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Background: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxaemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage (BAL), evaluation of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), genetic testing and, eventually, lung biopsy. The management options are focused on removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis and lung transplantation. The presented diagnostic and management guidelines aim to provide guidance to physicians managing patients with PAP., Methods: A European Respiratory Society Task Force composed of clinicians, methodologists and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of evidence and strength of recommendations. The Task Force formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions and two narrative questions to develop specific evidence-based recommendations., Results: The Task Force developed recommendations for the five PICO questions. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis and lung transplantation. Also, the Task Force made recommendations regarding the use of GM-CSF antibody testing, diagnostic BAL and biopsy based on the narrative questions. In addition to the recommendations, the Task Force provided information on the hierarchy of diagnostic interventions and therapy., Conclusions: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas the diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited., Competing Interests: Conflict of interest: C. McCarthy, F. Bonella, B.C. Trapnell and M. Griese report membership of a scientific advisory board of Savara Inc. B.C. Trapnell reports grants from the NHLBI (HL085453) and Savara, consultancy fees from Savara, and support for attending meetings from Savara. T. Wang reports grants from Savara, consultancy fees from Partner Therapeutics and Savara, payment or honoraria for lectures, presentations, manuscript writing or educational events from Partner Therapeutics and Savara, support for attending meetings from the PAP Foundation, participation on a data safety monitoring board or advisory board with Partner Therapeutics and Savara Inc., and a leadership role with the PAP Foundation (Clinical Director and Vice President). C. McCarthy reports grants from Health Research Board, Ireland, Enterprise Ireland and The LAM Foundation, consultancy fees from Theravance Inc., Savara Inc. and AI Therapeutics, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara Inc. F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and Savara Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, AstraZeneca, Atyr and Savara Pharma, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. M. Fally reports leadership roles with the European Respiratory Society (Member of the Clinical Practice Guidelines Methodology Network and Secretary of Assembly 10, Group 1) and Danish Medical Journal (Associate Editor). A. Hadchouel reports patent issued (PCT/EP2022/064179). S. Jouneau reports the following financial (or non-financial) interests: PI for IMPALA and IMPALA-2 studies (Savara Inc.). R. Borie reports honoraria from Boehringer Ingelheim, Sanofi and Ferrer, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara. I. Campo reports consultancy fees from Partner's Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. E. Manali reports grants from Savara, consulting fees from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and a leadership role with the European Respiratory Society (Chair in ERS Task Force for Transition of chILD). H. Prosch reports grants from Boehringer Ingelheim, AstraZeneca, Siemens Healthineers, the Christian Doppler Research Association and EU Commission (EU4Health, Horizon Europe Health), consultancy fees from Boehringer Ingelheim and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, BMS, Boehringer Ingelheim, Bracco, Daiichi Sankyo, Janssen, MSD, Novartis, Roche, Sanofi, Siemens Healthineers and Takeda, support for attending meetings from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, and a leadership role with the European Society of Thoracic Imaging (Vice President). M. Veltkamp reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Chiesi, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Xentria. E. Bendstrup reports honoraria from Boehringer Ingelheim, AstraZeneca and Daichii Sankyo, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Simbec-Orion. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear., Methods: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated., Results: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele., Conclusions: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committees of Ruhrlandklinik (IRB 06-3170) and Hiroshima University Hospital (IRB33 and M326). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD., Methods: We utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort., Results: Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD., Conclusion: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD., (This article is protected by copyright. All rights reserved.)

Background: Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that can result in end-stage fibrosis. We investigated the influence of body composition and pulmonary fat attenuation volume (CTpfav) on overall survival (OS) in NSIP patients., Methods: In this retrospective single-center study, 71 NSIP patients with a median age of 65 years (interquartile range 21.5), 39 females (55%), who had a computed tomography from August 2009 to February 2018, were included, of whom 38 (54%) died during follow-up. Body composition analysis was performed using an open-source nnU-Net-based framework. Features were combined into: Sarcopenia (muscle/bone); Fat (total adipose tissue/bone); Myosteatosis (inter-/intra-muscular adipose tissue/total adipose tissue); Mediastinal (mediastinal adipose tissue/bone); and Pulmonary fat index (CTpfav/lung volume). Kaplan-Meier analysis with a log-rank test and multivariate Cox regression were used for survival analyses., Results: Patients with a higher (> median) Sarcopenia and lower (< median) Mediastinal Fat index had a significantly better survival probability (2-year survival rate: 83% versus 71% for high versus low Sarcopenia index, p = 0.023; 83% versus 72% for low versus high Mediastinal fat index, p = 0.006). In univariate analysis, individuals with a higher Pulmonary fat index exhibited significantly worse survival probability (2-year survival rate: 61% versus 94% for high versus low, p = 0.003). Additionally, it was an independent risk predictor for death (hazard ratio 2.37, 95% confidence interval 1.03-5.48, p = 0.043)., Conclusion: Fully automated body composition analysis offers interesting perspectives in patients with NSIP. Pulmonary fat index was an independent predictor of OS., Relevance Statement: The Pulmonary fat index is an independent predictor of OS in patients with NSIP and demonstrates the potential of fully automated, deep-learning-driven body composition analysis as a biomarker for prognosis estimation., Key Points: This is the first study assessing the potential of CT-based body composition analysis in patients with non-specific interstitial pneumonia (NSIP). A single-center analysis of 71 patients with board-certified diagnosis of NSIP is presented Indices related to muscle, mediastinal fat, and pulmonary fat attenuation volume were significantly associated with survival at univariate analysis. CT pulmonary fat attenuation volume, normalized by lung volume, resulted as an independent predictor for death., (© 2024. The Author(s).)

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) in sensitized individuals caused by a large variety of inhaled antigens. The clinical form of acute HP is often misdiagnosed, while the chronic form, especially the chronic fibrotic HP, is difficult to differentiate from other fibrotic ILDs. The present guideline for the diagnosis and treatment of HP replaces the former German recommendations for the diagnosis of HP from 2007 and is amended explicitly by the issue of the chronic fibrotic form, as well as by treatment recommendations for the first time. The evidence was discussed by a multidisciplinary committee of experts. Then, recommendations were formulated for twelve questions on important issues of diagnosis and treatment strategies. Recently published national and international guidelines for ILDs and HP were considered. Detailed background information on HP is useful for a deeper insight into HP and the handling of the guideline., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-036., (Thieme. All rights reserved.)

