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Objectives: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and as facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), the data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of inflammasomes and IL-1-related cytokines. We aimed to analyse ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen PR3., Methods: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production in whole blood of patients with active GPA was evaluated and compared with that in the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analysed., Results: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients., Conclusion: Our data suggests that ROS production and regulation of inflammasomes in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target., Trial Registration: ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT01862068., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases., Approach and Results: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001)., Conclusions: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Computational advances in artificial intelligence have led to the recent emergence of U-Net convolutional neural networks (CNNs) applied to medical imaging. Our objectives were to assess the progression of fibrotic interstitial lung disease (ILD) using routine CT scans processed by a U-Net CNN developed by our research team, and to identify a progression threshold indicative of poor prognosis., Methods: CT scans and clinical history of 32 patients with idiopathic fibrotic ILDs were retrospectively reviewed. Successive CT scans were processed by the U-Net CNN and ILD quantification was obtained. Correlation between ILD and FVC changes was assessed. ROC curve was used to define a threshold of ILD progression rate (PR) to predict poor prognostic (mortality or lung transplantation). The PR threshold was used to compare the cohort survival with Kaplan Mayer curves and log-rank test., Results: The follow-up was 3.8 ± 1.5 years encompassing 105 CT scans, with 3.3 ± 1.1 CT scans per patient. A significant correlation between ILD and FVC changes was obtained (p = 0.004, ρ = -0.30 [95% CI: -0.16 to -0.45]). Sixteen patients (50%) experienced unfavorable outcome including 13 deaths and 3 lung transplantations. ROC curve analysis showed an aera under curve of 0.83 (p < 0.001), with an optimal cut-off PR value of 4%/year. Patients exhibiting a PR ≥ 4%/year during the first two years had a poorer prognosis (p = 0.001)., Conclusions: Applying a U-Net CNN to routine CT scan allowed identifying patients with a rapid progression and unfavorable outcome., Competing Interests: Declaration of Competing Interest XG, SR, CF, MB, DIBI, JFB, DV, JCj, JMN, PYB have no conflicts of interest. MPD received fees (presentations or participation in expert groups) from Boehringer-Ingelheim. HN received fees from Roche/Genentech, Boehringer-Ingelheim, Galapagos., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy., Methods: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety., Findings: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group., Interpretation: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection., Competing Interests: Conflict of interest: A. Caille reports grants from French National Research Agency, outside the submitted work. P. Bonniaud reports grants from AstraZeneca, personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Sanofi and GSK, and non-financial support (reimbursement for national and international conferences) from Chiesi and Stallergene. R. Borie has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from Boehringer, Roche, Sanofi-Genzyme, Savara and Chiesi, outside the submitted work. J. Cadranel reports honoraria for educational events from Boehringer Ingelheim and Roche, outside the submitted work. B. Crestani has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from BMS, Boehringer Ingelheim, Roche, Apellis, Sanofi, Novartis, AstraZeneca and Chiesi, outside the submitted work; and has also received equipment/drugs or other services from Translate Bio. M-P. Debray has received or reimbursement for national and international conferences and educational events over the past 3 years from Boehringer Ingelheim and Roche, outside the submitted work. D. Israel-Biet reports consulting fees from Boehringer Ingelheim, honoraria for educational events from Boehringer Ingelheim and Roche, payments from Galapagos as a member of an adjudication committee, and support for attending meetings and/or travel from Boehringer Ingelheim, outside the submitted work. S. Jouneau has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AIRB, Bellorophon Therapeutics, Biogen, Boehringer, Chiesi, Fibrogen, Galecto Biotech, Gilead, LVL, Novartis, Olam Pharm, Pfizer, Pliant Therapeutics, Roche, Sanofi-Genzyme and Savara. J-M. Naccache has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca and Boehringer Ingelheim, outside the submitted work. L. Plantier has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Sanofi, Humanair and Arair, outside the submitted work. V. Valentin has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, outside the submitted work. L. Wémeau-Stervinou reports personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, Sanofi and BMS, outside the submitted work. V. Cottin reports grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Roche, personal fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, MSD, CSL Behring, Galapagos, Galecto, Shionogi, Fibrogen, RedX, PureTech and Promedior, outside the submitted work. S. Marchand-Adam has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, Roche, BMS, Novartis, AstraZeneca, Pfizer, GSK and Chiesi, outside the submitted work. The remaining authors declare no competing interests., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably., Methods: Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale., Results: After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis., Conclusion: These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France., Methods: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases., Results: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications., Conclusion: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis., Competing Interests: Declaration of Competing Interest Vincent COTTIN has no conflict of interest to disclose in relation with the content of the manuscript. Elodie BLANCHARD has no conflict of interest to disclose in relation with the content of the manuscript. Mallorie KERJOUAN declares research fees paid by Pfizer and Novartis to her institution. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Martine REYNAUD-GAUBERT has no conflict of interest to disclose in relation with the content of the manuscript. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Camille TAILLE declares consulting fees paid to her by Novartis. Yurdagül UZUNHAN has no conflict of interest to disclose in relation with the content of the manuscript. Lidwine WEMEAU has no conflict of interest to disclose in relation with the content of the manuscript. Claire ANDREJAK has no conflict of interest to disclose in relation with the content of the manuscript. Dany BAUD has no conflict of interest to disclose in relation with the content of the manuscript. Philippe BONNIAUD has no conflict of interest to disclose in relation with the content of the manuscript. Pierre-Yves BRILLET has no conflict of interest to disclose in relation with the content of the manuscript. Alain CALENDER has no conflict of interest to disclose in relation with the content of the manuscript. Lara CHALABREYSSE has no conflict of interest to disclose in relation with the content of the manuscript. Isabelle COURT-FORTUNE has no conflict of interest to disclose in relation with the content of the manuscript. Nicolas DESBAILLETS has no conflict of interest to disclose in relation with the content of the manuscript. Gilbert FERRETTI has no conflict of interest to disclose in relation with the content of the manuscript. Anne GUILLEMOT has no conflict of interest to disclose in relation with the content of the manuscript. Laurane HARDELIN has no conflict of interest to disclose in relation with the content of the manuscript. Marianne KAMBOUCHNER has no conflict of interest to disclose in relation with the content of the manuscript. Violette LECLERC (deceased). Mathieu LEDERLIN has no conflict of interest to disclose in relation with the content of the manuscript. Marie-Claire MALINGE has no conflict of interest to disclose in relation with the content of the manuscript. Alain MANCEL has no conflict of interest to disclose in relation with the content of the manuscript. Sylvain MARCHAND-ADAM declares consulting fees paid by Novartis. Jean-Michel MAURY has no conflict of interest to disclose in relation with the content of the manuscript. Jean-Marc NACCACHE has no conflict of interest to disclose in relation with the content of the manuscript. Mouhamad NASSER has no conflict of interest to disclose in relation with the content of the manuscript. Hilario NUNES has no conflict of interest to disclose in relation with the content of the manuscript. Gaële PAGNOUX has no conflict of interest to disclose in relation with the content of the manuscript. Grégoire PRÉVOT has no conflict of interest to disclose in relation with the content of the manuscript. Christine ROUSSET-JABLONSKI has no conflict of interest to disclose in relation with the content of the manuscript. Olivier ROUVIERE has no conflict of interest to disclose in relation with the content of the manuscript. Salim SI-MOHAMED has no conflict of interest to disclose in relation with the content of the manuscript. Renaud TOURAINE has no conflict of interest to disclose in relation with the content of the manuscript. Julie TRACLET has no conflict of interest to disclose in relation with the content of the manuscript. Ségolène TURQUIER has no conflict of interest to disclose in relation with the content of the manuscript. Stéphane VAGNARELLI has no conflict of interest to disclose in relation with the content of the manuscript. Kaïs AHMAD has no conflict of interest to disclose in relation with the content of the manuscript., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

