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High-resolution computed tomography (HRCT) has revolutionized the diagnosis, prognosis and in some cases the prediction of therapeutic response in interstitial lung disease (ILD). HRCT represents an essential second step to a patient's clinical history, before considering any other investigation, including lung biopsy. Areas covered: This review describes the current place of HRCT in the diagnosis, prognosis and monitoring of ILD. It also lists some perspectives for the near future. Expert commentary: Since the 1980s, HRCT and its interpretation have improved, the diagnosis value of patterns, and the integration of bio-clinical elements to HRCT have been better standardized. The interobserver agreement has been investigated, allowing a better use of some limits in the interpretation of various signs. It not only takes into account one particular predominant sign, but the combination of patterns and the distribution of findings. Thanks to HRCT, the range of diagnoses and their probability are more accurately identified. The contribution of HRCT has been optimized during the multidisciplinary discussion that a difficult diagnosis calls for. HRCT quantification of the extent of diffuse lung disease becomes possible and is linked to prognosis. In the future, artificial intelligence may significantly modify the practice of radiology.

Sarcoidosis is a multifactorial disease induced by environmental and genetic factors. Whole exome sequencing in 5 familial cases of the disease suggest that genetic defects in Rac1 and mTor functional hubs may be relevant to sarcoidosis pathogenesis. http://bit.ly/2xooHx3

Introduction La sarcoidose est une maladie systemique d’evolution variable. Les donnees sur le traitement des formes refractaires restent peu nombreuses. Methodes Dans cette etude retrospective, multicentrique, les patients ont ete inclus si ils remplissaient les criteres suivants: sarcoidose selon les criteres de l’ATS/WASOG, et administration d’au moins une perfusion de biotherapie hors anti-TNF-alpha. Les criteres de non selection etaient les suivants: perfusion realisee pour une indication autre que la sarcoidose, donnees non suffisantes. L’evaluation de l’efficacite a ete realisee par les scores ePOST et SDAI. Les donnees de tolerance ont ete recueillies dans les dossiers medicaux. Resultats Un total de 14 patients a ete inclus, 10 femmes et 4 hommes d’âge median au diagnostic de sarcoidose 31 ans (15–53). Parmi eux, 11 patients (79 %) avaient une atteinte mediastinale ou hilaire, 9 (64 %) une atteinte pulmonaire parenchymateuse, 9 (64 %) une atteinte ophtalmologique, 8 (57 %) une atteinte du systeme nerveux central. Avant la biotherapie, tous les patients avaient ete traites par corticoides, 10 (71 %) avaient recu du methotrexate, 9 (64 %) une biotherapie anti-TNF-alpha, 6 (43 %) de l’azathioprine. Chaque patient a recu au moins une ligne de biotherapie, qui etait du tocilizumab (un anti- recepteur de l’IL6) chez 6 patients, du rituximab chez 4, et de l’ustekinumab (un anti-IL12-IL23) chez 4. De facon concomitante a la biotherapie, 12 patients recevaient des corticoides (contre-indication chez 2), 6 recevaient du methotrexate, et un de l’azathioprine. L’ePOST median avant biotherapie etait de 7 et a la derniere visite sous traitement de 3 (difference non significative p 0,05), le SDAI median avant biotherapie etait de 8,5 et a la derniere visite sous traitement de 5,0 (p 0,01). Sous tocilizumab, on observait 3 reponses partielles, 2 patients stables, et une progression. La tolerance etait globalement bonne, sans evenement indesirable grave. Un patient decidait de suspendre les injections de tocilizumab apres une perfusion. Deux patients etaient traites par inhibiteurs de JAK en raison d’un echec de tocilizumab avec une bonne efficacite. Conclusion Les biotherapies non anti-TNF-alpha constituent une option therapeutique au cours de la sarcoidose. Leur place par rapport aux antagonistes du TNF-alpha qui restent l’option de seconde ligne la plus frequente parmi les immunosuppresseurs reste a preciser.

Introduction Peu d’etudes ont analyse la survie et les differences de caracteristiques initailes des patients atteints de la fibrose pulmonaire idiopathique (FPI) selon le genre. L’objectif de l’etude etait d’explorer les differencesselon le genre dans une cohorte francaise de FPI. Methodes 236 patients atteints d’une FPI incidente ont ete inclus dans la cohorte prospective longitudinale multicentrique COhorte FIbrose (COFI), et a suivi pendant 5 ans. Les hommes et les femmes ont ete compares pour les caracteristiques a l’inclusion (test t, Qui-squared ou ANOVA) et une l’analyse de survie sans transplantation a ete realise (Log rank, modele de Cox). Resultats La population etait composee de 51 (22 %) femmes et 185 (78 %) hommes. A l’inclusion, les femmes avaient un age plus avance que les hommes, (âge > a 65 ans 78 % contre 61 %, p = 0,028), une proportion plus faible de fumeurs (p Conclusion Au moment du diagnostic de FPI, les femmes semblent avoir une meilleure CVF et une presentation radiologique distincte, possiblement du fait qu’elles ont ete moins exposees par rapport aux hommes. Toutefois, la survie sans transplantation reste comparable entre les hommes et les femmes. La diminution de l’acces a la transplantation pulmonaire chez les femmes pourrait etre due a l’âge et aux comorbidites.

Introduction Les donnees sur l’infection a Sars-Cov-2 chez les patients atteints de sarcoidose sont rares. L’hypothese d’un risque accru de formes severes de Covid-19 dans cette population a ete soulevee, du fait de l’atteinte pulmonaire sous-jacente, des comorbidites associees a l’utilisation de corticoides, et l’utilisation d’immunosuppresseurs. Nous decrivons ici la presentation clinique et le pronostic de l’infection a Sars-Cov-2 chez des patients atteints de sarcoidose a partir d’un registre multicentrique francais. Methodes Nous avons collecte retrospectivement les donnees de tous les patients atteints de sarcoidose et d’infection a Sars-Cov-2 vus dans 15 centres francais, entre le 1er mars et le 1er septembre 2020. Les criteres d’inclusion etaient un diagnostic de sarcoidose selon les criteres ATS/ERS/WASOG, et une infection a Sars-Cov-2 definie par une RT-PCR sur ecouvillon nasopharynge ou tracheal positif ou une serologie positive. Resultats Un total de 36 patients a ete inclus. La majorite des patients (72%) etaient des hommes, avec un âge median a l’infection a Sars-Cov-2 de 54,5 ans (29–100) et une duree mediane d’evolution de la sarcoidose de 10 ans (0–50) au moment de l’infection. Plus de 95% des patients avaient une atteinte ganglionnaire intrathoracique ou une atteinte parenchymateuse pulmonaire, et 33% avaient une fibrose pulmonaire. La presentation clinique de Covid-19 etait classique, et comprenait de la fievre chez la plupart des patients (67%), malgre l’utilisation de corticoides. Vingt-cinq (69%) patients prenaient un traitement par corticoides au long cours au moment de l’infection, avec une dose quotidienne mediane de 7,7 mg (5–50). Les corticoides ont ete arretes chez 1 patient au moment de l’infection. Le methotrexate a ete plus frequemment arrete au moment de l’infection, chez 4/8 (50%) patients. Parmi les 6 patients sous anti-TNF-alpha, le traitement a ete temporairement suspendu chez tous. Cinq patients sont decedes au cours de l’infection a Sars-Cov-2: 4 d’une insuffisance respiratoire aigue et le dernier d’une hypercapnie non controlee dans un contexte d’obesite. Deux de ces patients presentaient une insuffisance renale chronique, une etait sous hemodialyse et l’autre avait presente une insuffisance renale aigue compliquant la maladie renale chronique. Un total de 13 patients (36%) a ete admis en reanimation. Conclusion Ces donnees nationales montrent que la sarcoidose n’est pas associee a un exces de formes severes d’infection a Sars-Cov-2.

