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Background: Circulating extracellular vesicles (EVs) have shown promising results as noninvasive biomarkers for predicting disease outcomes in solid organ transplantation. Because in situ graft cell expression of the tolerogenic molecule HLA-G is associated with acceptance after lung transplantation (LTx), we hypothesized that plasma EV-bound HLA-G (HLA-GEV) levels could predict chronic lung allograft dysfunction (CLAD) development., Methods: We analyzed 78 LTx recipients from the Cohort-for-Lung-Transplantation cohort, all in a stable (STA) state within the first year post-LTx. At 3 y, 41 patients remained STA, and 37 had CLAD (bronchiolitis obliterans syndrome, BOS, [n = 32] or restrictive allograft syndrome [n = 5]). HLA-GEV plasma levels were measured at month 6 (M6) and M12 in 78 patients. CLAD occurrence and graft failure at 3 y post-LTx were assessed according to early HLA-GEV plasma levels., Results: In patients with subsequent BOS, (1) HLA-GEV levels at M12 were significantly lower than those in STA patients (P = 0.013) and (2) also significantly lower than their previous levels at M6 (P = 0.04).A lower incidence of CLAD and BOS and higher graft survival at 3 y were observed in patients with high HLA-GEV plasma levels at M12 (high versus low HLA-GEVs patients [cutoff 21.3 ng/mL]: freedom from CLAD, P = 0.002; freedom from BOS, P < 0.001; and graft survival, P = 0.04, [log-rank]). Furthermore, in multivariate analyses, low HLA-GEV levels at M12 were independently associated with a subsequent risk of CLAD, BOS, and graft failure at 3 y (P = 0.015, P = 0.036, and P = 0.026, respectively [Cox models])., Conclusions: This exploratory study suggests the potential of EV-bound HLA-G plasma levels as a liquid biopsy in predicting CLAD/BOS onset and subsequent graft failure., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUND Lung transplantation (LTx) is a life-extending therapy for specific patients with terminal lung diseases. This study aimed to evaluate the associations and causes of 1-year mortality after lung transplantation at Strasbourg University Hospital, France, between 2012 and 2021. MATERIAL AND METHODS We carried out a retrospective analysis on 425 patients who underwent LTx at Strasbourg University Hospital between January 1, 2012, and December 31, 2021. Pre-transplant, perioperative, and postoperative data were collected from the electronic medical records. RESULTS Among all patients, 94.6% had a LTx, 4.0% a heart-lung transplantation, and 1.4% underwent pancreatic islet-lung transplantation. The median age at transplantation was 57 years, with 55.3% male patients. The main native lung disease leading to LTx was chronic obstructive pulmonary disease in 51.1% of patients; 16.2% needed super-urgent LTx. The 1-year mortality rate was 11.5%. Most deaths were either caused by multi-organ failure or septic shock. In our multivariate analysis, we identified 3 risk factors significantly related to 1-year mortality after LTx: body mass index (BMI) between 25 and 30 kg/m² vs BMI between 18.5 and 25 kg/m² (P=0.032), postoperative extracorporeal membrane oxygenation support (P=0.034), and intensive care unit length of stay after transplantation (P<0.001). Two other factors were associated with a significantly lower 1-year mortality risk: longer hospital stay after LTx (P=0.024) and tacrolimus prescription (P=0.004). CONCLUSIONS Our study reported a 1-year mortality rate of 11.5% after LTx. Although LTx candidates are carefully selected, additional data are required to improve understanding of the risk factors for post-LTx mortality.

Microbial ion-pumping rhodopsins (MRs) are extensively studied retinal-binding membrane proteins. However, their biogenesis, including oligomerisation and retinal incorporation, remains poorly understood. The bacterial green-light absorbing proton pump proteorhodopsin (GPR) has emerged as a model protein for MRs and is used here to address these open questions using cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulations. Specifically, conflicting studies regarding GPR stoichiometry reported pentamer and hexamer mixtures without providing possible assembly mechanisms. We report the pentameric and hexameric cryo-EM structures of a GPR mutant, uncovering the role of the unprocessed N-terminal signal peptide in the assembly of hexameric GPR. Furthermore, certain proteorhodopsin-expressing bacteria lack retinal biosynthesis pathways, suggesting that they scavenge the cofactor from their environment. We shed light on this hypothesis by solving the cryo-EM structure of retinal-free proteoopsin, which together with mass spectrometry and MD simulations suggests that decanoate serves as a temporary placeholder for retinal in the chromophore binding pocket. Further MD simulations elucidate possible pathways for the exchange of decanoate and retinal, offering a mechanism for retinal scavenging. Collectively, our findings provide insights into the biogenesis of MRs, including their oligomeric assembly, variations in protomer stoichiometry and retinal incorporation through a potential cofactor scavenging mechanism., (© 2024. The Author(s).)