Diagnosing pulmonary sarcoidosis raises challenges due to both the absence of a specific diagnostic criterion and the varied presentations capable of mimicking many other conditions. The aim of this review is to help non-sarcoidosis experts establish optimal differential-diagnosis strategies tailored to each situation. Alternative granulomatous diseases that must be ruled out include infections (notably tuberculosis, nontuberculous mycobacterial infections, and histoplasmosis), chronic beryllium disease, hypersensitivity pneumonitis, granulomatous talcosis, drug-induced granulomatosis (notably due to TNF-a antagonists, immune checkpoint inhibitors, targeted therapies, and interferons), immune deficiencies, genetic disorders (Blau syndrome), Crohn's disease, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and malignancy-associated granulomatosis. Ruling out lymphoproliferative disorders may also be very challenging before obtaining typical biopsy specimen. The first step is an assessment of epidemiological factors, notably the incidence of sarcoidosis and of alternative diagnoses; exposure to risk factors (e.g., infectious, occupational, and environmental agents); and exposure to drugs taken for therapeutic or recreational purposes. The clinical history, physical examination and, above all, chest computed tomography indicate which differential diagnoses are most likely, thereby guiding the choice of subsequent investigations (e.g., microbiological investigations, lymphocyte proliferation tests with metals, autoantibody assays, and genetic tests). The goal is to rule out all diagnoses other than sarcoidosis that are consistent with the clinical situation. Chest computed tomography findings, from common to rare and from typical to atypical, are described for sarcoidosis and the alternatives. The pathology of granulomas and associated lesions is discussed and diagnostically helpful stains specified. In some patients, the definite diagnosis may require the continuous gathering of information during follow-up. Diseases that often closely mimic sarcoidosis include chronic beryllium disease and drug-induced granulomatosis. Tuberculosis rarely resembles sarcoidosis but is a leading differential diagnosis in regions of high tuberculosis endemicity., Competing Interests: The authors declare that this review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Valeyre, Brauner, Bernaudin, Carbonnelle, Duchemann, Rotenberg, Berger, Martin, Nunes, Naccache and Jeny.)