Purpose: Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease, with a median survival time of 2 to 5 years. The focus of this study is to establish a novel imaging biomarker., Materials and Methods: In this study, 79 patients (19% female) with a median age of 70 years were studied retrospectively. Fully automated body composition analysis (BCA) features (bone, muscle, total adipose tissue, intermuscular, and intramuscular adipose tissue) were combined into Sarcopenia, Fat, and Myosteatosis indices and compared between patients with a survival of more or less than 2 years. In addition, we divided the cohort at the median (high=≥ median, low=

Rationale: Idiopathic pulmonary fibrosis is a fatal and progressive disease with limited treatment options. Objectives: We sought to assess the efficacy and safety of CC-90001, an oral inhibitor of c-Jun N-terminal kinase 1, in patients with idiopathic pulmonary fibrosis. Methods: In a Phase 2, randomized (1:1:1), double-blind, placebo-controlled study (ClinicalTrials.gov ID: NCT03142191), patients received CC-90001 (200 or 400 mg) or placebo once daily for 24 weeks. Background antifibrotic treatment (pirfenidone) was allowed. The primary endpoint was change in the percentage of predicted FVC (ppFVC) from baseline to Week 24; secondary endpoints included safety. Measurements and Main Results: In total, 112 patients received at least one dose of study drug. The study was terminated early because of a strategic decision made by the sponsor. Ninety-one patients (81%) completed the study. The least-squares mean changes from baseline in ppFVC at Week 24 were -3.1% (placebo), -2.1% (200 mg), and -1.0% (400 mg); the differences compared with placebo were 1.1% (200 mg; 95% confidence interval: -2.1, 4.3; P  = 0.50) and 2.2% (400 mg; 95% confidence interval: -1.1, 5.4; P  = 0.19). Adverse event frequency was similar in patients in the combined CC-90001 arms versus placebo. The most common adverse events were nausea, diarrhea, and vomiting, which were more frequent in patients in CC-90001 arms versus placebo. Fewer patients in the CC-90001 arms than in the placebo arm experienced cough and dyspnea. Conclusions: Treatment with CC-90001 over 24 weeks led to numerical improvements in ppFVC in patients with idiopathic pulmonary fibrosis compared with placebo. CC-90001 was generally well tolerated, which was consistent with previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT03142191).

Pulmonary alveolar proteinosis (PAP) is a syndrome that results from the accumulation of lipoproteinaceous material in the alveolar space. According to the underlying pathogenetic mechanisms, three different forms have been identified, namely primary, secondary and congenital. Primary PAP is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling due to the presence of neutralising autoantibodies (autoimmune PAP) or GM-CSF receptor genetic defects (hereditary PAP), which results in dysfunctional alveolar macrophages with reduced phagocytic clearance of particles, cholesterol and surfactant. The serum level of GM-CSF autoantibody is the only disease-specific biomarker of autoimmune PAP, although it does not correlate with disease severity. In PAP patients with normal serum GM-CSF autoantibody levels, elevated serum GM-CSF levels is highly suspicious for hereditary PAP. Several biomarkers have been correlated with disease severity, although they are not specific for PAP. These include lactate dehydrogenase, cytokeratin 19 fragment 21.1, carcinoembryonic antigen, neuron-specific enolase, surfactant proteins, Krebs von Lungen 6, chitinase-3-like protein 1 and monocyte chemotactic proteins. Finally, increased awareness of the disease mechanisms has led to the development of pathogenesis-based treatments, such as GM-CSF augmentation and cholesterol-targeting therapies., Competing Interests: Conflict of interest: F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and CSL-Behring, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, Astra Zeneca and Atyr, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. I. Campo reports consultancy fees from Partner Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism. Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage. Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed. In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was endorsed by the European Reference Network (ERN)-LUNG, SARCOIDOSIS Core Network. Aknowledgements, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Objectives: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity., Methods: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient., Results: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods., Conclusions: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Background: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis., Research Question: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact?, Study Design and Methods: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival., Results: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk., Interpretation: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. K. reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Galapagos. P. M. reports lecture fees from Boehringer Ingelheim. F. B. reports grants and personal fees from Boehringer Ingelheim, Roche, Galapagos, and Savara Pharma. N. B. reports personal fees from Actelion, Boehringer Ingelheim, Roche, Pfizer, MSD, and AbbVie; and grants and personal fees from Novartis and SOBI. C. P. reports personal fees from Boehringer Ingelheim, Pfizer, and Takeda; grants and personal fees from Actelion and Novartis; and grants from Corbus and Amgen. M. S. reports grants and personal fees from Roche/Chugai, Hexal/Sandoz, Janssen, and BMS; and personal fees from AbbVie, Novartis, UCB, Boehringer Ingelheim, and Gilead. P. K. reports personal fees and nonfinancial support from AbbVie, Chugai, Novartis, and Pfizer, unrelated to the present manuscript; and personal fees from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline, unrelated to the present manuscript. N. H. reports lecture fees from Boehringer Ingelheim and Janssen. Nothing declared (M. O., J. W., G. R., U. M.-L., J. H., E. S., C. G., I. K., G. Z., L. S., A. J., M. W., I. J., J. E., C. S., G. K., A. R., T. S., A. K., H. M.-L.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM., Materials and Methods: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro., Results: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort., Conclusion: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed., (© 2023. The Author(s).)

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-infection is associated with an extremely variable disease course. When interstitial pneumonia (IP) occurs, it can lead to acute respiratory distress syndrome and death. Serum Krebs von den Lungen-6 (KL-6) is an established marker of IP, but its role as a marker of SARS-CoV-2 pneumonia is debated. This bicentric study included 157 patients with SARS-CoV-2 pneumonia. The WHO Ordinal Scale for Clinical Improvement (0-10 points) was used to classify the clinical course. Serum samples were collected at admission, and on days 3 and 7 of hospitalization. KL-6 was measured by using automated chemiluminescence immunoassay. A total of 68 patients developed a severe SARS-CoV-2 pneumonia, 135 of them required oxygen, and 15 died during hospitalization. The patients requiring non-invasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation had significantly higher serum KL-6 levels at admission. The serum KL-6 levels were tendentially higher in patients who died than in those who survived. Logistic regression identified serum KL-6 at a cut-off of 335 U/mL at admission as a significant predictor of severe SARS-CoV-2 pneumonia outcome. Serum KL-6 seems to be a candidate biomarker for the clinical routine to stratify patients with SARS-CoV-2 pneumonia for the risk of a severe disease outcome or death.