Introduction Une analyse des proteines du SARS-CoV-2 par modelisation bioinformatique a suggere que ce coronavirus pourrait se lier a l’hemoglobine (Hb) [1] . Les auteurs ont emis l’hypothese que ce phenomene pourrait entrainer une alteration de la fixation de l’oxygene (O 2) sur l’Hb, ainsi qu’une anemie hemolytique. Le but de notre travail etait de verifier si l’affinite de l’Hb pour l’O 2 etait modifiee au cours de la COVID-19. Methodes Dans cette etude retrospective, observationnelle, monocentrique, les gaz du sang (GDS) de 100 patients atteints de COVID-19 prouvee par PCR ayant consulte au CHU Avicenne (Bobigny) en mars-avril 2020 (n = 253 prelevements) ont ete compares a ceux de 100 patients non-COVID-19 de mars-avril 2019 (n = 221 prelevements). Cinquante-cinq patients avec une carboxyhemoglobine (HbCO) ≥ 8% ont egalement ete inclus dans un troisieme groupe comme temoins positifs d’une affinite anormale de l’Hb. La P 50 a ete corrigee pour des valeurs standard de temperature corporelle (37 °C.), pH (7,4) et PCO 2 (40 mmHg). Les dossiers des patients anemiques (Hb ≤ 11 g.dl–1) ont ete revus avec un hemobiologiste. Resultats L’âge median et le sex ratio n’etaient pas significativement differents entre les patients COVID-19 et non-COVID-19 Fig. 1 ). La P 50 mediane sur le GDS d’entree etait respectivement de 26 mmHg [25,2–26,8] contre 25,9 mmHg [24–27,3] (p = 0,42). Comme attendu, la P 50 mediane etait significativement inferieure dans le groupe avec HbCO ≥ 8%: 22,5 mmHg (p Conclusion Cette etude n’a pas retrouve d’argument biologique pour conforter l’hypothese que le SARS-CoV-2 pourrait alterer la fixation de l’O 2 sur l’Hb.

Importance Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19). Objective To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia. Design, setting, and particpants This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes. Interventions Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants. Main outcomes and measures Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events. Results Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] -9.0%; 90% credible interval [CrI], -21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21). Conclusions and relevance In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results. Trial registration ClinicalTrials.gov Identifier: NCT04331808.

Sarcoidosis is a granulomatous disease of unknown cause. This proteiform disease is characterized by an almost constant and often predominant lung involvement. The natural history of disease is difficult to predict at presentation. Diagnosis is based on a compatible clinical and radiological presentation and evidence of non-caseating granulomas. Exclusion of alternative diseases is also required according to clinical presentation. Biopsy samples of superficial lesions should be considered before other sites like per-endoscopic bronchial biopsies or endobronchial ultrasound-guided transbronchial needle aspiration. Therapeutic strategy for lung disease has to take into account the possible spontaneous resolution observed in newly diagnosed patients. Corticosteroids are the first choice when a treatment is decided, which concerns half of patients. Second and third line therapy are based respectively on immunosuppressive drugs and anti-TNFα drugs. Sarcoidosis mortality and morbidity are mainly linked to advanced pulmonary sarcoidosis - lung fibrosis, pulmonary hypertension, bronchial stenosis and chronic pulmonary aspergillosis. "Non anti-inflammatory" treatments have to be considered as well. Clinicians have an essential role in treatment indication, end-point targets and evaluation of response to treatment during follow-up and in finding the best benefice to risk balance. Progress made on pharmacogenetics may offer more personalized treatments for the patients.

Sarcoidosis is a systemic disease of unknown cause with very diverse presentation, outcome, severity and need for treatments. While some presentations may be very typical, for many patients, the presentation is nonspecific, with shared associations with other diseases at times being by far more frequent or misleading, which can be a cause of significant delay and often several consultations before a diagnosis of sarcoidosis can be confirmed. This is particularly the case when pulmonary manifestations are in the forefront. The diagnosis relies on three well-known criteria. In clinical practice, these criteria are not easily implemented, particularly by physicians without expertise in sarcoidosis, which can lead to a risk of either under- or over-diagnosis. Qualifying the presentation according to sarcoidosis diagnosis is essential. However, it is often not easy to classify the presentation as typical versus compatible or compatible versus inconsistent. Further investigations are needed before any other hypothesis is to be considered. It is important to detect events and to determine whether or not they are indicative of a flare of sarcoidosis. Eventually, treatment needs to be related to the correct indications. The evaluation of the efficacy and safety of treatments is crucial. To address such issues, we present five emblematic cases that illustrate this.

Background: Idiopathic interstitial pneumonia (IIP) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality. They have been associated with an increased frequency of lung cancer. A genetic cause is identified in up to 20% of familial cases, telomerase and surfactant genes (SFTPA2, SFTPB, SFTPC, ABCA3) mutations being the first etiologies. Objectives:This study investigates the implication of SFTPA1 (NM_005411) in 12 families affected by IPF and lung cancer. Methods:SFTPA1 was sequenced by Sanger method in 12 unrelated index cases. An informed signed consent was obtained for each patient. New SFTPA1 variations were studied with functional experimentations. Results: A heterozygous missense disease-causing mutation (p.Trp211Arg, W211R), in SFTPA1, that encodes the Surfactant Protein (SP)-A1, was identified in a large family. The affected members, aged 7 months to 59 years, presented with various forms of IIP, and adenocarcinoma. The W211R mutation segregated in a dominant pathway with the disease. The mutation involved an amino-acid that is located in the carbohydrate recognition domain (CRD) of SP-A1 and involved a residue invariant throughout evolution in SP-A1, but also in SP-A2 and in other CRD-containing proteins. The W211R mutation impaired SP-A1 secretion, and an abnormal expression pattern of SP-A was found in the alveolar epithelium of lung tissue from a patient carrying the SFTPA1 mutation. Conclusion: This first report of the involvement of SFTPA1 in a Mendelian disorder unveils the key role of SP-A1 in the pathophysiology of IIP from infancy to elderly, and open up a new field of research on the mechanisms involved in IIP and lung cancer.