Background and Importance: Clinical diagnosis of community-acquired pneumonia (CAP) is difficult to establish with certainty. Adherence to antibiotic guidelines independently affects the prognosis of CAP patients., Objective: We aimed to determine whether guidelines' adherence was related to CAP diagnosis level of certainty and could be reinforced accordingly to diagnosis improvement., Design: Secondary analysis of a prospective, multicenter study, which evaluated the impact of early thoracic CT scan on diagnosis and therapeutic plan in patients with clinically suspected CAP visiting emergency departments., Setting and Participants: In total 319 patients with clinically suspected CAP were enrolled in four emergency departments, Paris, France, between Nov 2011 and Jan 2013., Outcome Measures and Analysis: We evaluated guidelines' adherence before and after CT scan and its relationship with CAP diagnosis level of certainty. Antibiotics were categorized as adherent according to 2010 French guidelines. CAP diagnosis level of certainty was prospectively classified by the emergency physicians based on a Likert scale as excluded, possible, probable or definite before and immediately after the CT scan. These classifications and therapeutic plans were also completed by an independent adjudication committee. Determinants of adherence were assessed using Poisson regression with robust variance., Main Results: Adherence to guidelines increased from 34.2% before CT scan to 51.3% after CT scan [difference 17.1% (95% CI, 9.5-24.7)], meanwhile CAP diagnosis with high level of certainty (definite and excluded CAP) increased from 46.1 to 79.6% [difference 33.5% (95% CI, 26.5-40.5)]. Diagnosis level of certainty before CT scan was the strongest determinant of adherence in multivariate analysis (RR, 2.63; 95% CI, 1.89-3.67)., Conclusion: Antibiotic guidelines' adherence was poor and positively related to CAP diagnosis level of certainty. The results suggest that improvements in CAP diagnosis may increase adherence to antibiotic guidelines. Clinical trial registered with www.clinicaltrials.gov (NCT01574066)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. This study prospectively assessed the yield of diagnosis and safety of video-assisted thoracoscopic surgical lung biopsy (VATS-LB) for ILD diagnosis., Methods: This prospective study, conducted in 6 ILD-referral Paris hospitals, included 103 patients with ILD. VATS-LB was proposed after initial multidisciplinary discussion. A final diagnosis was made after the procedure, during a second multidisciplinary discussion. The main outcome was to determine the final diagnoses and their proportion after VATS-LB. Other outcomes were the percentage of change in diagnosis and treatment propositions after VATS-LB and adverse events during 3 months after the operation, postoperative pulmonary function, quality of life, and pain., Results: A definite diagnosis was reached in 87 patients (84.4%), and 16 remained unclassifiable (15.6%). After VATS-LB, the hypothesized diagnosis changed in 65 patients (63.1%) and treatment changed in 41 patients (39.8%). One patient died of acute exacerbation. In-hospital complications were predicted by a shorter preoperative 6-minute walking test distance and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months, whereas forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% of patients at 1 month and in 2% at 3 months., Conclusions: VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause, with good patient survival in ILD referral centers., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated., Methods: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale., Results: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis., Conclusion: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness., Methods: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here., Results: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms., Discussion: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Carriers of germline telomerase-related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range [IQR] 46-59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow-up of 26 months (IQR 15-46), 38 patients received LT. The overall post-LT median survival was 3.75 years (IQR 1.8-NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 [95% CI 1.5-11.5]) or short telomere (HR 2.2 [1.0-5.0]) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated., Methods: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale., Results: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis., Conclusion: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background and Objective: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations., Methods: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network., Results: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation., Conclusion: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed., (© 2022 Asian Pacific Society of Respirology.)