Objectives: Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD)., Methods: We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan-Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death., Results: It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9-93.8); n = 290] and after 5 years [91.4% (89.2-93.8); n = 357 vs 70.9% (65.2-77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6-97.3); n = 745 vs 86.4% (82.9-90.1); n = 278] and after 5 years [66.8% (63.0-70.8); n = 286 vs 45.9% (39.6-53.2); n = 69; P < 0.0001]., Conclusion: GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Purpose of Review: We discuss the most recent advances in the treatment of pulmonary alveolar proteinosis (PAP), an ultra-rare syndrome., Recent Findings: Whole lung lavage (WLL) remains the gold standard of treatment for PAP syndrome. For the autoimmune form, recent trials with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) confirmed the efficacy in up to 70% of cases, especially under continuous administration. In patients with hereditary PAP with underlying GM-CSF receptor mutations, ex vivo autologous hematopoietic stem-cell gene therapy and transplantation of autologous ex vivo gene-corrected macrophages directly into the lungs are promising approaches., Summary: There are no drugs approved for PAP at present, but cause-based treatments such as GM-CSF augmentation and pulmonary macrophage transplantation are paving the way for targeted therapy for this complex syndrome., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures., Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations., Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement., Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis., Competing Interests: FB received from Boehringer Ingelheim, Fujirebio, Galapagos NV and Roche; personal travel support from Boehringer Ingelheim and Roche, board membership fees from Boehringer Ingelheim, Bristol Myers Squibb, Fujirebio, Galapagos, GlaxoSmithKline, Roche and Takeda. DB grants paid to the institution from Synairgen and Sanofi; personal honoraria received from Chiesi, Norvatis and Sanofi; personal honoraria for lectures received from Astra Zeneca, Eli Lilly and Norvatis; not for profit activities for ministry of health, Romania. AF received a grant from the German Research Foundation. BF: received grants from Bristol Myers Squibb and AdVita Lifescience paid to the institution; personal honoraria for lectures from Boehringer Ingelheim, Astra Zeneca and Roche, personal travel support from Boehringer Ingelheim; reports a pending patient WO2020225246A1 and stocks from Relief Therapeutics. CG received lecture fees from Astra Zeneca paid to the institution. MK received consulting fees from Boehringer Ingelheim. JM-Q grants from German Research Council, Bristol Myers Squibb and AdVita Lifesciences paid to the institution, received personal honoria from AdVita Lifesciences and Roche, received lecture fees from Astra Zeneca and Roche, received payments for expert testimony from AdVita Lifescience; received travel support from AdVita Lifescience and Grifols, reports a pending patent WO2020225246A1 and stocks from Relief Therapeutics. MaP received grants from Palacky University paid to the institution. MiP reports fiduciary activities for Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin. VP received personal consulting fees from Ambu and Erbe; lecture honoraria from Boehringer Ingelheim and Roche and participated in a data safety monitoring board for Boehringer Ingelheim. AP received personal consulting fees from Boehringer Ingelheim, Roche, AstraZeneca and Galapagos, lecture fees from Boehringer Ingelheim, Norvatis and Gilead, participated in data safety monitoring boards for Boehringer Ingelheim, Roche and AstraZeneca and reports fiduciary activities for the European Rare Disease Network Interstitial Lung Disease Group and the steering committee of the World Association of Sarcoidosis and Other Granulomtous Disorders. SS reports grants from the German Research Council paid to the institution, personal consulting fees from Abbvie, Arenal, BMS, Biogen, Celltrion, Celgen, IMAB, Gilead, MSD, Mylan, Pfizer, Fresinius, Janssen, Takeda, Theravance, Provention Bio, Protagonist, Falk, Ferring, UCB, Amgen, Sandoz Hexal, Lilly, Galapagos. JCS grants from the German Research Council, Else Kröner-Fresenius Foundation, and Fritz Thyssen-Foundation paid to the institution; received personal lecture honoraria from Boehringer Ingelheim. LS received personal honoraria from Boehringer Ingelheim for educational events. D received personal honoraria from Boehringer Ingelheim for activities in advisory boards and lecture fees from Boehringer Ingelheim and AstraZeneca and reports travel support from Boehringer Ingelheim. WW grants from Roche, Boehringer Ingelheim, and Galapagos, consulting fees from Sanofi, Boehringer Ingelheim and Roche, honoraria for lectures from Roche and Beohdringer Ingelheim and payments for activities in data safety monitoring boards from Boehringer Ingelheim and Roche all paid to the institution. GZ reports a pending patent (EP 2585089 A1) and stock options for Moderna, Biontech and Relief Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Freitag-Wolf, Schupp, Frye, Fischer, Anwar, Kieszko, Mihailović-Vučinić, Milanowski, Jovanovic, Zissel, Bargagli, Rottoli, Bumbacea, Jonkers, Ho, Gaede, Dubaniewicz, Marshall, Günther, Petrek, Keane, Haraldsdottir, Bonella, Grah, Peroš-Golubičić, Kadija, Pabst, Grohé, Strausz, Safrankova, Millar, Homolka, Wuyts, Spencer, Pfeifer, Valeyre, Poletti, Wirtz, Prasse, Schreiber, Dempfle and Müller-Quernheim.)

Introduction: Prevalence and predisposing factors for the development of thoracic pain (TP) in patients with chronic interstitial lung disease (cILD) are largely unknown. Underestimation and insufficient therapy of pain can lead to worsened ventilatory function. Quantitative sensory testing is an established tool for characterization of chronic pain and its neuropathic components. We investigated frequency and intensity of TP in cILD patients and the potential association with lung function and quality of life., Materials and Methods: We prospectively investigated patients with chronic interstitial lung disease to analyze risk factors for the development of thoracic pain and quantify thoracic pain through quantitative sensory testing. In addition, we studied the relationship between pain sensitivity and lung function impairment., Results: Seventy-eight patients with chronic interstitial lung disease and 36 healthy controls (HCs) were included. Thoracic pain occurred in 38 of 78 patients (49%), most frequently in 13 of 18 (72%, p = 0.02) patients with pulmonary sarcoidosis. The occurrence was mostly spontaneous and not related to thoracic surgical interventions (76%, p = 0.48). Patients with thoracic pain showed a significant impairment of mental well-being ( p = 0.004). A higher sensitivity to pinprick stimulation during QST can be observed in patients with thoracic pain ( p < 0.001). Steroid treatment was associated with lower sensitivity within thermal ( p = 0.034 and p = 0.032) and pressure pain testing ( p = 0.046). We observed a significant correlation between total lung capacity and thermal ( p = 0.019 and p = 0.03) or pressure pain sensitivity ( p = 0.006 and p = 0.024)., Conclusion: This study was performed to investigate prevalence, risk factors and thoracic pain in patients with chronic interstitial lung disease. Thoracic pain mostly occurs spontaneous as a frequent symptom, and seems to be an underestimated symptom in patients with chronic interstitial lung disease, especially those with pulmonary sarcoidosis. Timely identification of thoracic pain may allow starting symptomatic treatment at early stage, before impairment in quality of life occurs., Clinical Trial Registration: https://www.drks.de/drks&#95;web/, Deutsches Register Klinischer Studien (DRKS) DRKS00022978., Competing Interests: FB and UC received speaker and advisor honoraria, travel and research grants from Boehringer Ingelheim Pharma, not related to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The handling editor PS declared a past co-authorship with the author FB., (Copyright © 2023 Scherer, Kampe, Fredebeul-Beverungen, Weinreich, Costabel and Bonella.)