Background: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment., Research Question: What are the most relevant changes in CT scan parameters over time for assessing response to treatment?, Study Design and Methods: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated., Results: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24)., Interpretation: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment., Trial Registration: ClinicalTrials.gov; No.: NCT02273661; URL: www., Clinicaltrials: gov)., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: C. G. reports having received speaker fees and travel support from Pfizer and MSD; fees for board memberships from SOS Oxygène and Pulmatrix; and grant support from Ohre Pharma, Pfizer, Merck Sharp & Dohme, SOS Oxygène, ISIS Medical, LVL Médical, Oxyvie, Vivisol, Elivie, CF Santé, Boehringer, Sandoz, and AstraZeneca. A.-L. B. reports speaker fees from Boehringer. F. C. reports having received research grant support from Bristol-Myers Squibb/Pfizer and Bayer; fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer, Merck Sharp & Dohme, and AstraZeneca; and travel support from Bayer, Bristol-Myers Squibb/Pfizer, Leo Pharma, Merck Sharp & Dohme, and LeoPharma. J.-P. F. reports having received grants from the French Ministry of Health, outside the submitted work; grants, personal fees, and nonfinancial support from Fisher & Paykel HealthCare, outside the submitted work; and personal fees and nonfinancial support from SOS Oxygène, outside the submitted work. S. M.-A. reports having received consultancy for board membership, and consultancy or speaker fees and travel support from AstraZeneca, Boehringer Ingelheim, Novartis, GSK, BMS, Chiesi, Pfizer, and Roche. F. Gagnadoux reports having received grants and personal fees from Resmed; personal fees and nonfinancial support from Boehringer Ingelheim, Inspire, Nyxoah, Sanofi, and Sefam; personal fees from Actelion, Cidelec, and Novartis; and nonfinancial support from Asten and Merck Sharp & Dohme, unrelated to the submitted work. E. B. reports having received consultancy or speaker fees and travel support from Pfizer, Merck Sharp & Dohme, Novartis, Gilead, Roche, Boehringer Ingelheim, SOS Oxygene, and ISIS Medical. C. T. reports having received consulting or advisory fees from Sanofi, GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, and Stallergenes; and research grants from Sanofi and GSK, outside the submitted work. B. P. reports having received travel support from Oxyvie. S. H. reports having received research grant support from CSL Behring, and consulting or advisory fees from Boehringer Ingelheim, not related to this study. C. A. reports having received fees for board memberships or symposia and travel support from GSK, Astra-Zeneca, Zambon, and Insmed. A. Bourdin reports having 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 coinvestigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Regeneron, and Vertex. C. C. reports having received grants from AstraZeneca, GlaxoSmithKline, Novartis, and Santelys, outside the submitted work; personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Sanofi-Regeneron, outside the submitted work; and congress support from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, and Sanofi-Regeneron. S. D. reports having received consultancy for board membership, speaker fees, and travel support from Roche, Chiesi, Boehringer-Ingelheim, Astra-Zeneca, Novartis, and Actelion, outside the submitted work. G. M. reports having received consultancy for board membership and speaker fees from AstraZeneca and Sanofi. M. M.-E. reports having received consultancy for board membership or speaker fees, or travel support, from Insmed, Pfizer, Vertex, and Zambon. F. R. reports having received consultancy fees from Roche and Boehringer-Ingelheim. G. G. reports having received grants from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron, and Chiesi; has provided consultancy for AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi-Regeneron; and has acted as an investigator or coinvestigator for trials sponsored by AstraZeneca, GlaxoSmithKline, and Sanofi-Regeneron. F. Goupil reports having received travel support from Aliseo/Asten Santé, GlaxoSmithKline, Chiesi, Novartis, and Actelion. A. Bergeron reports being on the safety board for ENANTA, personal fees for the scientific committee, and speaker fees from Astra Zeneca, Novartis, and Congrès voyage Boehringer. P. P. reports having received travel support from Asten Santé and Viatris. H. M. reports having received consultancy or speaker fees, or travel support, from LFB, Grifols, CSL Behring, Novartis, Boehringer, and PulmonX. J. C. reports having received speaker fees from Merck Sharp & Dohme and Pfizer. None declared (F. L., F.-X. B., T. F., J. K., S. R.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Due to the COVID-19 pandemic, France underwent several lockdown periods during 2020. Our aim was to evaluate its clinical and social impact on lung transplant (LT) patients treated at Strasbourg University Hospital, by comparing three periods: first lockdown (T1: March-May 2020), end of the first lockdown (T2: May-October 2020), and second lockdown (T3: November-December 2020) and the incidence of COVID-19 infections. A cohort of patients with rare lung disease (RLD) was also studied during T2., Methods: We used clinical and paraclinical data collected during routine follow-up. A questionnaire was submitted to each patient at each period to assess their lifestyle, adherence to protective measures against COVID-19, contacts with their family and friends, and contagion risk. The incidence of new COVID-19 cases was also assessed., Results: Overall, 283 LT and 57 RLD patients were included. We observed only eight COVID-19 cases over the three periods (n = 4 during T1, n = 0 during T2, and n = 4 during T3) in LT patients, with 37.5 % of patients hospitalized, no ICU transfers, and 100 % favorable outcomes. No case of COVID-19 was diagnosed in the RLD cohort. When comparing the three periods in the LT group, fewer patients limited their out-of-home activities during T2 (p < 0.0001). The frequency of these activities increased after the first lockdown, for the purchase of basic necessities (p < 0.0001), and professional activity continued (p = 0.008). We observed a significant increase in unscheduled medical consultations and in the prescription of anti-infective treatments during the end of the lockdown (p = 0.0002 and p = 0.005, respectively). Adherence to lockdown and to protective measures was high in both groups of patients., Conclusion: COVID-19 incidence remained low in both groups and there were significant lifestyle evolutions in LT patients and in those with RLD between first and second lockdown., 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers., Methods: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers., Results: We identified 99 SRG adult variant carriers ( SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer ( SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1 / SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7)., Conclusions: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated., Competing Interests: Conflict of interest: P. Bonniaud reports grants from AstraZeneca, lecture honoraria from Sanofi and AstraZeneca, travel support from AstraZeneca, Novartis, Sanofi, Boehringer and Stallergenes, and advisory board membership with AstraZeneca, Novartis, Sanofi, GSK and Boehringer. J. Cadranel had a patent planned, received consulting fees and participated on a data safety monitoring board or advisory board for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Daichi, Lilly, Pfizer, Novartis, MSD, Roche and Takeda. A. Cazes reports lecture honoraria and travel support from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consulting fees from Apellis, BMS, Boehringer Ingelheim and Sanofi, lecture honoraria from Apellis, AstraZeneca, BMS, Boehringer Ingelheim, Novartis and Sanofi, support for attending meetings or travel from AstraZeneca, BMS, Boehringer Ingelheim and Sanofi, participated on a data safety monitoring board or advisory board for Apellis, BMS, Boehringer Ingelheim and Sanofi, and had a leadership role as President of the Board of Trustees of the Fondation du Souffle. R. Epaud reports consulting fees from AstraZeneca, lecture honoraria from GSK, AstraZeneca and Menarini, travel support from GSK and AstraZeneca, and advisory board membership with AstraZeneca and Novartis. M-P. Debray reports lecture honoraria and travel support from Boehringer Ingelheim. E. Manali reports lecture honoraria from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings or travel from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and had a leadership role as a Chair in the ERS Task Force for transition of chILD to adult care. S. Papiris reports lecture honoraria from Boehringer Ingelheim and Hoffmann-La Roche, and travel support from Boehringer Ingelheim and Elpen. N. Nathan reports grants from Legs poix de la Chancellerie des Universités 2022 (number 2022000594). C. Andréjak participated on a data safety monitoring board or advisory board for the EVER-ILD2 study (rituximab in diffuse interstitial pneumonia) and received funding via a grant from the French Research Ministry. S. Jouneau reports grants from AIRB, Boehringer Ingelheim and Roche, lecture honoraria from AIRB, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Genzyme, GSK, LVL, Novartis, Pfizer, Roche and Sanofi, travel support from Boehringer Ingelheim, Roche and AIRB, and advisory board participation for Boehringer Ingelheim, GSK and Sanofi. G. Beltramo reports lecture honoraria from Bristol Myers Squibb, and support for attending meetings or travel from Sanofi Aventis France and Boehringer Ingelheim France. S. Hirschi reports research grants from Agence de la Biomedécine, CSL Behring and Adiral medical assistance, lecture honoraria from Boehringer Ingelheim, travel support from CSL Behring, Boehringer Ingelheim and ISIS Medical, and received medical equipment from ISIS Medical. C. Picard reports lecture honoraria and consulting fees from Boehringer Ingelheim. G. Prévot reports honoraria for presentations and educational event from Boehringer Ingelheim, Sanofi, Jansen and MSD. G. Zalcman reports consulting fees from AstraZeneca, BMS, Pfizer and Sanofi, lecture honoraria from BMS, AstraZeneca and Sanofi, support for attending meetings or travel from AstraZeneca and BMS, and participated on a data safety monitoring board or advisory board for AstraZeneca and BMS. V. Cottin reports grants from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, lecture honoraria from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, support for attending meetings or travel from Boehringer Ingelheim and Roche, participated on a data safety monitoring board or advisory board for Galapagos, Galecto and GSK, and had a leadership role in an adjudication committee for Fibrogen. R. Borie reports consulting fees from Boehringer Ingelheim, Ferrer and Sanofi, lecture honoraria from Boehringer Ingelheim and Roche, travel support from Boehringer Ingelheim, Roche and Chiesi, and advisory board participation for Savara. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs., Study Design and Methods: A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry., Results: Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005)., Conclusions: Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice., (© 2024. The Author(s).)