Background: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed. Objectives: We aimed to evaluate the association of antecedent MTX use with development of RA-ILD. Methods: Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. Results: Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; P Conclusion: Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD. Disclosure of Interests: Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodriguez Henriquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramces Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoit Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Liote: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphael Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieude: None declared

Introduction Les faibles revenus sont des indicateurs pronostiques connus dans diverses maladies respiratoires chroniques mais peu etudies dans la fibrose pulmonaire idiopathique (FPI). La FPI est la plus frequente et grave des pneumopathies interstitielles diffuses. Son histoire naturelle reste mal comprise. Nous faisons l’hypothese que les faibles revenus ont un impact pronostique dans la FPI. Methodes Les patients sont issus de la cohorte prospective multicentrique francaise COFI. Le revenu individuel n’etant pas disponible, il a ete estime a partir des donnees de l’Institut national de la statistique et des etudes economiques (INSEE) qui archive le revenu annuel median des habitants de toutes les villes ou arrondissements en France. Ce revenu annuel median a ete attribue a chaque patient en fonction de son domicile. Les patients ont ete separes en deux groupes, « faible revenu » et « revenu superieur », selon que le revenu annuel etait a 18 170 €/an (premier quartile de l’ensemble de la population incluse). La probabilite de survie sans progression (SSP) des groupes a ete comparee par un test du log-rank et un modele de Cox en analyse multivariee. Resultats Deux cent patients ont ete inclus et suivis pendant une moyenne de 33,8 ± 22,7 mois. A la fin de l’etude, 6 (3 %) ont ete perdus de vue, 17 (9 %) ont ete transplantes, et 120 (60 %) sont decedes. Les patients du groupe « faible revenu » etaient plus susceptibles d’etre d’origine non europeenne (p Conclusion Le revenu semble etre un facteur pronostique de la FPI, independant de l’âge, du sexe et de la severite de la maladie. Cet effet negatif pourrait etre lie a une exposition excessive aux polluants professionnels et/ou environnementaux chez les patients les plus defavorises. Des etudes futures utilisant une approche globale des facteurs socio-economiques, environnementaux et professionnels sont necessaires. Grants : (Legs Poix, no 637), PHRC (AOR 07076).

Resume Objectifs Le traitement d’une osteoporose au cours de la sarcoidose, qu’elle soit ou non cortico-induite n’est pas consensuel. Methodes Nous rapportons ici la premiere serie de 4 patients atteints d’une sarcoidose histologiquement documentee et traites par teriparatide pour une osteoporose severe avec cascade fracturaire vertebrale. A l’instauration du teriparatide, 1 patient recevait 10 mg d’equivalent prednisone par jour, un autre etait sous corticotherapie a doses decroissantes et 2 patients n’avaient jamais recu de corticotherapie. Resultats Chez ces 4 patients, le teriparatide a permis de stopper la cascade fracturaire y compris chez les 2 patients qui beneficiaient d’une corticotherapie au long cours. Aucun des patients n’a developpe d’hypercalcemie. Durant le traitement par teriparatide, 3 patients ont rapporte une poussee ou une complication de sarcoidose. Seul le patient qui recevait une dose stable de corticoides n’a presente aucun evenement indesirable. Avant l’instauration du teriparatide, la sarcoidose etait bien controlee chez ces 3 patients depuis plusieurs annees. Conclusions Meme si l’implication du teriparatide n’est pas clairement demontree, la survenue d’effets indesirables chez 3 des 4 patients de cette petite serie incite a une utilisation prudente chez les patients atteints de sarcoidose.

Background: Idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis with emphysema (CPFE) are associated with an increased risk of pulmonary hypertension (PH). Few data are available regarding PH severity and correlation with respiratory physiology. Aim: To evaluate baseline respiratory and hemodynamic characteristics of patients with IPF-PH and CPFE-PH. Methods: Patients with a diagnosis of IPF or CPFE were analysed from a prospective multicenter observational study (HYPID) conducted in French expert centers for rare pulmonary diseases and/or PH (NCT01443598). Severe PH was defined as mean pulmonary artery pressure (mPAP) > 35 mmHg or cardiac index (CI) Results: Out of 220 patients included in the cohort, 61 had IPF-PH and 75 CPFE-PH. Patients were 74% males, with a mean age of 69 ± 9 years. The mean FVC at baseline was 75 ± 25%, and mean DLco was 25 ± 10%. NYHA class was I-II in 18% of patients, III in 56%, IV in 24%, N/A in 2%. Six-min walk distance was 276 ± 145 m. Hemodynamic characteristics were mPAP 38 ± 9 mmHg, CI 2.5 ± 0.6 L/min/m², and pulmonary vascular resistance (PVR) 8.7 ± 3 WU. Kco was lower in CPFE-PH than in IPF-PH (table); other parameters were comparable between groups. DLco at baseline significantly correlated with mPAP (p=0.01 in IPF and 0.04 in CPFE group). DLco also correlated with PVR and CI in IPF-PH (p=0.001 and 0.01 respectively), but not in CPFE-PH. Conclusion: Hemodynamic severity is comparable in patients with IPF-PH and CPFE-PH, and correlates with DLco. Further study is needed to evaluate the prognostic significance of hemodynamic severity.

Introduction: Although the clinical expression of sarcoidosis in each organ has been well described, there are few data on the associations among the various disorders. Methods: 1237 patients (45% men, mean age=43.5±13 yrs) were recruited through the French Medical Information Systems Program (PMSI) databases from January 2013 to December 2016. Medical records were reviewed by a panel of experts to validate inclusion criteria (sarcoidosis with histological documentation and at least one extra-pulmonary disease, or Lofgren9s syndrome) and determine patient characteristics. Results: Cluster analysis identified 5 phenotypes. Cluster 1 (n=180) associating erythema nodosum and joint involvement, characterized by female sex (F:M ratio=2.4), being more European (51%) and less manual workers (30%). This phenotype was the less treated (corticotherapy (53% of cases), anti-TNF alfa (4%)). Cluster 2 (n=137) associating nervous system involvement and uveitis, characterized by being mainly European (62.5%), men (F:M=1.3) and manual workers (44%). Cluster 3 (n=630) identified a preferential association of pulmonary lesions, sometimes fibrosing, with cardiac lesions associated mainly with a 1.1 F:M ratio, being manual workers (46%) and non-European (58%). Cluster 4 (n=41) marked by the presence of lupus pernio occurring more in non-Europeans (80%). This was the most commonly treated phenotype (corticotherapy (88%), anti-TNF alfa (41%)). Cluster 5 (n=249) associating hepato-splenic involvement with extra-mediastinal lymphadenopathy, characterized by being mainly non-European (62.5%), women (F:M=1.1) and manual workers (35%). Conclusion: We identified 5 clinical phenotypes of sarcoidosis with distinct demographic features and outcomes.

Background: The course of IPF is very difficult to predict, survival is variable among patients. We aimed to develop a simple prognostic tool in a two-way classification model, usable at the time of diagnosis. Methods: This post-hoc study was conducted on a French, monocentric, prospective cohort of incident IPFs followed in Avicenne University Hospital. Patients underwent pulmonary function test (PFT) and high-resolution computed tomography at baseline. The composite physiologic index (CPI) and the ratio between pulmonary artery diameter / body surface (PAD/BS) were calculated. Patients were classified as low risk (LR) when CPI ≤ 40 and PAD/BS ≤ 15 mm/m2; intermediate risk (IR) when either CPI was > 40 or PAD/BS > 15; high risk (HR) when CPI > 40 and PAD/BS > 15. Performance of our model was compared to other prognostic scores. Results: On 66 screened patients, 63 managed to complete PFT (required to calculate CPI) and were included (age: 65.9±11.6 yo, BMI: 27±4.5 kg/m2, M/F: 52/11, FVC: 77.7±17.4%, DLCO: 42.8±15.8%, CPI: 49.6±12.7, PAD/BS: 16±2.9 mm/m2). Transplant-free survivals at 5 years were: 82% [62-100] in the 11 LR patients, 43% [26-70] in the 21 IR patients, and 6% [2-25] in the 31 HR patients (p=0.0001). The area under the ROC curve at 5 years was 0.83 [0.72-0.93], better than for CPI alone, GAP score or CT-GAP score: 0.77 [0.64-0.90], 0.71 [0.58-0.83] and 0.62 [0.55-0.77] respectively. The agreement between observed outcomes and predictions was excellent (internal validation by calibration curve). Conclusion: Our physio-radiological rating, using CPI and PAD/BS ratio at baseline, seems very effective to predict the outcome in IPF patients. External validation on another, larger cohort is presently ongoing.