The evaluation of a patient with interstitial lung disease (ILD) includes assessment of clinical, radiological, and often histopathological data. As there were no specific recommendations to guide the evaluation of patients under the suspicion of an ILD within the German practice landscape, this position statement from an interdisciplinary panel of ILD experts provides guidance related to the diagnostic modalities which should be used in the evaluation of ILD. This includes clinical assessment rheumatological evaluation, radiological examinations, histopathologic sampling and the need for a final discussion in a multidisciplinary team., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-028., (Thieme. All rights reserved.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT , RTEL1 , common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Background and Objective: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients., Methods: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed., Results: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10 -12 )., Conclusion: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients., (© 2022 Asian Pacific Society of Respirology.)

Genetic predisposition to pulmonary fibrosis has been confirmed by the discovery of several gene mutations that cause pulmonary fibrosis. Although genetic sequencing of familial pulmonary fibrosis (FPF) cases is embedded in routine clinical practice in several countries, many centres have yet to incorporate genetic sequencing within interstitial lung disease (ILD) services and proper international consensus has not yet been established. An international and multidisciplinary expert Task Force (pulmonologists, geneticists, paediatrician, pathologist, genetic counsellor, patient representative and librarian) reviewed the literature between 1945 and 2022, and reached consensus for all of the following questions: 1) Which patients may benefit from genetic sequencing and clinical counselling? 2) What is known of the natural history of FPF? 3) Which genes are usually tested? 4) What is the evidence for telomere length measurement? 5) What is the role of common genetic variants (polymorphisms) in the diagnostic workup? 6) What are the optimal treatment options for FPF? 7) Which family members are eligible for genetic sequencing? 8) Which clinical screening and follow-up parameters may be considered in family members? Through a robust review of the literature, the Task Force offers a statement on genetic sequencing, clinical management and screening of patients with FPF and their relatives. This proposal may serve as a basis for a prospective evaluation and future international recommendations., Competing Interests: Conflict of interest: R. Borie reports grants from Boehringer Ingelheim, consulting fees from Sanofi, lecture honoraria from Boehringer Ingelheim, Roche and Sanofi, and travel support from Boehringer Ingelheim, outside the submitted work. K. Antoniou reports consulting fees from Boehringer Ingelheim, Roche and GlaxoSmithKline, lecture honoraria from Boehringer Ingelheim, Roche, Chiesi, Menarini, GlaxoSmithKline and AstraZeneca, outside the submitted work. F. Bonella reports lecture honoraria from Boehringer Ingelheim, Fujirebio, Galapagos NV and Roche, travel support from Boehringer Ingelheim and Roche, participation on advisory boards with Boehringer Ingelheim, BMS, Fujirebio, Galapagos NV, GlaxoSmithKline, Roche and Takeda, outside the submitted work. B. Crestani reports grants from BMS, Boehringer Ingelheim and Roche, consulting fees from Apellis, lecture honoraria from Boehringer Ingelheim, BMS, Roche, Sanofi, Novartis, AstraZeneca and Chiesi, and is in receipt of equipment from Translate Bio, outside the submitted work. A. Froidure reports grants and consulting fees from Boehringer Ingelheim, lecture honoraria from Boehringer Ingelheim and GlaxoSmithKline, and travel support from Sanofi, outside the submitted work. L. Galvin reports travel support from the European Lung Foundation, European Respiratory Society and European Pulmonary Fibrosis Federation, leadership roles with the European Pulmonary Fibrosis Federation, Irish Lung Fibrosis Association, European Lung Foundation and European Reference Network On Rare Respiratory Diseases, outside the submitted work. M. Griese reports grants and travel support from Boehringer Ingelheim, outside the submitted work. M. Molina-Molina reports grants from Roche and Boehringer Ingelheim, consulting fees from Esteve-Teijin, Ferrer, Roche and Boehringer Ingelheim, and lecture honoraria from Chiesi, Roche and Boehringer Ingelheim, outside the submitted work. V. Poletti reports lecture honoraria from AMBU, Boehringer Ingelheim, ERBE and Roche, outside the submitted work. E. Renzoni reports grants from Boehringer Ingelheim, and lecture honoraria from Boehringer Ingelheim, Roche and Novartis, outside the submitted work. C.H.M. van Moorsel reports grants from the European Respiratory Society supporting the present manuscript, grants and lecture honoraria from Boehringer Ingelheim, and a leadership role as co-chair of the European Respiratory Society Task Force for genetics in pulmonary fibrosis, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

The SARS-CoV-2 pandemic had a tremendous impact on diagnosis and treatment of interstitial lung diseases (ILD). Especially in the early phase of the pandemic, when the delta variant was prevailling, a huge number of viral pneumonias were observed, which worsened pre-existing, triggered de novo occurence or discovery of previously subclincal interstitial lung diseases. The effect of SARS-CoV-2 infection - without or with accompanying viral pneumonia - on the further development of pre-existing ILD as well of new pulmonary inflitrates and consolidiations is difficult to predict and poses a daily challenge to interdisciplinary ILD boards. This position paper of the German Respiratory Society (DGP e.V.) provides answers to the most pressing questions based on current knowledge., Competing Interests: JB erhielt Honorare für Vortragstätigkeit und Beratung von AstraZeneca, Boehringer-Ingelheim, Ferrer, Galapagos, Novartis, Roche und Sanofi/Gemzyme. MPB hat Honorare für Vorträge, Beratung und Kongresssponsoring von Boehringer-Ingelheim und Roche erhalten. TGB erhielt Honorare für Vortragstätigkeit und Beratung von Astra-Zeneca, Boehringer-Ingelheim, Johnson & Johnson, MSD, Pfizer und Roche (ohne Zusammenhang mit dieser Arbeit). FB erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Sanofi, Fujirebio und Fibrogen. JD erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Parexel und Astrazeneca. SG erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Berlin Chemie, Novartis, Astra Zeneca. LH erhielt Honorare für Vortragstätigkeit und Beratung für Boehringer-Ingelheim und Roche. NK hat keine Interessenkonflikte. DK erhielt Honorare für Vortragstätigkeit und Beratung sowie finanzielle Unterstützung bei Kongressbesuchen von Boehringer Ingelheim und Roche. AP erhielt Vortragshonorare von Boehringer Ingelheim, Novartis, Roche, Pfizer und Chiesi und Beratungshonorare von Boehringer Ingelheim, Novartis, Amgen, und Astra-Zeneca. Forschungsprojekte am Fraunhofer ITEM bestehen mit Boehringer Ingelheim, Novartis, Chiesi, AdAlta, Alentis und AiThera. ESP erhielt Honorare für Vortragstätigkeit von Boehringer-Ingelheim, Roche und Bristol-Myers-Squibb. HS hat keine Interessenskonflikte. HW hat Beratungs-/Vortragshonorare von Astra Zeneca, Allergopharma, Boehringer Ingelheim, Bioprojet, GSK, Inspire Medical, Jazz Pharma, Novartis, ResMed, Sanofi, VitalAire sowie Vivisol erhalten. MK erhielt Honorare für Vortragstätigkeit und Beratung von Boehringer-Ingelheim, Roche, Ferrer, Galapagos., (Thieme. All rights reserved.)