Background: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population., Methods: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m 2 ) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m 2 ) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ 2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588., Findings: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group., Interpretation: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients., Funding: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals., Competing Interests: Declaration of interests J-MN reports grants from the French Ministry of Health and Roche, during the conduct of the study; personal fees from AstraZeneca and Boehringer Ingelheim; and non-financial support from Boehringer Ingelheim. SJ reports personal fees from Actelion, Association pour les Insuffisants Respiratoires de Bretagne, AstraZeneca, Bristol Myers-Squibb, Boehringer Ingelheim, Chiesi, Galacto Biotech, Genzyme, Gilead, GlaxoSmithKline, LVL Medical, Mundipharma, Novartis, Pfizer, Roche, and Savara-Serendex; and received funding for clinical trials from Bellorophon Therapeutics, Biogen, Olam Pharm, and Pliant Therapeutics. RB reports grants from Boerhinger Ingelheim and Roche; and personal fees from Boerhinger Ingelheim, Roche, Sanofi, and SAvara. AB has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron; has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MedinCell, Merck, Novartis, Roche, and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Regeneron, and Vertex. PB reports personal fees from AstraZeneca, Boehringer, Chiesi, Novartis, Roche, Sanofi, Stallergene, and Teva. SM-A reports personal fees from Boerhinger Ingelheim and Roche. FG reports grants from Resmed; personal fees from Actelion, Cidelec, Novartis, Nyxoah, Resmed, and Sefam; and non-financial support from Asten, Boehringer Ingelheim, Novartis, Nyxoah, and Sefam. SD reports personal fees from Boehringer Ingelheim. AT reports personal fees from Bristol Myers Squibb and Chiesi; and travel accomodation fees from AstraZeneca, Boehringer Ingelheim, Teva, and Vitalaire. PYB reports grants from Laboratoire Boehringer Ingelheim and Laboratoire Roche; and personal fees from Laboratoire Boehringer Ingelheim and Laboratoire Roche. MPD reports personal fees from Boehringer Ingelheim; and non-financial support from Roche. GB reports non-financial support from Boehringer Ingelheim France, Novartis Pharma, and Roche. LW-S reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Roche, and Sanofi; and non-financial support from Boehringer Ingelheim and Roche. CC reports grants from Santelys; personal fees from Boehringer Ingelheim; and non-financial support from Roche. DV reports personal fees from Boehringer Ingelheim and Roche. BC reports personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Genzyme, Roche, and Sanofi; non-financial support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Roche, and Sanofi; and grants from Boehringer Ingelheim and Roche. VC reports personal fees from Actelion, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Fibrogen, Galapagos, Galecto, Merck Sharp & Dohme, Novartis, Promedior, Roche, Sanofi, and Shionogi; grants from Boehringer Ingelheim; and non-financial support from Actelion, Boehringer Ingelheim, Promedior, and Roche. TS reports personal fees from AstraZeneca, Bayer, BMS, Novartis, and Sanofi; and grants from AstraZeneca, Amgen, Bayer, Boehringer, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Novartis, and Sanofi. HN reports grants from Boehringer Ingelheim and Roche/Genentech; personal fees from Actelion Pharmaceuticals, Boehringer Ingelheim, Galapagos, and Roche/Genentech; and was the investigator of a clinical trial for Galecto Biotech AB, Gilead, Novartis, and Sanofi, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Chronic interstitial lung abnormalities have been described in sickle cell disease (SCD) and attributed to repetitive episode of acute chest syndrome. We report a series of 22 cases of diffuse cystic lung disease in SCD with a case-control study to hunt for mechanism. On pathological analysis of a surgical lung biopsy of the index case, the bronchioles had the appearance of constrictive bronchiolitis. Pulmonary function test results revealed lower forced expiratory flow from 25% to 75% of vital capacity in cases versus controls. These findings suggest a bronchiolar mechanism that was not associated with more acute chest syndrome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the proportion of patients meeting the 2010 SPILF-AFSSAPS guiding criteria for Streptococcuspneumoniae in patients consulting at the emergency departments of four French university hospitals for acute community-acquired pneumonia (CAP) suspicion., Patients and Methods: The PACSCAN study prospectively included 319 patients. Medical history, clinical, biological, and radiological presentations were collected. An adjudication committee retrospectively classified the diagnostic certainty based on the initial chest CT scan data and the follow-up data up to Day 28. S. pneumoniae was looked for according to the clinician's choice of blood culture, pneumococcal urinary antigen test, nasopharyngeal PCR, and/or sputum microbiological examination., Results: All patients (100%) met at least one criterion for S. pneumoniae CAP and six (2%) met all criteria. The distribution of criteria ranged from 32% (chest pain criterion) to 86% (age≥40years criterion). These figures were respectively 100%, 3%, 38%, and 82% when the study population was restricted to the 139 patients with definite or probable CAP, according to the adjudication committee. Taking into account the microbiological results, the criteria taken one by one or combined did not make it possible to differentiate the 19 S. pneumoniae CAP from the other CAPs., Conclusion: The 2010 SPILF-AFSSAPS guiding criteria for S. pneumoniae CAP are found in very variable proportions and do not, in their current form, make it possible to accurately guide towards a pneumococcal etiology in patients included in the PACSCAN study., (Copyright © 2020. Published by Elsevier Masson SAS.)