Background and Objective: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults., Methods: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed., Results: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DL CO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DL CO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group., Conclusion: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients., Methods: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed., Results: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%., Conclusions: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx)., Methods: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure., Results: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046)., Conclusions: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality., (© 2023 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking., Research Question: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections., Methods: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data., Results: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection., Interpretation: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage., Competing Interests: Competing interests: The authors reported no conflict of interest related to this work. SMA reports having received consultancy for board membership, consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis and Roche, GSK, BMS, Chiesi and Pfizer; and travel support from Boehringer Ingelheim. Other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation., Methods: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018., Results: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m -2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis., Conclusions: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation., Competing Interests: Conflict of interest: V. Cottin reports grants, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees and nonfinancial support from Roche/Promedior, and personal fees from Celgene/BMS, Galapagos, Galecto, Shionogi, Fibrogen, RedX and PureTech, outside the submitted work. Conflict of interest: R. Borie reports grants or contracts from Roche and Boehringer Ingelheim, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Boehringer Ingelheim and Sanofi, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Savara, outside the submitted work. Conflict of interest: P-A. Thomas reports consulting fees from AstraZeneca, outside the submitted work; payment for expert testimony from Ethicon Endosurgery, outside the submitted work; and support for attending meetings and/or travel from Europrisme, outside the submitted work. Conflict of interest: S. Hirschi reports receiving a research grant from Agence Biomedecine and CSL Behring, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche and Boehringer, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Basigin is an essential host receptor for invasion of Plasmodium falciparum into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. Here, we show that erythrocyte basigin is exclusively found in one of two macromolecular complexes, bound either to plasma membrane Ca 2+ -ATPase 1/4 (PMCA1/4) or to monocarboxylate transporter 1 (MCT1). PfRH5 binds to each of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca 2+ export is not affected by PfRH5, making it unlikely that this is the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth-inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context., Competing Interests: AJ, CC, SH, WB No competing interests declared, SH is affiliated with Roche Pharma AG. The author has no financial interests to declare, BF is a shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis, SD is a named inventor on patents related to PfRH5-targeting antibodies.(PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885), US is an employee and shareholder of Logopharm GmbH and BF is shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis, MH US is an employee and shareholder of Logopharm GmbH and BF is shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis.named inventor on patents related to PfRH5-targeting antibodies (PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885), (© 2023, Jamwal et al.)