Background: The progressive course of pulmonary fibrosis (PPF) is observed with variable prevalence in different entities of fibrosing interstitial lung disease (fILD). PPF is characterised by worsening respiratory symptoms, declining lung function and increasing extent of fibrosis on high-resolution computer tomography. In Germany, data are limited on the characteristics and management of such patients., Methods/design: INSIGHTS-ILD is a prospective observational longitudinal registry designed to describe characteristics, management and course of newly diagnosed (incident) and prevalent patients with fILD on the long term. The registry uses a non-probability sampling approach to collect data on characteristics, therapeutic interventions, health-related quality of life and health economic parameters. It is planned to include 900 patients in ambulatory care in about 30 expert sites over three years. The study has been initiated in December 2021, and currently (January 2023) follows 360 patients., Discussion: The registry is expected to provide much-needed data on the characteristics, management, and trajectories of patients fILD in Germany. The start of the study comes at a time when new treatment options are available for PPF. We hypothesize that PPF represents a broad clinical phenotype that is differentially influenced by inflammatory and fibrotic pathomechanisms that need to be treated with anti-inflammatory and/or anti-fibrotic treatment strategies. This registry will allow comparisons with other countries. Gap analyses based on current guidelines for management of these patients will be possible. Trial registration DRKS00027389 (registered on 7.12.2021), BfArM NIS 7562., (© 2023. The Author(s).)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter: http://awmf.org; AWMF-Registriernummer 020-025.

The development of a progressive phenotype of interstitial lung disease (ILD) is still unpredictable. Whereas tools to predict mortality in ILD exist, scores to predict disease progression are missing. The aim of this study was to investigate whether baseline serum KL-6 as an established marker to assess disease activity in ILD, alone or in combination with clinical variables, could improve stratification of ILD patients according to progression risk at any time. Consecutive patients with fibrotic ILD, followed at our institution between 2008 and 2015, were investigated. Disease progression was defined as relative decline of ≥10% in forced vital capacity (FVC) or ≥15% in diffusing capacity of the lung for carbon monoxide (DLco)% from baseline at any time. Serum KL-6 was measured using an automated immunoassay (Fujirebio Europe, Gent, Belgium). A stepwise logistic regression was performed to select variables to be included in the score. A total of 205 patients (49% idiopathic pulmonary fibrosis (IPF), 51% fibrotic nonspecific interstitial pneumonia (NSIP)) were included, of them 113 (55%) developed disease progression during follow up. Male gender (G) and serum KL-6 strata (K) were significant predictors of progression at regression analysis and were included in the GK score. A threshold of 2 GK score points was best for discriminating patients at high risk versus low risk to develop disease progression at any time. Serum KL-6 concentration, alone or combined in a simple score with gender, allows an effective stratification of ILD patients for risk of disease progression at any time.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ., Competing Interests: Conflict of interest: S.A. Papiris reports grants, personal fees and nonfinancial support from La Roche Hoffman and Boehringer Ingelheim, and other support from Savara, outside the submitted work. Conflict of interest: F. Bonella reports grants and personal fees from Savara Pharma outside the submitted work. Conflict of interest: R. Borie has received consulting fees from Boehringer Ingelheim, Roche and Sanofi, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and Roche, outside the submitted work; support for attending meetings and/or travel received from Boehringer Ingelheim, Roche and Chiesi outside the submitted work; and participation on a data safety monitoring or advisory board for Savara, outside the submitted work. Conflict of interest: M. Molina-Molina reports personal fees and grants from Esteve-Teijin, Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: E. Jouneau reports personal fees and other support from Actelion, AIRB, AstraZeneca, Bellerophon Therapeutics, Biogen, BMS, Boehringer Ingelheim, Chiesi, FibroGen, Galecto Biotech, Genzyme, Gilead, GlaxoSmithKline, LVL, Mundipharma, Novartis, Pharm-Olam, Pfizer, Pliant Therapeutics, F. Hoffmann-La Roche, Ltd, Sanofi and Savara-Serendex, outside the submitted work. Conflict of interest: C. McCarthy is a scientific advisory board member of Savara Inc. unrelated to this work and has not received any payment from Savara Inc. for any work to date. Conflict of interest: E. Bendstrup reports grants and personal fees from Boehringer Ingelheim and Hofmann la Roche, and personal fees from Galapagos, outside the submitted work. Conflict of interest: M. Griese has received grants or contracts from Boehringer Ingelheim, outside the submitted work; has participated on a data safety or advisory board for Boehringer Ingelheim, outside the submitted work; and is the Head of chILD-EU, outside the submitted work. Conflict of interest: E.D. Manali reports personal fees and nonfinancial support from La Roche Hoffman; grants, personal fees and nonfinancial support from Boehringer Ingelheim; and other support from Savara, all outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background and Objective: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry., Methods: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021., Results: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/μl than patients with monocyte count ≥0.95 K/μl (HR [<0.60 vs. ≥0.95 K/μl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/μl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02)., Conclusion: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed., (© 2022 Asian Pacific Society of Respirology.)

Introduction: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a standard procedure in cases of enlarged mediastinal lymph nodes. Recently, new tools were developed aiming to improve the diagnostic yield. A novel crown-cut needle is considered to obtain tissue cores which can be beneficial for the evaluation by the pathologist. This study aimed to compare the novel 22G crown-cut needle with a conventional 22G needle with EBUS guidance in the diagnosis of sarcoidosis., Methods: We designed a single-center prospective randomized clinical trial between March 2020 and January 2021 with 30 patients with mediastinal lymphadenopathy and suspected sarcoidosis., Results: 24 patients (mean age 49.5 vs 54.1, mean FVC 73.7% vs 86.7%, mean DLCO 72.4% vs 72.5% for crown-cut needle vs conventional needle, respectively) were diagnosed with sarcoidosis. In the remaining six patients, sarcoidosis was reasonably excluded. The diagnostic yield for sarcoidosis was 77% with the crown-cut needle vs. 82% with the conventional needle (p > 0.05). In patients with histopathologic hallmarks typical of sarcoidosis (n = 19), the crown-cut needle was superior in detecting granulomas (8.3 vs 3.8 per cytoblock, p < 0.05) and histiocytes (502 vs 186 per cytoblock, p < 0.05). Four of seven bronchoscopists experienced difficulties passing through the bronchial wall with the crown-cut needle and one episode of bleeding occurred in this group which made interventions necessary., Conclusions: Despite equivalence in diagnostic accuracy, the crown-cut needle was superior to the conventional needle in detecting granulomas and histiocytes. This indicates greater potential for obtaining higher quality sample material with the crown-cut needle in cases of granulomatous inflammation., (© 2022. The Author(s).)