Introduction: Nonspecific interstitial pneumonia (NSIP) are rare but severe diseases, with high mortality and morbidity, with no effective pharmacological treatment allowing for long-term remission, and therefore no clear therapeutic recommendations. Classic immunosuppressants are used as first-line treatment, with only one third of patients being responders and no clear recommendations exist for the choice of the second-line therapy. The EvER-ILD study is the first one to prospectively evaluate the efficacy and safety of rituximab and mycophenolate mofetil (MMF) versus placebo and MMF in a broad range of NSIP patients that did not respond to a first-line therapy. A pharmacokinetic-pharmacodynamic analysis based on rituximab serum concentrations will allow identification of potential factors associated with therapeutic response and/or adverse effects., Methods: EvER-ILD study is a French multicenter, prospective, randomized, double blind, placebo-controlled, superiority trial. Patients with severe and progressive NSIP non-responding to a first line immunosuppressive treatment will be randomized in 2 groups of treatment: one course of rituximab plus 6 months MMF (RTX-MMF group) and one course of placebo plus 6 months MMF (Placebo-MMF group). The primary outcome is the change in Forced Vital Capacity (FVC, % of predicted) from baseline to 6 months. Several clinical, biological, and quality of life secondary outcomes will be measured at 3, 6 and 12 months. A sample size of 122 patients (61 patients per group) would allow to show a point difference between groups in the change of FVC at 6 months, based on a common standard deviation for FVC change of 8% with a power of 90%, alpha 5% two-sided, and anticipating an extreme 10% drop-out rate., Ethics and Dissemination: The protocol was approved by the French Research Ethics Committee (CPP Tours Ouest 1 2016-R28) on November 10, 2016, and by the French competent authority (ANSM, reference 160771A-22) on December 1st, 2016. This article refers to protocol V2, dated November 18, 2016. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. Results will be disseminated via peer reviewed publication and presentation at international conferences., Trial Registration Number: NCT02990286 (clinicaltrials.gov), EudraCT 2016-003026-16 (European Medicines agency)., (Copyright © 2020 SPLF and Elsevier Masson SAS. All rights reserved.)

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3-44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0-32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood., Competing Interests: F.C.-A. is the PI of an academic study of the efficacy of infliximab in extrapulmonary sarcoidosis. T.A. reports personal fees from Chiesi, other from Vital Aire, other from Astrazeneca, other from Boehringer Ingelheim, outside the submitted work. D.V. reports personal fees from Roche, personal fees from Boehringer Ingelheim, outside the submitted work. N.N. reports grants from Société de pneumologie pédiatrique et d’allergologie (France), outside the submitted work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All others authors declared no direct conflict of interest related to the present work.

Background: Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function., Methods: The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death. The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra)., Findings: From March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0·22 [95% CI 0·11-0·41; p<0·0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR 0·22 [95% CI 0·10-0·49]; p=0·0002). An increase in liver aminotransferases occurred in seven (13%) patients in the anakinra group and four (9%) patients in the historical group., Interpretation: Anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. Confirmation of efficacy will require controlled trials., Funding: Groupe Hospitalier Paris Saint-Joseph., (© 2020 Elsevier Ltd. All rights reserved.)

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD., Results: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years., Conclusions: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

Introduction: The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014., Methods: We conducted a national survey using a specific questionnaire distributed by the professional pathology services., Results: In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%)., Conclusion: In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Interstitial lung disease (ILD) seems to be associated with an increased risk of lung cancer (LC) and to have a poorer prognosis than LC without ILD. The frequency of ILD in an LC cohort and its prognosis implication need to be better elucidated. This retrospective, observational, cohort study evaluated the frequency of ILD among LC patients (LC-ILD) diagnosed over a 2-year period. LC-ILD patients' characteristics were compared to those with LC without ILD (LC-noILD). Lastly, we conducted a case-control study within this cohort, matching three LC-noILDs to each LC-ILD patient, to evaluate the ILD impact on LC patients' prognoses. Among 906 LC patients, 49 (5.4%) also had ILD. Comparing LC-ILD to LC-noILD patients, respectively, more were men (85.7% vs. 66.2%; p = 0.02); adenocarcinomas were less frequent (47.1% vs. 58.7%, p = 0.08); median [range] and overall survival was shorter: (9 [range: 0.1-39.4] vs. 17.5 [range: 0.8-50.4] months; p = 0.01). Multivariate analysis (hazard ratio [95% confidence interval]) retained two factors independently associated with LC risk of death: ILD (1.79 [1.22-2.62]; p = 0.003) and standard-of-care management (0.49 [0.33-0.72]; p < 0.001). Approximately 5% of patients with a new LC diagnosis had associated ILD. ILD was a major prognosis factor for LC and should be taken into consideration for LC management. Further studies are needed to determine the best therapeutic strategy for the LC-ILD population.