Objective: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers., Methods: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease., Results: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded., Conclusion: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Structural and functional characterization of proteins as well as the design of targeted drugs heavily rely on recombinant protein expression and purification. The polyhistidine-tag (His-tag) is among the most prominent examples of affinity tags used for the isolation of recombinant proteins from their expression hosts. Short peptide tags are commonly considered not to interfere with the structure of the tagged protein and tag removal is frequently neglected. This study demonstrates the formation of higher-order oligomers based on the example of two His-tagged membrane proteins, the dimeric arginine-agmatine antiporter AdiC and the pentameric light-driven proton pump proteorhodopsin. Size exclusion chromatography revealed the formation of tetrameric AdiC and decameric as well as pentadecameric proteorhodopsin through specific interactions between their His-tags. In addition, single particle cryo-electron microscopy (cryo-EM) allowed structural insights into the three-dimensional arrangement of the higher-order oligomers and the underlying His-tag-mediated interactions. These results reinforce the importance of considering the length and removal of affinity purification tags and illustrate how neglect can lead to potential interference with downstream biophysical or biochemical characterization of the target protein., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The bottom-up assembly of biological and chemical components opens exciting opportunities to engineer artificial vesicular systems for applications with previously unmet requirements. The modular combination of scaffolds and functional building blocks enables the engineering of complex systems with biomimetic or new-to-nature functionalities. Inspired by the compartmentalized organization of cells and organelles, lipid or polymer vesicles are widely used as model membrane systems to investigate the translocation of solutes and the transduction of signals by membrane proteins. The bottom-up assembly and functionalization of such artificial compartments enables full control over their composition and can thus provide specifically optimized environments for synthetic biological processes. This review aims to inspire future endeavors by providing a diverse toolbox of molecular modules, engineering methodologies, and different approaches to assemble artificial vesicular systems. Important technical and practical aspects are addressed and selected applications are presented, highlighting particular achievements and limitations of the bottom-up approach. Complementing the cutting-edge technological achievements, fundamental aspects are also discussed to cater to the inherently diverse background of the target audience, which results from the interdisciplinary nature of synthetic biology. The engineering of proteins as functional modules and the use of lipids and block copolymers as scaffold modules for the assembly of functionalized vesicular systems are explored in detail. Particular emphasis is placed on ensuring the controlled assembly of these components into increasingly complex vesicular systems. Finally, all descriptions are presented in the greater context of engineering valuable synthetic biological systems for applications in biocatalysis, biosensing, bioremediation, or targeted drug delivery.

Almost 25% of patients with pulmonary fibrosis referred for lung transplantation have a germline rare variant of a telomere-related gene. Acquired TERT promoter mutations may counterbalanced the germline defect and reduce the risk of hematological complications in this population. In a series of 34 patients with a germline telomere-related gene mutation who underwent lung transplantation, 12 (35%) patients had at least 1 acquired TERT promoter mutation. Six patients presented myelodysplasia before lung transplantation, with no difference between patients with and without an acquired TERT promoter mutation. After lung transplantation, myelodysplasia developed in only 1 of 8 patients with an acquired TERT promoter mutation versus 7 of 18 patients without a mutation. Survival did not differ between patients with and without an acquired mutation. The presence of an acquired TERT promoter mutation could be associated with reduced hematological complications after transplantation and with better outcome in telomere-related gene mutation carriers but requires further study., (Copyright © 2022 International Society for Heart and Lung Transplantation. 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.)