Background: Heterozygous mutations in the SFTPA1 and SFTPA2 genes, encoding the surfactant protein SP-A1 and SP-A2 have been associated with rare forms of familial IIP and lung adenocarcinoma. We previously described 11 new heterozygous SFTPA1 and SFTPA2 variations in 13 unrelated patients including one newborn. The study aims to analyze the pathogenicity of those variations. Methods: We first analyzed the intrafamilial segregation of the identified variations with IIP and lung cancer. The production and the secretion of the mutant proteins were subsequently studied in HEK293T cells transiently expressing the SP-A proteins carrying the variations. Finally, SP-A expression was assessed on lung tissues of the patients. Results: In the studied families (38 adults, 3 children), the variations segregated with either IIP and/or lung cancer (37%) with an incomplete penetrance of the disease phenotype. The mean age at onset of the IIP was 45 years (0-68). Nine of the variations were located in the highly conserved carbohydrate recognition domain of the protein. In vitro, the mutant proteins were produced but their secretion was absent (n=9) or altered (n=2). The lung expression of SP-A studied in 3 unrelated patients showed an increased expression of SP-A in the cytoplasm of hypertrophic type 2 alveolar cells. Discussion and conclusion: The 11 identified SFTPA1 and SFTPA2 variations are pathogenic. They are associated with IIP and with an increased risk of lung cancer. They were identified mainly in adults but also in children. The pathophysiological consequences of their abnormal secretion/expression remain to be elucidated.

Introduction: The reasons for developing intra-thoracic lymph nodes (LN) in ILDs are varied: simple non-specific inflammatory process, dustiness, infection, neoplasia. Thus, invasive or “minimally invasive” diagnostic exploration, with possible complication, is sometimes necessary. The objective was to study the prevalence of the different cytological diagnoses obtained by EBUS from LN associated with ILD, to describe their computed tomography (CT) and PET-CT features and to determine the predictive factors of the diagnosis. Methods: A retrospective, observational, multicenter study (pneumology departments of Avicenne and Amiens University Hospitals, and St-Quentin Hospital), including 32 patients who underwent EBUS between 2008 and 2017 for LN associated with ILD excluding sarcoidosis (age: 63 ± 14.7 years, men: n = 21, smokers or former smokers: n = 19). Results: LN cytology was normal in 20 cases (62.5%), and showed anthracosis in 8 cases (25%), cancer in 3 cases (9.4%) and non-necrotizing granulomatosis in one case. There was no correlation between cytological diagnoses and CT features. Patients with cancer had a lower number of LN tracer uptake (1.00 ± 0, p = 0.002), and a higher mean SUV (14.36 ± 10, p = 0.041) at PET-CT. In multivariate analysis, no factor was significantly associated with the malignant or benign nature of LN. Conclusion: LN in ILDs appear to be mainly related to the inflammatory process of ILD or to anthracosis. Few items are predictive of malignant LN. In this context, the diagnostic impact of EBUS is important for management of these patients.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms involve a concomitant accumulation of scar tissue together with myofibroblasts activation and a strong abnormal vascular remodeling. Endothelial progenitor cells (ECFC subtype) have been investigated in several human lung diseases as a potential actor in IPF. We previously demonstrated that ECFCs are down-regulated in IPF in contrast to healthy controls. We postulated here that ECFCs might behave as a liquid biopsy in IPF patients and that they exert modified vasculogenic properties. ECFCs isolated from controls and IPF patients expressed markers of the endothelial lineage and did not differ concerning adhesion, migration, and differentiation in vitro and in vivo. However, senescent and apoptotic states were increased in ECFCs from IPF patients as shown by galactosidase staining, p16 expression, and annexin-V staining. Furthermore, conditioned medium of IPF-ECFCs had increased level of interleukin-8 that induced migration of neutrophils in vitro and in vivo. In addition, an infiltration by neutrophils was shown in IPF lung biopsies and we found in a prospective clinical study that a high level of neutrophils in peripheral blood of IPF patients was associated to a poor prognosis. To conclude, our study shows that IPF patients have a senescent ECFC phenotype associated with an increased IL-8 secretion potential that might contribute to lung neutrophils invasion during IPF.

The Fleischner Society White Paper and the ATS/ERS/JRS/ALAT guidelines recently redefined the computed tomography (CT) scanning patterns of usual interstitial pneumonia (UIP) [1,2]. Both publications confirmed honeycombing as the cornerstone of UIP pattern diagnosis, and introduced peripheral traction bronchiolectasis (PTB) as a key feature of the new “probable UIP” category. Therefore, improving the distinction between these two features may be critical, especially when the clinical likelihood of IPF is uncertain: a lung biopsy should be discussed for patients with PTB without honeycombing, but is not recommended for patients presenting with clear honeycombing and typical UIP pattern [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. de Margerie-Mellon reports grants from Institut Servier, grants from Olea Medical, outside the submitted work. Conflict of interest: Dr. Belin has nothing to disclose. Conflict of interest: Dr. Boussouar has nothing to disclose. Conflict of interest: Dr. Khafagy has nothing to disclose. Conflict of interest: Dr. Debray reports personal fees and non-financial support from Boehringer-Ingelheim, personal fees and non-financial support from Roche, outside the submitted work. Conflict of interest: Dr. Levand has nothing to disclose. Conflict of interest: Dr. Chabi has nothing to disclose. Conflict of interest: Dr. KHALIL has nothing to disclose. Conflict of interest: Dr. Benattia has nothing to disclose. Conflict of interest: Dr. Israel-Biet has nothing to disclose. Conflict of interest: Dr. crestani reports personal fees and non-financial support from astra zeneca, grants, personal fees and non-financial support from boehringer ingelheim, grants from MedImmune, grants, personal fees and non-financial support from Roche, personal fees from Sanofi, outside the submitted work. Conflict of interest: Dr. Nunes reports grants and personal fees from Roche/Genentech, grants and personal fees from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. Cadranel has nothing to disclose. Conflict of interest: Dr. GRENIER has nothing to disclose. Conflict of interest: Dr. Valeyre reports personal fees from Boehringer ingelheim, personal fees from Roche, personal fees from Boehringer ingelheim Roche, outside the submitted work. Conflict of interest: Dr. Naccache has nothing to disclose. Conflict of interest: PYB has received personal fees for teaching actions from Boehringer Ingelheim and Roche.