Background and Objective: Genetic analysis is emerging for interstitial lung diseases (ILDs); however, ILD practices are not yet standardized. We surveyed patients', relatives' and pulmonologists' experiences and needs on genetic testing in ILD to evaluate the current situation and identify future needs., Methods: A clinical epidemiologist (MT) together with members of the ERS taskforce and representatives of the European Idiopathic Pulmonary Fibrosis and related disorders Federation (EU-IPFF) patient organisation developed a survey for patients, relatives and pulmonologists. Online surveys consisted of questions on five main topics: awareness of hereditary ILD, the provision of information, genetic testing, screening of asymptomatic relatives and clinical impact of genetic analysis in ILD., Results: Survey respondents consisted of 458 patients with ILD, 181 patients' relatives and 352 pulmonologists. Most respondents think genetic testing can be useful, particularly for explaining the cause of disease, predicting its course, determining risk for developing disease and the need to test relatives. Informing patients and relatives on genetic analysis is primarily performed by the pulmonologist, but 88% (218) of pulmonologists identify a need for more information and 96% (240) ask for guidelines on genetic testing in ILD. A third of the pulmonologists who would offer genetic testing currently do not offer a genetic test, primarily because they have limited access to genetic tests. Following genetic testing, 72% (171) of pulmonologists may change the diagnostic work-up and 57% (137) may change the therapeutic approach., Conclusion: This survey shows that there is wide support for implementation of genetic testing in ILD and a high need for information, guidelines and access to testing among patients, their relatives and pulmonologists., (© 2022 Asian Pacific Society of Respirology.)

Introduction: IL-9, mainly produced by T helper 9 (Th9) cells, promotes allergic airway inflammation and remodeling through the interaction with its receptor (IL-9R). Th9 cells and IL-9 have also been implicated in tissue fibrosis and autoimmunity pathways. However, the role of IL-9/IL-9R in the pathogenesis of interstitial lung disease (ILD) is unknown., Aim: To evaluate IL-9/IL-9R expression in bronchoalveolar lavage fluid (BALF) lymphocytes of patients with various ILDs., Methods: Consecutive patients with ILD, who underwent BAL for diagnostic purposes, were studied. As control group, consecutive patients without evidence of ILD were included. Immunocytochemical staining of BALF lymphocytes for IL-9 and IL-9R was performed and evaluated by two independent readers., Results: 45 patients, of them 8 had idiopathic pulmonary fibrosis (IPF), 12 nonspecific interstitial pneumonia (NSIP), 10 sarcoidosis, 9 hypersensitivity pneumonitis (HP), 6 cryptogenic organizing pneumonia (COP), and 24 controls were studied. In the ILD group, the highest BALF lymphocyte count was seen in HP followed by NSIP, COP, sarcoidosis, and IPF (p < 0.05 for HP vs IPF). The highest percentages of IL-9 and IL-9R positive lymphocytes were seen in COP. Conversely, NSIP showed the lowest rate of IL-9, and sarcoidosis the lowest rate of IL-9R positive lymphocytes. Only in NSIP, a direct correlation between IL and 9 and IL-9R positive lymphocytes was seen (r = 0.639, p = 0.025)., Conclusion: BALF lymphocytes IL-9 and IL-9R expression differs between various ILDs and could reflect different pathogenetic mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a "post-test probability of IPF." The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

Introduction: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials., Methods: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I 2 statistic, τ 2 and corresponding p value from a Q test for heterogeneity., Results: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I 2  = 0%, τ 2  = 0, p = 0.93)., Conclusions: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations., (© 2022. The Author(s).)

This article provides an overview of scientific highlights in the field of interstitial lung disease (ILD), presented at the virtual European Respiratory Society Congress 2021. A broad range of topics was discussed this year, ranging from translational and genetic aspects to novel innovations with the potential to improve the patient pathway. Early Career Members summarise a selection of interesting findings from different congress sessions, together with the leadership of Assembly 12 - Interstitial Lung Disease., Competing Interests: Conflict of interest: S.A. Guler reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim and Hoffmann-La Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim (disclosures made outside the submitted work). Conflict of interest: S. Cuevas-Ocaña reports receiving support for attending meetings and/or travel from the ERS (disclosure made outside the submitted work). Conflict of interest: M. Nasser reports receiving consulting fees from Boehringer Ingelheim, AstraZeneca, Hoffman-La Roche and Chugai, outside the submitted work. Conflict of interest: W.A. Wuyts reports grants or contracts received form Roche, Boehringer Ingelheim, Galapagos, the NIH and Fund Scientific Research Flanders (disclosures made outside the submitted work). Conflict of interest: M.S. Wijsenbeek reports receiving grants or contracts from Hoffmann-La Roche and Boehringer Ingelheim; consulting fees from Roche, Boehringer Ingelheim, Galapagos, Bristol Myers Squibb, Galecto and Respivant; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Hoffmann-La Roche and Novartis; support for attending meetings and/or travel from Boehringer Ingelheim and Hoffmann-La Roche; and participation on a Data Safety Monitoring Board for Savara and Galapagos. Unpaid positions: Chair of the Idiopathic Interstitial Pneumonia Group of the ERS; member of the board of the Netherlands Respiratory Society; member of the scientific advisory board of the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation; Chair of the educational committee of the European Reference Network for Rare Lung Diseases; and advisory board of the Dutch lung fibrosis and sarcoidosis patient associations (disclosures made outside the submitted work). Conflict of interest: A. Froidure reports grants or contracts received from Roche and Boehringer Ingelheim; and consulting fees received from Boehringer Ingelheim and Roche (disclosures made outside the submitted work). Conflict of interest: E. Bargagli has nothing to disclose. Conflict of interest: E.A. Renzoni reports grants or contracts received from Boehringer Ingelheim; consulting fees received from Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Roche and Chiesi; and support for attending meetings and/or travel received from Boehringer Ingelheim (disclosures made outside the submitted work). Conflict of interest: M. Veltkamp reports receiving consulting fees from Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Chiesi Pharmaceutical; and participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim and the COLD study (disclosures made outside the submitted work). Conflict of interest: P. Spagnolo reports grants or contracts received from PPM Services, Roche and Boehringer Ingelheim; consulting fees received from PPM Services, Chiesi, Novartis and Pieris; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Roche and Chiesi; support for attending meetings and/or travel received from PPM Services and Boehringer Ingelheim; and participation on a Data Safety Monitoring Board or Advisory Board for Galapagos (disclosures made outside the submitted work). Conflict of interest: H. Nunes reports receiving consulting fees from Boehringer Ingelheim, Roche and Genentech; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Roche and Genentech; support for attending meetings and/or travel received from Boehringer Ingelheim, Roche and Genentech; participation on a Data Safety Monitoring Board or Advisory Board for Galapagos and Actelion Pharmaceuticals; and was an investigator of clinical trials for Sanofi, Gilead, Novartis, Galecto Biotech AB and BMS (disclosures made outside the submitted work). Conflict of interest: C. McCarthy reports receiving grants or contracts from Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Roche Ltd and Aerogen; support for attending meetings and/or travel received from Boehringer Ingelheim and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Savara Inc. (disclosures made outside the submitted work). Conflict of interest: M. Molina-Molina reports grants or contracts received from Roche and Boehringer Ingelheim; consulting fees received from Esteve-Teijin, Ferrer and Chiesi; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim; and support for attending meetings and/or travel received from Boehringer Ingelheim (disclosures made outside the submitted work). Conflict of interest: F. Bonella reports receiving consulting fees from Boehringer Ingelheim and Savara Pharma; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Fujirebio, Galapagos NV and Roche; support for attending meetings and/or travel received from Boehringer Ingelheim and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Bristol Myers Squibb, Fujirebio, Galapagos NV, GlaxoSmithKline, Roche and Takeda (disclosures made outside the submitted work). Conflict of interest: V. Poletti has nothing to disclose. Conflict of interest: M. Kreuter reports receiving grants or contracts from Roche and Boehringer Ingelheim; consulting fees received from Roche, Boehringer Ingelheim and Galapagos; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Roche and Boehringer Ingelheim (disclosures made outside the submitted work). Conflict of interest: K.M. Antoniou reports receiving consulting fees from Boehringer Ingelheim and Roche; payment of honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Boehringer Ingelheim and Roche; and support for attending meetings and/or travel received from Boehringer Ingelheim and Roche; she is head of ERS Assembly 12 (disclosures made outside the submitted work). Conflict of interest: C.C. Moor reports receiving grants or contracts from Roche and Boehringer-Ingelheim; and speaker fees from Roche and Boehringer-Ingelheim. All grants and fees were paid to her institution (disclosures made outside the submitted work)., (Copyright ©The authors 2022.)