Background: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission., Methods: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters., Results: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group., Conclusions: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research., Competing Interests: Conflict of interest: C. Godet reports having received speaker fees, travel support from Pfizer, MSD; fees for board memberships from SOS Oxygène and Pulmatrix; grant support from Ohre Pharma, Pfizer, MSD, SOS Oxygène, ISIS Medical and AstraZeneca. Conflict of interest: F. Couturaud reports having received research grant support from Bristol-Myers Squibb/Pfizer and fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer, Merck Sharp & Dohme and AstraZeneca, and having received travel support from Bayer, Bristol-Myers Squibb/Pfizer, Leo Pharma, Merck Sharp & Dohme and Actelion. Conflict of interest: S. Marchand-Adam reports having received consultancy for board membership, consultancy or speaker fees and travel support from AstraZeneca, Boehringer Ingelheim, Novartis and Roche. Conflict of interest: C. Pison reports having received, outside of the submitted work, consultancy for board membership, consultancy or speaker fees, travel support from AGIR à Dom, Chiesi, Boehringer Ingelheim, GSK, SOS Oxygène, AstraZeneca and Novartis. Conflict of interest: F. Gagnadoux reports having received grants and personal fees from Resmed; personal fees and non-financial support from Boehringer Ingelheim, Nyxoah, Sefam; personal fees from Actelion, Cidelec, Novartis, and non-financial support from Asten, unrelated to the submitted work. Conflict of interest: E. Blanchard reports having received consultancy or speaker fees, travel support from Pfizer, MSD, Novartis, Gilead, Roche, Boehringer Ingelheim, SOS Oxygene and ISIS Medical. Conflict of interest: C. Taillé reports having received consulting or advisory fees from Sanofi, GSK, AstraZeneca, Novartis and Chiesi, and research grants from Sanofi and GSK, outside the submitted work. Conflict of interest: B. Philippe reports having received speaker fees, travel support from Chiesi, Novartis and Oxyvie. Conflict of interest: S. Hirschi reports having received research grant support from CSL Behring and Adiral, and fees for board membership from Boehringer Ingelheim and Roche. Conflict of interest: C. Andréjak reports having received fees for board memberships or symposia and travel support from GSK, AstraZeneca, Zambon and Insmed. Conflict of interest: A. Bourdin reports having 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. Conflict of interest: C. Chenivesse reports having received grants from AstraZeneca and Santelys outside the submitted work, personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKlein, Novartis, Sanofi-Regeneron and TEVA outside the submitted work and congress support from ALK-Abello, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pierre Fabre, Pfizer, Roche and TEVA. Conflict of interest: S. Dominique reports having received consultancy for board membership, speaker fees, travel support from Roche, Chiesi, Boehringer Ingelheim, AstraZeneca, Novartis and Actelion, outside the submitted work. Conflict of interest: L. Bassinet has nothing to disclose. Conflict of interest: M. Murris-Espin reports having received consultancy for board membership or speaker fees, or travel support, from Insmed, MSD, Pfizer, Asten, LVL, Vertex, Vivisol and Zambon. Conflict of interest: F. Rivière reports having received consultancy fees from Roche and Boehringer Ingelheim. Conflict of interest: G. Garcia reports having received grants from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron and Chiesi; has provided consultancy for AstraZeneca, GlaxoSmithKline, Novartis and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. Conflict of interest: D. Caillaud reports having received consultancy or speaker fees, travel support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini and Novartis. Conflict of interest: F-X. Blanc has nothing to disclose. Conflict of interest: F. Goupil reports having received travel support from Aliseo/Asten Santé, GSK, Chiesi, Novartis and Actelion. Conflict of interest: A. Bergeron reports having received consultancy or speaker fees, from Pfizer, Gilead, MSD, AstraZeneca and Takeda, and grants from SOS Oxygene. Conflict of interest: A. Gondouin reports having received consultancy or speaker fees, or travel support from Roche, Boehringer Ingelheim, Vitalaire, Actelion, LFB, GSK and Pfizer. Conflict of interest: J-P. Frat reports having received grants from the French Ministry of Health, outside the submitted work; grants, personal fees and non-financial support from Fisher & Paykel HealthCare, outside the submitted work; personal fees and non-financial support from SOS Oxygène, outside the submitted work. Conflict of interest: T. Flament has nothing to disclose. Conflict of interest: B. Camara reports having received outside of the submitted work, consultancy for speaker fees, travel supports from AGIR à Dom. Conflict of interest: P. Priou received travel support from Asten Santé. Conflict of interest: A-L. Brun has nothing to disclose. Conflict of interest: F. Laurent reports having received consultancy for board membership, consultancy or speaker fees, travel support from Bayer, Roche, Chiesi, Boehringer Ingelheim, SOS Oxygène, AstraZeneca, Basilea, Novartis and Actelion. Conflict of interest: S. Ragot has nothing to disclose. Conflict of interest: J. Cadranel reports having received speaker fees from MSD and Pfizer., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Survival after lung transplantation (LTx) still remains limited by chronic lung allograft dysfunction (CLAD), thought to represent a form of chronic rejection. We investigated whether the immune checkpoint HLA-G/ILT2 expressed by peripheral T-cell subpopulations could predict CLAD., Methods: We used data for 150 LTx recipients from COLT (Cohort-For-Lung-Transplantation) cohort with ≥1 available blood sample at 1-, 6-, or 12-months post-Tx. Analysis of T cells by flow cytometry focused on the ILT2 receptor of HLA-G and other markers (CD57, CD25, CD127). T-cell subset analyses compared stable patients and those with CLAD at 3 years post-LTx., Results: With data for 78 stable and 72 CLAD patients, among 21 T-cell subsets expressing ILT2, only CD4+CD57+ILT2+ T cells were associated with outcome. At 1-month post-Tx, low proportion of CD4+CD57+ILT2+ T cells was associated with reduced 3-year incidence of CLAD (CD4+CD57+ILT2+ T cells ≤ first IQR [25%] vs > first IQR, log-rank test, p = 0.028). Furthermore, the incidence of CLAD was higher with >2.6- vs ≤2.6-fold increased proportion of CD4+CD57+ILT2+ T cells over the first year post-LTx (3-year freedom frequencies: 27% [95%CI: 8-50] vs 64% [95%CI: 48-77] (log-rank test, p = 0.014). On multivariable analysis, increased proportion of CD4+CD57+ILT2+ T cells over the first year predicted CLAD (hazard ratio 1.25; 95%CI: 1.09-1.44; p = 0.001). Focusing on CD4+CD57+ILT2+ T cells, we demonstrated ex vivo that they are cytotoxic CD4+ T cells, selectively inhibited by HLA-G., Conclusions: Our data suggest that an early increase of CD4+CD57+ILT2+ T cells after LTx may be associated with CLAD onset., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: Bronchiolitis obliterans syndrome (BOS) is the main limitation to long-term survival following lung transplantation. Several studies generated promising results regarding the efficacy of extracorporeal photopheresis (ECP) in BOS management. We aimed to compare FEV1 evolution in ECP-treated versus non-ECP treated patients among BOS recipients., Methods: Overall, 25 BOS patients were included after receiving optimized treatment. Data were collected retrospectively. Twelve patients with moderate and refractory BOS received ECP treatment., Results: Among non-ECP treated control patients (n = 13), six experienced persistent decline without undergoing ECP for various reasons. ECP stabilized pre-ECP lung function during the subsequent 6 to 24 months (repeated measures one-way Anova, p = 0.002), without any significant impact observed by either FEV1 decline speed prior to ECP or time between BOS diagnosis and ECP onset. ECP-treated patients displayed a similar risk of an additional permanent 20% or higher drop in FEV1 after BOS onset compared to controls, but a lower risk compared to control decliners (p = 0.05). ECP quickly stabilized FEV1 decline in refractory BOS patients compared to non-treated decliners., Conclusions: We confirmed that this therapeutic option against refractory BOS can be managed in a medium-size LTx center, with a satisfactory efficacy and an acceptable tolerance., Competing Interests: Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose., (Copyright © 2022 SPLF and Elsevier Masson SAS. All rights reserved.)