Background Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) share phenotypic similarities. The gain-of-function MUC5B promoter variant rs35705950 is the strongest risk factor for development of IPF Objectives We hypothesised that rs35705950 would also contribute to the risk of ILD in RA patients. Methods Using a French discovery population and multi-ethnic validation populations from 6 different countries, we tested the association of the MUC5B promoter variant in RA-ILD (n=620), RA without ILD (n=614), and unaffected controls (n=5448). Results The discovery population revealed an association of the MUC5B promoter variant with RA-ILD when compared to unaffected controls (ORadj=3.8 95% CI: 2.8 to 5.2; p=9.7x10–17) (figure 1A). Similar to the discovery cohort, the MUC5B promoter variant was significantly over-represented among the cases of RA-ILD in the multi-ethnic study cohorts when compared to unaffected controls (ORadj=5.5 95% CI: 4.2 to 7.2; p=4.7x10–35) (figure 1A), and when the discovery population and the multi-ethnic cohorts were combined (ORcombined=4.7 95% CI: 3.9 to 5.8; p=1.3x10–49) (figure 1A). Additionally, the MUC5B promoter variant was found to increase the risk of ILD among patients with RA (ORcombined=3.1 95% CI: 1.8 to 5.4; p=7.4x10–5), however, no statistical association with the MUC5B promoter variant was observed for RA without ILD (figure 1B). The association of the MUC5B promoter variant with RA-ILD increased significantly when restricted to the usual interstitial pneumonia (UIP) by high-resolution computed tomography (ORcombined=6.1 95% CI: 2.9 to 13.1; p=2.5x10–6) (figure 1C). Immunohistochemical and in-situ hybridization analysis of RA-ILD lung tissue demonstrated expression of MUC5B by type 2 alveolar epithelial cells undergoing endoplasmic reticulum stress. Conclusions Our findings demonstrate that MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of UIP. Disclosure of Interest None declared

AIM To compare combined 2-[18F]-fluoro-2-deoxy- d- glucose (FDG)-positron-emission tomography (PET) and cardiac magnetic resonance imaging (CMR) for the diagnosis and therapy monitoring of cardiac sarcoidosis (CS). MATERIALS AND METHODS Eighty patients with sarcoidosis and a suspicion of CS who underwent PET and CMR were included retrospectively. PET was undertaken after a low-carbohydrate–high-fat diet in all patients using a combined 16-section PET/computed tomography (CT) camera. PET was considered positive (PET+) in cases of focal or multifocal FDG uptake. CMR was considered positive (CMR+) in cases of subepicardial late gadolinium enhancement (LGE). A subgroup of 50 patients (50/80) was monitored during therapy and classified as responders or non-responders. RESULTS Eighty-two percent of patients with PET+ (9/11) also had CMR+ imaging, with good spatial agreement (kappa=0,79; 95% confidence interval [CI]: 0.65–0.94). Twenty-seven percent (22/80) had residual physiological FDG uptake, with a standardised uptake value (SUV) not significantly different compared to the SUV from pathological uptake (6.4 versus 6 respectively, p=0,92). The clinical response was more frequent in patients with baseline PET+ compared to baseline PET– (80% versus 45%, p=0.07). PET findings improved in all cases under treatment (7/7), whereas LGE improved in only 33% of patients (3/9). CONCLUSION Due to high risk of false-positive or undetermined findings, PET might be performed as a second-line study in cases of LGE, to assess inflammatory load. In addition, PET seems suitable to predict and assess response under therapy.

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

Regulator of telomere length 1 (

In this retrospective study, a beneficial effect of pirfenidone on lung function decline could not be demonstrated in patients carrying TERT/TERC mutation

Background. Severe obstructive sleep apnea (OSA) with chronic intermittent hypoxia (IH) is common in idiopathic pulmonary fibrosis (IPF). Here, we evaluated the impact of IH on bleomycin- (BLM-) induced pulmonary fibrosis in mice. Methods. C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO2 nadir: 6%; 8 hours/day) or intermittent air (IA). In the four experimental groups, we evaluated (i) survival; (ii) alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii) lung cell apoptosis; and (iv) pulmonary fibrosis. Results. Survival at day 21 was lower in the BLM-IH group (p<0.05). Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content (p=0.02) and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, (p<0.001). Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice (p<0.05 versus BLM-IA group). At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group. Conclusion. These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.

International audience; BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7x10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7x10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3x10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4x10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5x10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Societe Francaise de Rhumatologie and others.).

We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day −1 ) and nintedanib (200–300 mg·day −1 ) in patients with idiopathic pulmonary fibrosis (IPF). This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day −1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day −1 ) and nintedanib (200–300 mg·day −1 ). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. 89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.

Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking.We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD.MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity-related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts.Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12-2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17-1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15-2.53; P = 0.008, respectively) when compared with subjects with MLN10 mm. Patients with MLN enlargement had lower lung function and decreased plasma concentrations of soluble CD40L (376 pg/ml vs. 505 pg/ml, P = 0.001) compared with those without MLN enlargement. Plasma IL-10 concentration45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21-14.68; P = 0.024). Independent analysis of external datasets confirmed these findings.MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.

Introduction La fibrose pulmonaire idiopathique (FPI) est une pathologie severe caracterisee par la destruction de l’architecture alveolaire pulmonaire qui entraine une degradation des capacites pulmonaires et conduit au deces du patient. Ses mecanismes physiopathologiques associent une activation des myofibroblastes, une accumulation importante de matrice extracellulaire et un remodelage pulmonaire vasculaire aberrant. Les progeniteurs endotheliaux circulants et plus particulierement le sous-type des « endothelial colony-forming cells » (ECFCs) ont deja ete impliques dans plusieurs pathologies respiratoires humaines dont la FPI. Nous avons precedemment montre que les ECFCs sont diminuees au niveau circulant dans la FPI [1] . Nous avons suppose que ces cellules pourraient etre considerees comme une biopsie liquide dans la FPI permettant d’explorer le compartiment vasculaire pulmonaire et posseder des proprietes vasculogenes modifiees. Methodes Les ECFCs ont ete isolees a partir de prelevements sanguins de patients FPI (FPI-ECFCs) ou de controles sains (PB-ECFCs). Leurs proprietes phenotypiques, fonctionnelles in vitro et in vivo (migration, adhesion, differenciation) et leur secretome ont ete compares. Nous avons egalement explore la senescence par marquage de la s-galactosidase, l’expression de p16, p21, p53, le cycle cellulaire par incorporation de BrDU et l’apoptose par marquage a l’annexine-V. Resultats Les FPI-ECFCs et les PB-ECFCs expriment les marqueurs de la lignee endotheliale et ne different pas en ce qui concerne leurs proprietes fonctionnelles. En revanche, la senescence et l’apoptose sont augmentes chez les FPI-ECFCs. De plus, la concentration en interleukine-8 (IL-8) est augmentee dans leur milieu conditionne et induit la migration de polynucleaires neutrophiles (PNNs) in vitro et in vivo. Nous avons egalement retrouve une infiltration moderee par les PNNs dans des biopsies pulmonaires de patients FPI et montre dans une etude clinique prospective qu’un taux eleve de PNNs circulants est associe a un pronostic defavorable de la FPI. Conclusion Notre etude montre que les FPI-ECFCs presentent un phenotype senescent associe a une augmentation de secretion d’IL-8 qui pourrait contribuer au recrutement des PNNs au niveau pulmonaire dans la FPI.