Sarcoidosis is a granulomatous systemic disease of unknown etiology most commonly affecting the lungs and thoracic lymph nodes. The diagnosis is based on typical clinical radiologic appearance and histology with evidence of noncaseating epithelioid cell granulomas without central necrosis. In the acute form, Löfgren's syndrome, histologic confirmation may not be necessary. Approximately half of patients may develop a chronic form, and extrathoracic organ involvement should be investigated during the course. Indications for therapy are based on functional limitations, marked organ-related or systemic symptoms, and life-threatening organ manifestations (cardiac, central nervous system, renal, and ocular sarcoidosis). To date, there is no approved drug therapy for sarcoidosis. Administration of immunosuppressants such as glucocorticosteroids and as add-on or sequential, methotrexate, azathioprine or mycophenolate mofetil is recommended in the currently published international guideline., Competing Interests: Erklärung zu finanziellen InteressenForschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht-Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein.Erklärung zu nicht-finanziellen InteressenDie Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background and Objective: Demographic and clinical variables, measured at baseline or over time, have been associated with mortality in subjects with progressive fibrosing interstitial lung diseases (ILDs). We used data from the INPULSIS trials in subjects with idiopathic pulmonary fibrosis (IPF) and the INBUILD trial in subjects with other progressive fibrosing ILDs to assess relationships between demographic/clinical variables and mortality., Methods: The relationships between baseline variables and time-varying covariates and time to death over 52 weeks were analysed using pooled data from the INPULSIS trials and, separately, the INBUILD trial using a Cox proportional hazards model., Results: Over 52 weeks, 68/1061 (6.4%) and 33/663 (5.0%) subjects died in the INPULSIS and INBUILD trials, respectively. In the INPULSIS trials, a relative decline in forced vital capacity (FVC) >10% predicted within 12 months (hazard ratio [HR] 3.77) and age (HR 1.03 per 1-year increase) were associated with increased risk of mortality, while baseline FVC % predicted (HR 0.97 per 1-unit increase) and diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 0.77 per 1-unit increase) were associated with lower risk. In the INBUILD trial, a relative decline in FVC >10% predicted within 12 months (HR 2.60) and a usual interstitial pneumonia-like fibrotic pattern on HRCT (HR 2.98) were associated with increased risk of mortality, while baseline DLCO % predicted (HR 0.95 per 1-unit increase) was associated with lower risk., Conclusion: These data support similarity in the course of lung injury between IPF and other progressive fibrosing ILDs and the value of FVC decline as a predictor of mortality., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Objectives: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance., Methods: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate., Results: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly., Conclusions: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

Communications between clinicians and patients with idiopathic pulmonary fibrosis (IPF) have the potential to be challenging. The variable course and poor prognosis of IPF complicate discussions around life expectancy but should not prevent clinicians from having meaningful conversations about patients' fears and needs, while acknowledging uncertainties. Patients want information about the course of their disease and management options, but the provision of information needs to be individualised to the needs and preferences of the patient. Communication from clinicians should be empathetic and take account of the patient's perceptions and concerns. Models, tools and protocols are available that can help clinicians to improve their interactions with patients. In this article, we consider the difficulties inherent in discussions with patients with IPF and their loved ones, and how clinicians might communicate with patients more effectively, from breaking the news about the diagnosis to providing support throughout the course of the disease., Competing Interests: Conflict of interest: M.S. Wijsenbeek reports grants, and non-financial and other support, with all grants and fees paid to her institution, from Boehringer Ingelheim and Hoffmann-La Roche; and other support, with all fees paid to her institution, from Galapagos NV, Novartis, Respivant and Savara. F. Bonella reports personal fees and non-financial support from Boehringer Ingelheim, Bristol-Myers Squibb, Fujirebio, Galapagos NV, GlaxoSmithKline and Roche. L. Orsatti is an employee of Boehringer Ingelheim. A-M. Russell reports grants and personal fees from Boehringer Ingelheim, and personal fees from Hoffmann-La Roche and the Irish Lung Fibrosis Association. C. Valenzuela reports personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos NV and Hoffmann-La Roche. W.A. Wuyts reports grants and other support, with all fees paid to his institution, from Boehringer Ingelheim, and grants, with all fees paid to his institution, from Roche. W.F. Baile reports fees for presentations from Boehringer Ingelheim., (Copyright ©The authors 2022.)