Background: Progressive fibrosing interstitial lung disease (ILD) is rarely associated with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). This study focused on the outcomes of ILD patients with associated AAV (AAV-ILD)., Methods: AAV-ILD (cases: microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) with ILD) were compared to AAV patients without ILD (controls). ILD was defined as a usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP) pattern. Two controls were matched to each case for age (>or ≤65 years), ANCA status (PR3-or MPO-positive) and creatininemia (≥or <150 μmol/L)., Results: Sixty-two cases (89% MPO-ANCA+) were included. Median age at AAV diagnosis was 66 years. ILD (63% UIP), was diagnosed before (52%) or simultaneously (39%) with AAV. Cases versus 124 controls less frequently had systemic vasculitis symptoms. One-, 3- and 5-year overall survival rates, respectively, were: 96.7%, 80% and 66% for cases versus 93.5%, 89.6% and 83.8% for controls (p = 0.008). Multivariate analyses retained age >65 years (hazard ratio (HR) 4.54; p < 0.001), alveolar haemorrhage (HR 2.25; p = 0.019) and UIP (HR 2.73; p = 0.002), but not immunosuppressant use, as factors independently associated with shorter survival., Conclusion: For AAV-ILD patients, only UIP was associated with poorer prognosis. Immunosuppressants did not improve the AAV-ILD prognosis. But in analogy to idiopathic pulmonary fibrosis, anti-fibrosing agents might be useful and should be assessed in AAV-ILD patients with a UIP pattern., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (<5%). ICI-P is more often observed in patients with nonsmall cell lung cancer (NSCLC) than in those with other cancers. Likewise, it is more common in those receiving programmed cell death (PD)-1/PD-1 ligand inhibitors rather than cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors alone. The frequency of ICI-P is higher when anti-PD-1 and anti-CTLA-4 are administered concomitantly. Despite the low fatality rate (≈13%), ICI-P is the leading cause of ICI-related deaths. This narrative review focuses on the epidemiology, clinical and radiological presentation and prognosis of ICI-P occurring in patients, especially those with advanced NSCLC. Emphasis is placed on the differences in terms of frequency or clinical picture observed depending on whether the ICI is used as monotherapy or in combination with another ICI or chemotherapy. Other pulmonary complications observed in cancer patients, yet not necessarily immune-related, are reviewed, such as sarcoid-like granulomatosis, tuberculosis or other infections. A proposal for pragmatic management, including differential diagnosis and therapeutic strategies, is presented, based on the ICI-P series reported in the literature and published guidelines., Competing Interests: Conflict of interest: J. Cadranel reports grants and personal fees from AstraZeneca, Novartis and Pfizer, and personal fees from Roche, MSD and BMS, outside the submitted work. Conflict of interest: A. Canellas reports personal fees from BMS, outside the submitted work. Conflict of interest: L. Matton has nothing to disclose. Conflict of interest: M. Darrason has nothing to disclose. Conflict of interest: A. Parrot has nothing to disclose. Conflict of interest: J-M. Naccache has nothing to disclose. Conflict of interest: A. Lavolé has nothing to disclose. Conflict of interest: A-M. Ruppert has nothing to disclose. Conflict of interest: V. Fallet reports personal fees from Bristol Meyers Squib and Lilly, outside the submitted work., (Copyright ©ERS 2019.)

Granulomatosis with polyangiitis (GPA) is an autoimmune vasculitis associated with anti-neutrophil-cytoplasmic antibodies (ANCA) against proteinase 3 leading to kidney damage. Neutrophils from those patients have increased expression of membrane proteinase 3 during apoptosis. Here we examined whether neutrophils from patients with GPA have dysregulated protein expressions associated with apoptosis. A global proteomic analysis was performed comparing neutrophils from patients with GPA, with healthy individuals under basal conditions and during apoptosis. At disease onset, the cytosolic proteome of neutrophils of patients with GPA before treatment was significantly different from healthy controls, and this dysregulation was more pronounced following ex vivo apoptosis. Proteins involved in cell death/survival were altered in neutrophils of patients with GPA. Several proteins identified were PR3-binding partners involved in the clearance of apoptotic cells, namely calreticulin, annexin-A1 and phospholipid scramblase 1. These proteins form a platform at the membrane of apoptotic neutrophils in patients with GPA but not healthy individuals and this was associated with the clinical presentation of GPA. Thus, our study shows that neutrophils from patients with GPA have an intrinsic dysregulation in proteins involved in apoptotic cell clearance, which could contribute to the unabated inflammation and autoimmunity in GPA. Hence, harnessing these dysregulated pathways could lead to novel biomarkers and targeted therapeutic opportunities to treat kidney disease., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, with a median survival of 2-3 years and variable natural history, characterized by gradual and progressive deterioration. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication, associated with poor survival and a mortality > 50%. To date, no treatment has proven effective in AE-IPF, with cyclophosphamide (CYC) the only therapy suggested to be effective on survival, primarily based on retrospective series. Considering the high fatality rates of AE-IPF, evaluating the efficacy of immunosuppressive agents in a randomized controlled trial proves crucial, as the results could significantly impact treatment and prognosis of AE-IPF., Methods: The EXAFIP study is a French national multicenter double-blind placebo-controlled randomized trial. Its primary objective is to evaluate the efficacy of CYC compared to placebo on early survival in patients treated with corticosteroids. We hypothesize that adding CYC to high-dose corticosteroids would reduce 3-month mortality in AE-IPF patients. The primary outcome is all-cause mortality rate at Month 3; secondary objectives are to evaluate the efficacy of CYC compared to placebo on overall survival at Months 6 and 12, respiratory disease-specific mortality, respiratory morbidity, and chest high-resolution computed tomography features, and to determine prognostic factors in AE-IPF and compare the safety of the two treatment arms during 6 months' follow-up., Discussion: There is an urgent unmet clinical need for effective AE-IPF treatment. The EXAFIP study is the first large Phase III placebo-controlled randomized trial evaluating the efficacy and safety of CYC added to corticosteroids in treating AE-IPF. The results of this study could significantly impact treatment strategy and prognosis of AE-IPF., Trial Registration: Clinical trials, NCT02460588 ; Date: June 2, 2015, prospectively; Issue date: 14/11/2017; Protocole Amendment Number: 03.