Introduction L’evolution de la FPI est difficile a predire et la survie est variable selon les patients. Nous avons developpe un outil pronostique simple utilisant un modele a double entree, utilisable au moment du diagnostic. Methodes Cette etude post-hoc, ancillaire de la cohorte nationale prospective COFI de FPI incidentes, a ete menee sur les patients suivis au CHU Avicenne. Ils ont realise a l’inclusion des explorations fonctionnelles respiratoires (EFR) et une tomodensitometrie thoracique. Le composite physiologic index (CPI) et le rapport entre le diametre du tronc de l’artere pulmonaire et la surface corporelle (AP/SC) ont ete calcules. Les patients ont ete classes risque faible (groupe F) si CPI ≤ 40 et AP/SC ≤ 15 mm/m2; risque intermediaire (groupe I) si CPI > 40 ou si AP/SC > 15 mm/m2; risque eleve (groupe E) si CPI > 40 et AP/SC > 15 mm/m2. Une validation interne a ete effectuee par courbe de calibration. Enfin, la performance de notre modele a ete comparee a d’autres scores pronostiques. Resultats Sur 66 patients eligibles, 63 ont pu realiser des EFR completes (necessaires pour calculer le CPI) et ont ete inclus : âge moyen = 65,9 ± 11,6 ans ; index de masse corporelle = 27 ± 4,5 kg/m2; sex-ratio = 52 hommes / 11 femmes ; capacite vitale forcee = 77,7 ± 17,4 % ; diffusion du monoxyde de carbone = 42,8 ± 15,8 % ; CPI = 49,6 ± 12,7 ; AP/SC = 16,0 ± 2,9 mm/m2 ( Fig. 1 ). En analyse univariee (modele de Cox), CPI > 40 et AP/SC > 15 mm/m2 etaient predictifs de deces ou transplantation pulmonaire (hazard ratios respectifs de 4,14 [1,45–11,82] et 3,02 [1,53–5,95], p Conclusion Notre classification physio-radiologique, utilisant le CPI et le rapport AP/SC a l’inclusion, semble tres performante pour predire le pronostic des patients avec FPI. Une validation externe, a partir de la cohorte des patients inclus dans COFI et suivis dans les autres centres, est actuellement en cours.

Introduction Les patients atteints d’une pneumopathie interstitielle diffuse associee a une mutation d’un gene regulateur du complexe telomerase (TRG) semblent presenter une moins bonne survie et des complications hematologiques plus frequentes apres transplantation pulmonaire (TxP). L’objectif de cette etude etait de determiner l’evolution apres TxP de ces patients dans une cohorte francaise. Methodes Tous les patients porteurs d’une mutation d’un TRG ayant eu une TxP en France entre 2009 et 2017 ont ete identifies par les centres de transplantation et le reseau francais OrphaLung. Resultats Vingt-sept patients ont ete inclus, dont 67 % etaient des hommes, avec des mutations de TERT (n = 17), TERC (n = 6), et RTEL1 (n = 4). Avant la greffe, 19 (70 %) presentaient une atteinte hematologique, dont 6 un syndrome myelodysplasique et 14 une hepatopathie. L’âge median lors de la TxP etait de 54 (± 9) ans. Apres la TxP, tous les patients presentaient une anemie, 74 % une thrombopenie, et 54 % une neutropenie. Quatre patients ont presente des complications hepatiques severes : une hemochromatose post transfusionnelle, une fibrose hepatique et deux patients une hypertension portale. 26 % ont presente une dysfonction chronique du greffon dans un delai median de 2,1 (± 1,3) ans. Quinze receveurs sont decedes (56 %) au cours du suivi. La mediane de survie apres la TP etait de 4,4 ans. La presence d’une myelodysplasie avant la TxP etait associee a une diminution de la survie (p Conclusion La survie apres TxP des patients porteurs d’une mutation d’un TRG est comparable a celle des patients sans mutation. Une TxP est possible apres un bilan exhaustif des comorbidites extra-respiratoires et une prise en charge post-greffe adaptee. La presence d’un syndrome myelodysplasique avant la greffe doit faire rediscuter le projet de greffe.

Introduction La prevalence d’un SAOS associe est importante en cas de FPI incidente. Nous avons formule l’hypothese que la presence d’un SAOS et son traitement par PPC pourraient modifier l’evolution de la FPI. Methodes Cette etude prospective, multicentrique, etait un travail ancillaire de la cohorte nationale COFI de FPI incidentes. Les patients de 5 hopitaux universitaires ont ete enregistres a l’inclusion par polysomnographie nocturne et ont realise des explorations fonctionnelles respiratoires (EFR) a l’inclusion, a 6 mois (M6) et 12 mois (M12). La survie sans transplantation pulmonaire a 30 mois (M30) a ete evaluee, en fonction de l’index apnees-hypopnees (IAH) et d’un eventuel traitement par PPC. Resultats Quarante-cinq patients consecutifs ont ete inclus : âge moyen = 68,8 ± 8,7 ans ; indice de masse corporelle = 28 ± 3,5 kg/m2 ; sex-ratio = 38 hommes / 7 femmes ; capacite vitale forcee (CVF) = 72,8 ± 20,2 % ; diffusion du monoxyde de carbone (DLCO) = 45,1 ± 18,9 %. Dix-sept de ces patients (38 %) presentaient un IAH Conclusion Dans une population francaise de patients avec FPI incidente, la presence d’un SAOS modere a severe semble aggraver le pronostic. Un traitement par PPC pourrait ralentir la progression de la maladie.

Introduction La sarcoidose est une maladie granulomateuse qui affecte principalement les poumons et dont le determinisme multifactoriel associe des facteurs environnementaux et genetiques. Nous avons publie en 2018 une analyse complete d’exome de cas pediatriques suggerant des anomalies dans l’autophagie, le cycle cellulaire et les processus de reponse immunitaire innee. Notre etude actuelle se focalise sur les formes familiales a presentation autosomique dominante et penetrance forte, afin de mettre en evidence des mutations deleteres agissant comme des triggers puissants de la predisposition. Methodes Nous avons sequence un total de 22 sujets, dont 14 malades et 8 controles internes sains, appartenant a 5 familles predisposees a la sarcoidose. Le protocole de sequencage est base sur la methodologie d’enrichissement en solution Agilent (SureSelect, Agilent) (Human Clinical Research Exome, Agilent), suivie d’un sequencage massif parallele sur Illumina HiSEQ 4000. La selection des variants geniques est basee sur la faible frequence allelique (MAF Resultats La selection des genes a permis d’identifier une serie de 192 genes dont 52 (27 %) semblent etre concentres autour de centres fonctionnels de Rac1 Rho GTPase et le hub du complexe mTor ( Fig. 1 ). Ces resultats ont ete confirmes par des methodes d’enrichissement de reseaux fonctionnels tel ConsensusPathDB. Un nombre significatif de mutations deleteres a egalement ete observe dans des genes codant pour des facteurs intrinseques de l’autophagie et du transport vesiculaire. Une analyse retrospective de 196 patients versus temoins suggere une concentration de mutations dans les genes regulateurs de Rac1 dans 4 % des cas, chez des patients presentant des formes severes, chroniques, multisystemiques et/ou evolutives de la maladie. Conclusion Notre travail suggere que la predisposition genetique a la sarcoidose pourrait etre liee a un effet combine de mutations deleteres de genes impliques dans la regulation de l’autophagie et des hubs fonctionnels Rac1 et mTor, ouvrant la voie a un depistage precoce des formes les plus evolutives.