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that requires ongoing care and is associated with considerable socioeconomic burden. We evaluated the IPF care pathway from symptom recognition to treatment. We describe the impact of IPF on healthcare resource use (HCRU), quality of life (QoL) and work impairment, and report differences in patient and physician perspectives using real-world data from France, Germany, Japan and the United States., Methods: Quantitative, point-in-time data were collected as part of the Adelphi IPF II Disease Specific Programme™. Physician-reported data (patient demographics, medical history, diagnoses, treatment) were matched to patient-reported data (HCRU, QoL, work impairment). HCRU was measured as physician visits and hospitalizations. QoL and work impairment were measured using the EuroQol-5 Dimensions (EQ-5D) and Work Productivity and Activity Impairment questionnaires., Results: Overall, 244 physicians reported data on 1249 patients, 739 of whom self-reported data. Diagnostic delays of 0.8 (Germany) to 2.0 (Japan) years after symptom onset were reported; treatment initiation was further delayed. In all countries, patients more often reported symptoms in the survey than did their physicians. On average, patients underwent 7-10 clinical tests before diagnosis. Antifibrotic use increased from 57% (2016) to 69% (2019); only 50% of patients with moderate/severe IPF were satisfied with their treatment. The 12-month hospitalization rates were 24% (Japan) to 64% (United States). Patients reported low QoL (mean EQ-5D visual analogue scale: 61.7/100)., Conclusion: Patients with IPF experience considerable diagnostic and treatment delays. More effective therapies and management are needed to reduce the disease burden., (© 2021 Galapagos NV. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background:  Quality of life (QoL) is significantly impaired in patients with pulmonary fibrosis, however reliable tools to assess QoL issues specific for this group of patients are still missing. We thus aimed to develop a new questionnaire called "Quality of life in patients with idiopathic pulmonary fibrosis" (QPF) to measure QoL in patients with fibrotic idiopathic interstitial pneumonias (IIP)., Methods:  An item pool was created on the basis of a German expert group with support of patients suffering from pulmonary fibrosis. In a 1st step, this version of the questionnaire was completed by 52 patients with idiopathic pulmonary fibrosis (IPF) or non-specific interstitial pneumonia (NSIP). Following this, an item- and an exploratory factor analysis was carried out and a 2nd version created. In a multicenter validation study in a one-group pre-post design, the questionnaire was filled in by 200 patients with IIP (IPF = 190, iNSIP = 10) at 2 time points with an interval of 6 months. Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ)., Results:  The mean age of the patients was 71.0 years (50-90 years), 82.5 % were male. Item analysis revealed that most of Cronbach alpha and selectivity values of QPF-scales could be considered as sufficient (e. g. QPF-scale "condition" [alpha = 0.827], "impairment" [alpha = 0.882]). At scale level, there were significant differences in terms of a deterioration or improvement in the QPF-condition and QPF-breathlessness scales and also in the SGRQ-activity scale. Analysis of construct validation of QPF and SGRQ showed moderate correlations between both questionnaires. A deterioration in health status from the patient's and doctor's perspective was seen in the scales "impairment", "shortness of breath" and "health status" of the QPF. The QPF was able to detect a change in the patient's mood ("condition" scale) in the course of treatment., Conclusion:  This newly developed questionnaire maps the special needs of the patients well. The QPF is suitable for screening of quality of life as well as for supplementing the medical history and for monitoring the course of disease in fibrotic IIPs., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations., Methods: A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations., Results: The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation., Conclusions: There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment., Competing Interests: Conflict of interest: R.P. Baughman reports grants from Gilead, Genentech, Bayer, aTyr and Bellephron, grants and personal fees for consultancy from Novartis, personal fees for consultancy from Methial, grants and personal fees for consultancy and lectures from Mallinckrodt, grants and personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: P. Korsten reports grants and personal fees from GlaxoSmithKline, personal fees from AbbVie, Pfizer, Chugai, Novartis Pharma, Sanofi-Aventis, Lilly and Gilead, outside the submitted work. Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: W.A. Wuyts has nothing to disclose. Conflict of interest: A. Wells reports personal fees for lectures and advisory board work from Boehringer Ingelheim and Roche, during the conduct of the study. Conflict of interest: P. Rottoli has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: E.E. Lower reports grants from Gilead, Genentech, Bayer and aTYR, grants and personal fees for consultancy from Novartis, outside the submitted work. Conflict of interest: M.A. Judson received grant support for his institution from Mallickrodt. Conflict of interest: D. Israël-Biet has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: M. Drent has nothing to disclose. Conflict of interest: D.A. Culver reports grants and personal fees from aTyr, Mallinckrodt, Boehringer Ingelheim and Foundation for Sarcoidosis Research, personal fees from Roche, outside the submitted work. Conflict of interest: F. Bonella reports personal fees and non-financial support from Boehringer Ingelheim, Roche, Galapagos, BMS and Savara Pharma, outside the submitted work. Conflict of interest: K. Antoniou has nothing to disclose. Conflict of interest: F. Martone has nothing to disclose. Conflict of interest: B. Quadder has nothing to disclose. Conflict of interest: G. Spitzer has nothing to disclose. Conflict of interest: B. Nagavci acts as an ERS methodologist. Conflict of interest: T. Tonia acts as an ERS methodologist. Conflict of interest: D. Rigau acts as an ERS methodologist. Conflict of interest: D.R. Oullette reports grants from PCORI (Patient-Centred Outcomes Research Institute, US Federal) and Sanofi, outside the submitted work; and has provided expert witness work for venous thromboembolic disease., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Health status and quality of life are impaired in patients with idiopathic pulmonary fibrosis (IPF) and idiopathic non-specific interstitial fibrosis (iNSIP). In Germany exists only the K-BILD questionnaire for patients with ILD 1 in a professional translation by Kreuter et al. 2 This questionnaire focuses on the main problems in patients with progressive lung fibrosis in a limited manner. Therefore a new quality of life questionnaire for patients with idiopathic pulmonary fibrosis was developed and linguistically validated., Methods:  The linguistic validation of our questionnaire was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by IPF- and iNSIP-patients ensured that the translated questionnaire reflected the intention of the original English version of our questionnaire.Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ)., Results:  The new questionnaire concerning the health status was composed in English and German language. The questions cover five scales (sensitivity, selectivity and symptoms like breathlessness and cough and a visual analog scale on general health status) with 23 items., Conclusions:  The results show that the FFB maps the special needs of the patients with IPF and iNSIP well and can support clinical and scientific questions and can be helpful in monitoring the clinical course., Competing Interests: D. Kirsten, U. de Vries, U. Costabel, D. Koschel, F. Bonella, A. Günther, J. Behr, M. Claussen, St. Schwarz, A. Prasse, M. Kreuter geben keinerlei Interessenkonflikte an., (Thieme. All rights reserved.)