, 19.0% by polymerase chain reaction [PCR])., Results: Of 23 tests, 52.2% were fully sensitive against the most important first-line drugs ethambutol (M), isoniazid (H), rifampicin (R), pyrazinamide (Z), und streptomycin (S). 13.0% had an isolated resistance against H (4.4%) or S (8.6%), 4.4% a multiple drug resistance (MDR) against R und H, 30.4% a polyresistance (S and H). Symptoms were quite often unspecific, not taken care of, or misinterpreted., Conclusion: Diagnosis and therapy of an active or latent TB illness remains, an important task and challenge, necessitating an effective cooperation of outpatient, hospital, and health authority institutions.

Idiopathic pulmonary hemosiderosis (IPH) is a rare clinical entity characterized by recurrent episodes of diffuse alveolar hemorrhage. The disease--also called Ceelen's syndrome--was subsequently defined as a clinical entity comprising the triade of hemoptysis, opacities in X-ray, and anemia, in which the etiology is still unknown. Intensive search for a specific etiology ends up negative, and there are no features, which are specifically pathognomonic for IPH. Therefore, the diagnosis relies solely on the exclusion of other disorders in which diffuse alveolar hemorrhage is a cardinal sign. Acute episodes may occur frequently, eventually leading to lung fibrosis in the chronic stage. Usually, the therapy consists of high doses of corticosteroids, which can be combined with immunosuppressive drugs. In addition to this review, a case having Ceelen's syndrome is presented. After a complicated clinical course, the patient could finally be stabilized with a combination therapy of prednisolone and azathioprine.

The GINA (Global Initiative for Asthma) 2006 guideline contains far-reaching innovations in asthma management and control. The dose and choice of recommended medication depend on the degree of asthma severity and the quality of asthma control, rather than using the known stepwise severity approach. This flexible scheme gives the treating physician great freedom in the choice of substance used. However, the coexistence of the nonetheless valid four-degree severity grading with the new five-degree therapy scheme may cause confusion. The asthma control-guided new treatment recommendations are based on the experience with the GOAL (Gaining Optimal Asthma controL) trial. Altogether, the GINA 2006 guideline represents a shift of paradigm in asthma management. The efficacy of these recommendations and their practicability, however, have still to be proven. The aim of this review is, first, to introduce these new aspects and, second, to critically discuss advantages and potential disadvantages.