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 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: 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.)

Introduction: Patients with short telomere-related interstitial lung disease (ILD) have worse outcomes after lung transplantation. We hypothesized that post-transplant airway complications, including dehiscence and bronchial stenosis, would be more common in the short telomere ILD lung transplant population., Methods: We conducted a multi-institutional (Brigham and Women's Hospital, Groupe de Transplantation de la SPLF) retrospective cohort study of 63 recipients between 2009 and 2019 with ILD and short telomeres, compared to 4359 recipients from the Scientific Registry of Transplant Recipients with ILD and no known telomeropathy., Results: In the short telomere cohort, six recipients (9.5%) developed dehiscence and nine recipients (14.3%) developed stenosis, compared to 60 (1.4%) and 149 (3.4%) in the control, respectively. After adjusting for age, sex, and bilaterality, the presence of short telomeres was associated with higher odds of dehiscence (odds ratio (OR) = 8.24, 95% confidence interval (CI) = 3.34 20.29, p < .001) and stenosis (OR = 4.63, 95% CI 2.21 9.69, p < .001)., Conclusion: The association between the presence of short telomeres and post-transplant dehiscence and stenosis suggest that airway complications may be a contributor to increased morbidity and mortality in patients with telomere-related ILD., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function, whereas RPA1T270A has binding properties similar to wild-type protein. To study the mutational effect in a cellular system, CRISPR/Cas9 was used to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patients with RPA1E240K, we discovered somatic genetic rescue in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the 2 somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS., (© 2022 by The American Society of Hematology.)

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies., Methods: We conducted a multicentre, international, retrospective cohort study., Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD., Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Background: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes., Objectives: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences., Methods: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender., Results: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females., Conclusions: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females., (© 2021 S. Karger AG, Basel.)

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.)

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up. Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t -test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed. Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [ n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [ n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [ n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [ n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28-40) vs. 40 months (CI 95%: 33-72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival. Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation., Competing Interests: LS reports personal fees and non-financial support from Roche/Genentech, non-financial support from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, outside the submitted work. HN reports grants and personal fees from Roche/Genentech, Boehringer Ingelheim, personal fees from Galapagos, other from Sanofi, Gilead, Novartis, Galecto Biotech AB, during the conduct of the study; personal fees from Actelion Pharmaceuticals, outside the submitted work. VC reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Bayer/MSD, Novartis, personal fees and non-financial support from Roche/Promedior, personal fees from Sanofi, Celgene, Galapagos, Galecto, Shionogi, Astra Zeneca, Fibrogen, outside the submitted work. BC reports personal fees from Astra Zeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, BMS, personal fees from Sanofi, grants, personal fees and non-financial support from Roche, outside the submitted work. AT reports personal fees from Chiesi, other from VitAlaire, Astrazeneca, Boehringer Ingelheim, outside the submitted work. SM-A reports other from roche, other from Boehringer Ingelheim, outside the submitted work. SH reports personal fees from Roche, Boerhinger ingelheim, grants from CSL Behring, outside the submitted work. SD reports personal fees from Boehringer-Ingelheim, Chiesi, Roche, outside the submitted work. PB reports personal fees and other from Roche, Boehringer, Novartis, personal fees from TEVA, other from Chiesi, personal fees from AstraZeneca, other from Stallergene, outside the submitted work. RB reports grants and personal fees from Roche, Boerhinger Ingelheim, personal fees from Savara, outside the submitted work. CP reports personal fees from ROCHE, outside the submitted work. DV reports personal fees from Roche, Boehringer Ingelheim, Roche & BI, outside the submitted work. YU reports personal fees and non-financial support from Boehringer, Roche, grants, personal fees and non-financial support from Oxyvie, outside the submitted work. 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 © 2021 Sesé, Nunes, Cottin, Israel-Biet, Crestani, Guillot-Dudoret, Cadranel, Wallaert, Tazi, Maître, Prévot, Marchand-Adam, Hirschi, Dury, Giraud, Gondouin, Bonniaud, Traclet, Juvin, Borie, Carton, Freynet, Gille, Planès, Valeyre and Uzunhan.)