Introduction L’etude observationnelle prospective europeenne PASSPORT a evalue dans la fibrose pulmonaire idiopathique (FPI), la tolerance a long terme de la pirfenidone en vie reelle, jusqu’a 2 ans apres son initiation. FAS, une etude ancillaire de PASSPORT, a evalue l’efficacite et la tolerance de la pirfenidone dans le sous-groupe des patients (pts) en France. Methodes Les pts de PASSPORT, traites par la pirfenidone depuis Resultats Au total, 192 pts ont ete inclus : âge moyen 70,6 ans ; 76,0 % âge ≥ 65 ans, 84,4 % d’hommes, 68,6 % anciens fumeurs, et 3,1 % fumeurs actuels. Duree mediane depuis le diagnostic de FPI ; 0,6 ans (maximum de 12,2 ans). CVF moyenne initiale 71,7 % ± 16,3 % de la valeur theorique. Variation absolue moyenne par rapport a la valeur de reference du pourcentage de CVF −2,4 % et de −3,8 % aux mois 12 et 24. Plus de la moitie des pts (52,1 %) avait un TM6 initial. Distance moyenne parcourue 412,9 m (105–702). Variation moyenne du TM6 8,6 m et 3,1 m aux mois 12 et 24, (intervalle 23,4 a −51,7 m). Au moins une exacerbation aigue de FPI rapportee chez 20,0 % des pts et une hypertension pulmonaire chez 8,4 % des pts. Au total, 40,6 % des pts n’ont pas presente de progression de la maladie ; 34,9 % ont progresse et 5,7 % sont decedes sans progression. Mediane de survie sans progression (SSP) 18,4 mois [IC95 % 12,9 −non evaluable]. Exposition mediane 16,3 mois (0,5–28,5). EI rapportes le plus frequemment et conduisant a l’arret de la pirfenidone : perte de poids (4,2 %), rash (4,2 %) et reactions de photosensibilite (3,1 %). Pas d’EI d’evolution fatale. Conclusion Les donnees d’efficacite de l’etude FAS sont globalement coherentes avec les resultats d’efficacite des essais cliniques de phase III dans la FPI. Pres d’un tiers des pts atteints de FPI traites par la pirfenidone dans des conditions de vie reelle etait toujours sous traitement deux ans apres son initiation. Les donnees de tolerance sont en accord avec le profil connu de la pirfenidone.

Introduction L’enquete RESPIR (Regards croisEs : fibroSe Pulmonaire Idiopathique et tRaitements), realisee a l’initiative de Roche, a pour objectif de decrire, au travers d’une perception croisee pneumologues, patients et aidants, un etat des lieux des ressentis et attentes de chacun concernant la prise en charge therapeutique de la FPI en France. Methodes Un auto-questionnaire, elabore par un comite scientifique, a ete adresse par courrier aux 3279 pneumologues exercant en France. Deux auto-questionnaires « en miroir » ont ete transmis aux patients FPI et a leur aidant principal par l’intermediaire de leur pneumologue. Resultats Du 01/12/17 jusqu’au gel intermediaire de la base le 16/06/18, 146 pneumologues et 103 patients, dont 78 % sous traitement anti-fibrosant (TAF), ont repondu a l’enquete (Tableau 1). La proportion de patients determines a se battre contre la maladie ou souhaitant etre impliques dans les decisions therapeutiques est elevee (83 % et 76 %). La perception des pneumologues est differente puisqu’ils estiment cette proportion de patients a 70 % et 50 %. Seuls 13 % des patients privilegient la qualite a la duree de vie au moment de l’initiation d’un TAF alors que les pneumologues estiment que cela en concerne 34 % de leurs patients. Ceci pourrait expliquer que 31 % des specialistes n’initient pas de TAF chez les patients asymptomatiques. Pourtant, 80 % des patients declarent qu’ils preferent vivre un peu plus longtemps meme si cela implique de prendre des medicaments pouvant entrainer des effets indesirables. Pour 75 % d’entre eux, la mise place d’un TAF a ete vecue comme positive, porteuse d’espoir et de soulagement. Ainsi, 72 % des patients (seulement 50 % selon les pneumologues) sous TAF auraient aime qu’il leur soit prescrit plus tot dans leur prise en charge. Globalement, les patients ont un regard plus positif sur le TAF que ce que croient les pneumologues : 75 % estiment qu’ils ont eu moins d’evenements indesirables que ce qu’ils pensaient au moment de l’initiation (vs 70 % selon les pneumologues), 39 % estiment avoir davantage de benefices que prevu (vs 30 % selon les pneumologues) et 73 % ont une image positive du rapport benefices/inconvenients (vs 62 % selon les pneumologues). Conclusion Meme si la perception des pneumologues et des patients est globalement proche, les patients interroges semblent prets a un traitement plus precoce et concerte que ce que les medecins percoivent. L’implication des patients dans la decision medicale partagee pourrait etre renforcee.

Background Safety data on combined pirfenidone and nintedanib use are limited. Methods A single-arm, open-label study (NCT02598193) assessed safety and tolerability of 24 weeks’ pirfenidone (1602–2403 mg/day) and nintedanib (200–300 mg/day) in patients with idiopathic pulmonary fibrosis (IPF) with forced vital capacity (FVC) ≥50% and diffusing capacity of the lung for carbon monoxide (DLco) ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg/day pirfenidone for ≥28 days. Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. Change from baseline FVC, DLco and King’s Brief Interstitial Lung Disease (K-BILD) score were assessed at 24 weeks. The study is monitored by a data monitoring committee. Results Eighty-nine patients were enrolled. A pre-specified interim analysis was conducted once 63 patients (mean age 68.7 years, 85.7% male) completed (n=50) or discontinued (n=13) 24 weeks’ combination treatment. Fifty patients had 330 treatment-related TEAEs (Table); 11 patients discontinued due to TEAEs. Two patients had serious treatment-related TEAEs (Table) but none led to death. Final Results for all 89 patients, including change from baseline FVC, DLco and K-BILD score, will be presented at BTS. Conclusions Combined pirfenidone and nintedanib use for 24 weeks did not reveal a different safety profile to that expected for either treatment alone. Patients had tolerated a stable dose of pirfenidone before initiation of nintedanib, which may explain why investigators attributed more TEAEs to nintedanib than pirfenidone. Funding F. Hoffmann-La Roche, Ltd./Genentech, Inc.