Introduction: In the diagnostic approach to interstitial lung disease (ILD), the use of transbronchial cryobiopsy (TBC) may offer an alternative to surgical lung biopsy (SLB). We report the diagnostic effectiveness and the safety of TBC in ILD based on the preliminary experience in two French university centers., Methods: Twenty four patients underwent TBC for the diagnosis of ILD in the operating room between 2014 and 2017. All the histological diagnoses obtained were then reviewed and validated during multidisciplinary discussions (MDD)., Results: Patients had an average of 3 TBC.TBC samples were analyzable in 22/24 (91.7%) patients. In these, samples allowed a histological diagnosis to be made in 14/22 (63.6%) patients and a diagnosis with certainty in 13/22 (59%) after MDD. The overall diagnostic yield from TBC was 13/24 (54.2%). Nine (37.5%) patients had a pneumothorax. Five (20.8%) patients had a bleeding. There were no deaths. Taking into account a possible initial learning curve and considering only the 15 patients who had their TBC after 2015, we note that a diagnosis could be made after MDD for 12 of them, that is, 80%., Conclusion: A prospective randomized study is needed to evaluate the technique in France in order to specify its diagnostic performance and its safety profile in comparison to SLB., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The association between lung cancer (LC) and interstitial lung disease (ILD) can be explained by the shared risk factors like smoking and physiopathology of fibrogenesis and cancerogenesis. The relative LC risk is shown to be 3.5- to 7.3-times higher in ILD, with LC occurrence estimated at 10-20% in ILD, with >15% of ILD patients likely to die from LC. ILD incidence upon LC diagnosis varied from 2.4-10.9%. Primary radiological presentations consist of peripheral lesions, mostly in the inferior pulmonary lobes, either close to or within the ILD areas. There is a trend towards inverted proportion of adenocarcinomas and squamous-cell carcinomas, with EGFR mutations very rarely found. ILD negatively impacted LC prognosis, with surgery associated with increased morbidity-mortality, particularly due to acute exacerbation (AE) of ILD. Limited resection reduced this risk, whilst increasing that of cancer mortality. Studies on radiotherapy that can induce AE-ILD are scarce. Chemotherapy was associated with similar response rates to those in LC patients without ILD, yet worse survival. This difference may be accounted for by ILD patients' poorer health and higher risk of drug-induced pneumonitis. Further studies are warranted to better understand cancer physiopathology within the fibrotic areas, along with the therapeutic strategies required., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody., Methods: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed., Results: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naïve to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced., Conclusions: These data do not support rituximab as a second line therapy for patients with refractory aPAP.