Study Question: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation., Patients and Methods: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres., Results: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications., Answer to the Study Question: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis., Competing Interests: Conflict of interest: J. Le Pavec has nothing to disclose. Conflict of interest: D. Valeyre has nothing to disclose. Conflict of interest: P. Gazengel has nothing to disclose. Conflict of interest: A.M. Holm has nothing to disclose. Conflict of interest: H.H. Schultz has nothing to disclose. Conflict of interest: M. Perch has nothing to disclose. Conflict of interest: A. Le Borgne has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: C. Knoop has nothing to disclose. Conflict of interest: L. Godinas has nothing to disclose. Conflict of interest: S. Hirschi has nothing to disclose. Conflict of interest: V. Bunel has nothing to disclose. Conflict of interest: R. Laporta has nothing to disclose. Conflict of interest: S. Harari has nothing to disclose. Conflict of interest: E. Blanchard has nothing to disclose. Conflict of interest: J.M. Magnusson has nothing to disclose. Conflict of interest: A. Tissot has nothing to disclose. Conflict of interest: J-F. Mornex has nothing to disclose. Conflict of interest: C. Picard has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: J-F. Bernaudin has nothing to disclose. Conflict of interest: P-Y. Brillet has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: M. Humbert has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: J. Gottlieb has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

The green-light absorbing proteorhodopsin (GPR) is the archetype of bacterial light-driven proton pumps. Here, we present the 2.9 Å cryo-EM structure of pentameric GPR, resolving important residues of the proton translocation pathway and the oligomerization interface. Superposition with the structure of a close GPR homolog and molecular dynamics simulations reveal conformational variations, which regulate the solvent access to the intra- and extracellular half channels harbouring the primary proton donor E109 and the proposed proton release group E143. We provide a mechanism for the structural rearrangements allowing hydration of the intracellular half channel, which are triggered by changing the protonation state of E109. Functional characterization of selected mutants demonstrates the importance of the molecular organization around E109 and E143 for GPR activity. Furthermore, we present evidence that helices involved in the stabilization of the protomer interfaces serve as scaffolds for facilitating the motion of the other helices. Combined with the more constrained dynamics of the pentamer compared to the monomer, these observations illustrate the previously demonstrated functional significance of GPR oligomerization. Overall, this work provides molecular insights into the structure, dynamics and function of the proteorhodopsin family that will benefit the large scientific community employing GPR as a model protein.