Studies reporting the effects of modern strategies with pulmonary arterial hypertension (PAH)-targeted therapies in sarcoidosis-associated pulmonary hypertension (S-APH) are limited.Clinical and haemodynamic data from newly diagnosed patients with severe S-APH (mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP 25–35 mmHg with cardiac index −1·m−2) were collected from the French Pulmonary Hypertension Registry between 2004 and 2015.Data from 126 patients with severe S-APH were analysed (mean±sd age 57.5±11.6 years, 74% radiological stage IV). 97 patients (77%) received PAH-targeted therapy and immunosuppressive therapy was initiated or escalated in 33 patients at the time of pulmonary hypertension diagnosis. Four months after PAH-targeted therapy initiation, mean±sd pulmonary vascular resistance decreased from 9.7±4.4 to 6.9±3.0 Wood units (pPAH-targeted therapy improved short-term pulmonary haemodynamics in severe S-APH without change in exercise capacity. Immunosuppressive therapy improved haemodynamics in selected patients. Pulmonary hypertension in sarcoidosis remains associated with a poor prognosis.

Introduction La sarcoidose est une maladie multisystemique caracterisee par la presence de granulomes epithelioides dans des organes varies. L’evolution est generalement benigne, mais des traitements immunosuppresseurs peuvent etre necessaires, en plus des corticosteroides, dans les atteintes graves d’organes et/ou les formes multisystemiques chroniques. Les immunosuppresseurs classiquement utilises sont le methotrexate, l’azathioprine, le leflunomide, le mycophenolate, le cyclophosphamide, et plus recemment l’infliximab. Le rituximab, un anticorps monoclonal chimerique anti-CD20, est rarement utilise dans la sarcoidose. Patients et methodes Il s’agissait d’une etude retrospective, multicentrique. Les patients inclus avaient une sarcoidose documentee et avaient recu au moins une injection de rituximab. Le critere principal de jugement etait la reponse au traitement evaluee par une diminution d’au moins 1 point dans chaque organe atteint sur l’ePOST. Resultats Nous avons interroge 11 centres et inclus 11 patients (3 H et 8 F, d’âge median au diagnostic de sarcoidose de 49 ans) ayant recu du rituximab. Les atteintes de la sarcoidose etaient pulmonaire (n = 7,64 %) dont fibrose pulmonaire (n = 2,18 %), systeme nerveux central (SNC) (n = 5, 45 %), ophtalmique, rhumatologique et splenique (n = 4 chacun, 36 %), ganglionnaire (n = 3, 27 %), hepatique (n = 2, 18 %), renale et cardiaque (n = 1 chacun, 9 %). Le nombre median d’organes cibles etait de 3 (IQR [2,5–5]). Les indications de rituximab etaient une sarcoidose refractaire (n = 4,36 %), une hemopathie (n = 4,36 %), une cytopenie auto-immune associee (n = 2,18 %) et une cryoglobulinemie liee au virus de l’hepatite C (n = 1,9 %). Lorsque la sarcoidose etait l’indication de l’utilisation du rituximab, elle etait utilisee en quatrieme ligne (mediane de nombre de traitements anterieurs 4,5 IQR [3,5–5]). Avant l’utilisation du rituximab, le score ePOST median etait de 10 (IQR [6,2–13,8]). Le rituximab etait efficace dans 2 cas (50 %), en particulier sur une atteinte renale et une atteinte neurologique. La variation mediane de l’ePOST dans les organes cibles etait de −1 point. Deux autres patients ont ete evalues comme refractaires au rituximab apres 2 perfusions. Le nombre median de perfusions de rituximab etait de 2 (IQR [1,75–3,5]). Parmi les patients dont l’indication du rituximab n’etait pas la sarcoidose, 3 patients presentaient une maladie quiescente, 2 presentaient des adenopathies mediastinales et/ou abdominales isolees, 1 patient presentait un nodule hepatique avec une documentation histologique de granulomes sans amelioration apres un regime R-CHOP pour un lymphome a cellules B. Chez ces patients, la sarcoidose etait consideree comme stable sous rituximab. Il n’y avait aucune information sur l’evolution de la sarcoidose apres l’utilisation du rituximab pour un patient. Discussion Vingt-sept cas de patients ayant une sarcoidose et ayant recu du rituximab etaient analyses a partir d’une revue systematique de la litterature (PubMed et Web Of Science). Il s’agissait de 16 femmes et 11 hommes, d’âge median 47 ans au moment de l’initiation du rituximab (IQR [41,3–50,0]). Parmi eux, la sarcoidose etait definie par une atteinte pulmonaire (n = 20,74 %), une atteinte cutanee et une uveite (n = 6,22 %), une atteinte ganglionnaire (n = 5,19 %) avec un lupus pernio (n = 4,15 %) et atteinte renale, osseuse, articulaire, hepatique et splenique (n = 1,4 %). Le nombre median d’organes cibles etait de 2 IQR [2–4]. Tous les patients avaient recu des corticosteroides avant l’utilisation du rituximab et, tous sauf un, au moins un traitement immunosuppresseur anterieur (donnees manquantes dans 1 cas) avec un nombre median de traitements anterieurs de 1,5 IQR [1–3]. Les traitements immunosuppresseurs anterieurs etaient le methotrexate (n = 10, 37 %), l’azathioprine (n = 7,26 %), l’infliximab (n = 6,22 %) et le cyclophosphamide (n = 5, 19 %) et le mycophenolate mofetil (n = 3,11 %). La dose utilisee de rituximab etait de 1000 mg (n = 17,63 %), ou 375 mg/m2 (n = 5,19 %), les autres doses etant variables. La mediane de perfusion etait de 2 IQR [2–4]. Le traitement etait considere comme efficace chez 22 patients (74 %). Conclusion Le rituximab est rarement utilise dans la sarcoidose. Dans notre experience, il a ete efficace dans 2 cas sur 4, chez des patients ayant recu prealablement une mediane de 4,5 traitements immunosuppresseurs. Dans la litterature, le rituximab a ete utilise apres un nombre median de traitements immunosuppresseurs de 1,5, et a ete efficace dans 74 % des cas.

Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58–73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6–34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05–8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05–7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41–99) and 94% (95% CI, 86–100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14–88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome.

In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue.

Background: Safety data on combined PFD and NIN use are limited. Methods: A single-arm, open-label study (NCT02598193) assessed safety and tolerability of 24 weeks’ PFD (1602–2403 mg/day) and NIN (200–300 mg/day) in patients with IPF with FVC ≥50% and DLco ≥30%. Before initiating NIN, patients had received PFD for ≥16 weeks and tolerated a stable dose of ≥1602 mg/day PFD for ≥28 days. Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to PFD, NIN, both or neither. Change from baseline FVC, DLco and K-BILD were assessed at 24 weeks. The study is monitored by a data monitoring committee. Results: Eighty-nine patients were enrolled. A pre-specified interim analysis was conducted once 63 patients (mean age 68.7 years, 85.7% male) completed (n=50) or discontinued (n=13) 24 weeks’ combination treatment. Fifty patients had 330 treatment-related TEAEs (Table); 11 patients discontinued due to TEAEs. Two patients had serious treatment-related TEAEs (Table) but none led to death. Final results for all 89 patients, including change from baseline FVC, DLco and K-BILD, will be presented at ERS. Conclusions: Combined PFD and NIN use for 24 weeks did not reveal a different safety profile to that expected for either treatment alone. Patients had tolerated a stable dose of PFD before initiation of NIN, which may explain why investigators attributed more TEAEs to NIN than PFD.