The objective of the study was to estimate the prevalence and incidence of interstitial lung diseases (ILDs) in Seine-Saint-Denis, a multi-ethnic county of Greater Paris, France.Patients with ILDs were identified between January and December 2012 by using several sources; all potentially involved medical specialists from public and private hospitals, community-based pulmonologists and general practitioners, and the Social Security system. Diagnoses were validated centrally by an expert multidisciplinary discussion.1170 ILD cases were reported (crude overall prevalence: 97.9/10 5 and incidence: 19.4/10 5 /year). In the 848 reviewed cases, the most prevalent diagnoses were sarcoidosis (42.6%), connective tissue diseases associated ILDs (CTDs-ILDs) (16%), idiopathic pulmonary fibrosis (IPF) (11.6%), and occupational ILDs (5.0%), which corresponded to a crude prevalence of 30.2/10 5 for sarcoidosis, 12.1/10 5 for CTDs-ILDs and 8.2/10 5 for IPF. The prevalence of fibrotic idiopathic interstitial pneumonias, merging IPF, nonspecific interstitial pneumonia and cases registered with code J84.1 was 16.34/10 5 An adjusted multinomial model demonstrated an increased risk of sarcoidosis in North Africans and Afro-Caribbeans and of CTDs-ILDs in Afro-Caribbeans, compared to that in Europeans.This study, with a comprehensive recruitment and stringent diagnostic criteria, emphasises the importance of secondary ILDs, particularly CTDs-ILDs and the relatively low prevalence of IPF, and confirms that sarcoidosis is a rare disease in France., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Interstitial lung disease (ILD) is a common form of extramuscular involvement in patients with polymyositis/dermatomyositis and is associated with poor prognosis. This study was designed to describe the long-term outcome of myositis-associated ILD. This retrospective observational study was conducted in 48 consecutive patients. Two groups defined according to outcome were compared to determine prognostic factors: a "severe" group (vital capacity [VC] < 50 % or carbon monoxide transfer factor [TLCO] < 35 % or death or lung transplantation) and a "nonsevere" group (other patients). The study population comprised 31 women and 17 men with a median age of 49.5 ± 13.6 years. Mean PFT results at the onset of ILD were 56.9 ± 23.1 % pred. for VC and 42.1 ± 16.6 % pred. for TLCO. Median (range) follow-up was 65 (2-204) months. Three patients (6.4 %) died. At last follow-up, 19 patients were classified in the "severe" group and 27 patients were classified in the "nonsevere" group. Two patients lost to follow-up after less than 12 months were excluded from this analysis. Multivariate analysis identified two independent prognostic factors: VC at onset of ILD [OR 0.95 (95 % CI 0.90-0.99)] and myopathic changes on electromyography [OR 5.76 (95 % CI 1.10-30.3)]. Patients treated in our pulmonology department for myositis-associated ILD had severe initial PFT results but a low mortality rate. Independent prognostic factors at presentation were initial VC and myopathic changes on electromyography. This study highlights the need for studies focusing on the correlation between muscle and lung pathogenic mechanisms.

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival., (Copyright ©ERS 2016.)

A 71-year-old-man was transferred to our hospital in November 2012 for a bronchial artery embolization in the context of recurrent blood clots obstructing the left lower bronchus. Since June 2012, he had been explored for a cystic hypermetabolic lesion of the entire left lobe, and underwent 3 bronchoscopies and 2 computed tomography scan-guided biopsies, with no success. A fourth bronchoscopy enabled the extraction of a large blood clot (8×1.5 cm) that obstructed the left main bronchus. The pathologic examination of the mucosal biopsy samples was inconclusive, whereas the cytologic examination of the blood clot revealed myxoid liposarcoma. Liposarcomas are the most common histologic types of soft-tissue sarcomas. They preferentially metastasize to the lungs and can appear as cystic mass. Bronchial obstruction by blood clots is not a rare finding on bronchoscopy, their main problem is their removal which could require rigid bronchoscope and large forceps. However, bronchial blood clot containing tumoral process had never been reported before. In conclusion, this case conveys 2 messages. First, pulmonary metastasis of myxoid liposarcoma can appear as cyst secondary to endobronchial tumoral growth. Second, endobronchial blood clots should always be sent for pathologic analysis.

Background: An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated., Methods: In this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH., Results: In the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18% of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22% of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5%) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort., Conclusions: Obtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management., Trial Registration: ClinicalTrials.gov: No. NCT01225601; URL: www.clinicaltrials.gov.

Rationale: Clinical decision making relative to community-acquired pneumonia (CAP) diagnosis is difficult. Chest radiograph is key in establishing parenchymal lung involvement. However, radiologic performance may lead to misdiagnosis, rendering questionable the use of chest computed tomography (CT) scan in patients with clinically suspected CAP., Objectives: To assess whether early multidetector chest CT scan affects diagnosis and management of patients visiting the emergency department with suspected CAP., Methods: A total of 319 prospectively enrolled patients with clinically suspected CAP underwent multidetector chest CT scan within 4 hours. CAP diagnosis probability (definite, probable, possible, or excluded) and therapeutic plans (antibiotic initiation/discontinuation, hospitalization/discharge) were established by emergency physicians before and after CT scan results. The adjudication committee established the final CAP classification on Day 28., Measurements and Main Results: Chest radiograph revealed a parenchymal infiltrate in 188 patients. CAP was initially classified as definite in 143 patients (44.8%), probable or possible in 172 (53.8%), and excluded in 4 (1.2%). CT scan revealed a parenchymal infiltrate in 40 (33%) of the patients without infiltrate on chest radiograph and excluded CAP in 56 (29.8%) of the 188 with parenchymal infiltrate on radiograph. CT scan modified classification in 187 (58.6%; 95% confidence interval, 53.2-64.0), leading to 50.8% definite CAP and 28.8% excluded CAP, and 80% of modifications were in accordance with adjudication committee classification. Because of CT scan, antibiotics were initiated in 51 (16%) and discontinued in 29 (9%), and hospitalization was decided in 22 and discharge in 23., Conclusions: In CAP-suspected patients visiting the emergency unit, early CT scan findings complementary to chest radiograph markedly affect both diagnosis and clinical management. Clinical trial registered with www.clinicaltrials.gov (NCT 01574066).