Background: Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF., Methods: Patients were selected from the French national prospective cohort COFI. Patients' income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis., Results: 200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM 2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI 95% : 1.24-2.62, p = 0.001) and overall survival (HR: 1.49; CI 95% : 1.0006-2.23, p = 0.049)., Conclusions: Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Scant data are currently available about a potential link between comorbid chronic lung diseases (CLD) and the risk and severity of the coronavirus disease 2019 (COVID-19) infection., Methods: To describe the clinical characteristics of and outcomes for patients with COVID-19 infection, including patients with comorbid respiratory diseases, who have been primarily hospitalized in the pulmonology department of Strasbourg University Hospital, France. In this retrospective, single-center study, we included all confirmed cases of COVID-19 from March 3 to April 15, 2020. We then compared the symptoms, biological and radiological findings, and outcomes for patients with and without CLD., Results: Of the 124 patients that were enrolled, the median age was 62 years, and 75 patients (60%) were male. Overall, 40% of patients (n=50) had preexisting CLD, including chronic obstructive pulmonary disease (COPD) (n=15, 12%) and asthma (n=19, 15%). Twenty-eight patients were transferred to the intensive care unit (ICU), and six patients died in our unit. CLD were not predictive of ICU hospitalization, but a significantly higher total mortality was observed (17.6% vs. 5.5%, P<0.05) in these patients., Conclusions: Our results suggest the lack of an over-representation of CLD in COVID-19, representing 40% of patients in this cohort and even within a pulmonology department. CLD were not a risk factor for ICU management. However, a tendency to higher global mortality was observed in COVID-19 patients with CLD. Further studies are warranted to determine the risk of COVID-19 for patients with comorbid CLD., (Copyright © 2020 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the posttransplant setting. Treatment is based on chemotherapy; surgery is still debated and should be performed in very select cases., Methods: We observed 2 patients out of 300 who underwent lung transplantation in the Nouvel Hopital Civil between 2013 and 2019 with primary hepatic lymphoma. Chemotherapy with a rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone protocol was performed in all patients. Mycophenolate mofetil was interrupted before treatment, and everolimus was introduced after chemotherapy by associating tacrolimus withdrawal., Results: One patient showed complete remission; after 7 years, no recurrence has been noticed. The second is still undergoing chemotherapy with no signs of disease progression., Conclusions: DLBCL risk is higher in solid organ transplant recipients than in the general population. Primary hepatic lymphoma diagnosis is often difficult and based on histologic findings after initial clinical and radiological suspicion of primary or secondary liver neoplasia. Diagnosis is challenging because no clinical, radiological, or biological features exist. Biopsy is always indicated for histologic confirmation. Chemotherapy is the mainstay of therapy, but surgery may be indicated in very select patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients., Methods: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed., Results: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 (40.6-62.9) years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6%) required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days (41.0-56.5). Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio, 16.0; 95% confidence interval, 1.5-170.6; P = 0.02)., Conclusions: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The clinical and social impacts of the COVID-19 epidemic on lung transplant (LTx) recipients remain poorly known. We aimed to evaluate its social, clinical, and behavioral consequences on the LTx patients followed in Strasbourg university hospital. A questionnaire was used to collect details concerning patients' lifestyles, their protection methods used to avoid COVID-19 contamination, and clinical infection-related information for March 2020. A specific score was created to quantify patients' contacts and the associated risk of infectious contagion. Data were collected from 322 patients (91.2%). A majority reported a higher application than usual of social distancing and barrier measures. 43.8% described infectious-related symptoms and 15.8% needed an anti-infective treatment. There was no difference in symptom onset according to age, native lung disease, diabetes, or obesity. Nineteen patients were tested for COVID-19, and four were diagnosed positive, all with a favorable outcome. The infection risk contact score was higher for symptomatic patients (p: 0.007), those needing extra-medical appointments (p < .001), and those receiving anti-infective treatments (p = .02). LTx patients reported a careful lifestyle and did not seem at higher risk for COVID-19. Our score showed encouraging preliminary results and could become a useful tool for the usual infection-related follow-up of the LTx patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Very few cases of lung transplant patients affected by coronavirus disease 2019 (COVID-19) have been reported to date. A 31-year-old patient who underwent bilateral lung transplantation for cystic fibrosis in 2012 was admitted for severe acute lower limb pain. He had a confirmed exposure to COVID-19 and a 3-week history of upper respiratory tract infection. Whole-body computed tomography (CT) angiography revealed an occlusion of the 2 common femoral arteries. CT angiography detected an intracardiac thrombus in the left ventricle. Chest CT angiography showed ground-glass opacities consistent with COVID-19. A bilateral femoral surgical embolectomy using Fogarty catheter was successfully performed. Specific reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 performed on an extracted thrombus was negative, but IgM antibodies specific for COVID-19 were detected. Cardiac magnetic resonance imaging demonstrated a subendocardial and almost transmural late gadolinium enhancement in the mid and distal inferolateral and inferior wall segments, consistent with a nonrecent myocardial infarction and an apical centimetric thrombus adjacent to the lesion. Thrombophilia laboratory tests found the presence of a positive lupus anticoagulant. Treatment with low-molecular-weight heparin and aspirin was prescribed. On day 13, the patient was discharged from the hospital. This case underlines the need to be vigilant with respect to the thrombotic complications of COVID-19 and raises the issue of thrombosis prevention in COVID-19 patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis., Methods: Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis., Results: We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy., Conclusions: New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The light-driven proton pump bacteriorhodopsin (BR) from the extreme halophilic archaeon Halobacterium salinarum is a retinal-binding protein, which forms highly ordered and thermally stable 2D crystals in native membranes (termed purple membranes). BR and purple membranes (PMs) have been and are still being intensively studied by numerous researchers from different scientific disciplines. Furthermore, PMs are being successfully used in new, emerging technologies such as bioelectronics and bionanotechnology. Most published studies used the wild-type form of BR, because of the intrinsic difficulty to produce genetically modified versions in purple membranes homologously. However, modification and engineering is crucial for studies in basic research and, in particular, to tailor BR for specific applications in applied sciences. We present an extensive and detailed protocol ranging from the genetic modification and cultivation of H. salinarum to the isolation, and biochemical, biophysical and functional characterization of BR and purple membranes. Pitfalls and problems of the homologous expression of BR versions in H. salinarum are discussed and possible solutions presented. The protocol is intended to facilitate the access to genetically modified BR versions for researchers of different scientific disciplines, thus increasing the application of this versatile biomaterial.

Long term survival post lung transplantation (LTx) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). One mechanism involved is the epithelial-mesenchymal transition (EMT). Membrane microparticles (MPs) are known to be involved in some respiratory diseases and in other organs allograft rejection episodes. We hypothesized that leukocyte-derived MPs likely contribute to EMT. To emphasize this physiological concept, our objectives were to: (1) confirm the presence of EMT on explanted lungs from patients who underwent a second LTx for BOS; 2) characterize circulating MPs in transplanted patients, with or without BOS; (3) evaluate in vitro the effect of monocyte-derived MPs in EMT of human bronchial epithelial cells. Our IHC analysis on explanted graft lungs revealed significant pathological signs of EMT with an inhomogeneous destruction of the bronchial epithelium, with decreased expression of the epithelial protein E-cadherin and increased expression of the mesenchymal protein Vimentin. The immunophenotyping of MPs demonstrated that the concentration of MPs carrying E-cadherin was lower in patients affected by BOS (p = .007). In vitro, monocyte-derived MPs produced with LPS were associated with decreased E-cadherin expression (p < .05) along with significant morphological and functional cell modifications. MPs may play a role in EMT onset in bronchial epithelium following LTx., Competing Interests: Declaration of Competing Interest None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The green-light absorbing proteorhodopsin (GPR) is the prototype of bacterial light-driven proton pumps. It has been the focus of continuous research since its discovery 20 years ago and has sparked the development and application of various biophysical techniques. However, a certain controversy and ambiguity about the oligomeric assembly of GPR still remains. We present here the first tag-free purification of pentameric GPR. The combination of ion exchange and size exclusion chromatography yields homogeneous and highly pure untagged pentamers from GPR overexpressing Escherichia coli . The presented purification procedure provides native-like protein and excludes the need for affinity purification tags. Importantly, three-dimensional protein crystals of GPR were successfully grown and analyzed by X-ray crystallography. These results together with data from single particle cryo-electron microscopy provide direct evidence for the pentameric stoichiometry of purified GPR., Competing Interests: 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., (© 2020 Published by Elsevier Inc.)