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Maéva Zysman,1 Gaëtan Deslee,2 Thierry Perez,3 Pierre-Régis Burgel,4 Olivier Le Rouzic,3 Graziella Brinchault-Rabin,5 Pascale Nesme-Meyer,6 Isabelle Court-Fortune,7 Gilles Jebrak,8 Pascal Chanez,9 Denis Caillaud,10 Jean-Louis Paillasseur,11 Nicolas Roche4 1Pulmonary Department, Pôle Cardio-thoracique, CHU Haut-Lévèque, INSERM U1045, Bordeaux, France; 2Pulmonary Department, Maison Blanche University Hospital, INSERM U01250, Reims, France; 3University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 9017 – CIIL - Center for Infection and Immunity of Lille, Lille, France; 4Respiratory Medicine, Cochin Hospital, AP-HP and Université de Paris, Institut Cochin, INSERM U1016, Paris, France; 5Service de Pneumologie, Hôpital Pontchaillou, Rennes, France; 6Service de Pneumologie, Hôpital de la Croix-Rousse, Lyon, France; 7Service de Pneumologie, CHU Saint Etienne, Saint Etienne, France; 8Service de Pneumologie, Hôpital Bichat, AP-HP, Paris, France; 9Département des Maladies Respiratoires, AP-HM, Université de la Méditerranée, Marseille, France; 10Service de Pneumologie, Hôpital Gabriel Montpied, CHU, Clermont-Ferrand, France; 11EFFI-STAT, Paris, FranceCorrespondence: Maéva ZysmanAvenue de Magellan, Service des Maladies Respiratoires, CHU Haut Lévèque, Pessac, 33600, FranceTel +33 5 56 79 56 79Email maeva.zysman@chu-bordeaux.frBackground: Chronic respiratory failure may occur as a consequence of chronic obstructive pulmonary disease (COPD) and is associated with significant morbidity and mortality. Hypoxemia is determined by underlying disease characteristics and comorbidities. Severe hypoxemia is typically only found in subjects with severe airflow obstruction (FEV1< 50% predicted). However, how hypoxemia relates to disease characteristics is not fully understood.Methods: In the French Initiatives BPCO real-life cohort, arterial blood gases were routinely collected in most patients. Relationships between severe hypoxemia, defined by a Pa02< 60 mmHg (8 kPa) and clinical/lung function features, comorbidities and mortality were assessed. In subjects with severe hypoxemia, clinical characteristics and comorbidities were compared between those with non-severe versus severe airflow limitation. Classification and regression trees (CART) were used to define clinically relevant subgroups (phenotypes).Results: Arterial blood gases were available from 887 subjects, of which 146 (16%) exhibited severe hypoxemia. Compared to subjects with a PaO2≥ 60 mmHg, the severe hypoxemia group exhibited higher mMRC dyspnea score, lower FEV1, higher RV and RV/TLC, more impaired quality of life, lower 6-minute walking distance, less frequent history of asthma, more frequent diabetes and higher 3-year mortality rate (14% versus 8%, p=0.026). Compared to subjects with Pa02< 60 mmHg and FEV1< 50% (n=115, 13%), those with severe hypoxemia but FEV1≥ 50% predicted (n=31) were older, had higher BMI, less hyperinflation, better quality of life and a higher rate of diabetes (29% versus 13%, p=0.02). Severe hypoxemia was better related to CART-defined phenotypes than to GOLD ABCD classification.Conclusion: In this cohort of stable COPD subjects, severe hypoxemia was associated with worse prognosis and more severe symptoms, airflow limitation and hyperinflation. Compared to subjects with severe hypoxemia and severe airflow limitation, subjects with severe hypoxemia despite non-severe airflow limitation were older, had higher BMI and more diagnosed diabetes.Trial Registration: 04– 479.Keywords: chronic obstructive pulmonary disease, severe hypoxemia, airflow limitation

Thierry Perez,1 Gaëtan Deslée,2 Pierre Régis Burgel,3 Denis Caillaud,4 Olivier Le Rouzic,1 Maeva Zysman,5 Roger Escamilla,6 Gilles Jebrak,7 Pascal Chanez,8 Isabelle Court-Fortune,9 Graziella Brinchault-Rabin,10 Pascale Nesme-Meyer,11 Jean-Louis Paillasseur,12 Nicolas Roche,3 On behalf of the Initiatives BPCO Scientific Committee1CHU Lille, Department of Respiratory Diseases, F-59000 Lille and Univ. Lille, Center for Infection and Immunity of Lille, INSERM U1019 - CNRS UMR 8204, F-59000, Lille, France; 2Department of Respiratory Diseases, Maison Blanche Hospital, CHU de Reims, INSERM UMRS 1250, Reims, France; 3Respiratory and Intensive Care Medicine Department, Cochin Hospital, AP-HP and Paris Descartes University (EA 2511), Sorbonne Paris Cité, Paris, France; 4Department of Respiratory Diseases, Gabriel Montpied Hospital, CHU de Clermont Ferrand, Clermont Ferrand, France; 5Department of Respiratory Diseases, CHU Nancy, Nancy, France; 6Department of Respiratory Diseases, CHU Toulouse, Toulouse, France; 7Department of Respiratory Diseases, Hôpital Bichat, APHP, Paris, France; 8Department of Respiratory Diseases, AP-HM, Université de Méditerranée, Inserm U 1077, Marseille, France; 9Department of Respiratory Diseases, CHU Saint Etienne, Saint Etienne, France; 10Department of Respiratory Diseases, Pontchaillou Hospital, CHU Rennes, Rennes, France; 11Department of Respiratory Diseases, La Croix Rousse Hospital, Lyon, France; 12EFFI-STAT, Paris, FranceBackground: The 6-min walk test (6MWT) allows exercise tolerance to be assessed, and it has a significant prognostic value in COPD. The goal of this study was to analyse the determinants (obtained in routine practice) of a low 6-min walking distance (6MWD) and exercise-induced desaturation (EID) in COPD, including comorbidities.Methods: Patients were recruited from the real-life French COPD cohort “Initiatives BPCO”. A low 6MWD was defined as 30 kg/m2,), low BMI (BMI

Maeva Zysman,1 Gaëtan Deslee,2 Denis Caillaud,3 Pascal Chanez,4 Roger Escamilla,5 Isabelle Court-Fortune,6 Pascale Nesme-Meyer,7 Thierry Perez,8 Jean-Louis Paillasseur,9 Christophe Pinet,10 Gilles Jebrak,11 Nicolas Roche,12,* Pierre-Régis Burgel12,* On behalf of the Initiatives BPCO (broncho-pneumopathie chronique obstructive) Scientific Committee and Investigators 1Pulmonary Dpt, Nancy, Inserm U955, team 04, Créteil, France; 2Pulmonary Dpt, Maison Blanche University Hospital, INSERM U903, Reims, France; 3Pulmonary Dpt, Gabriel Montpied University Hospital, Auvergne University, Clermont-Ferrand, France; 4Pulmonary Dpt, APHM, INSERM U1077, CNRS UMR 7733 Aix Marseille Université, Marseille, France; 5Pulmonary Dpt, Larrey University Hospital, Toulouse, France; 6Pulmonary Dpt, University Hospital, Saint-Etienne, France; 7Pulmonary Dpt, La Croix Rousse University Hospital, Lyon, France; 8Clinique des Maladies Respiratoires, Albert Calmette University Hospital, Lille, France; 9EFFI-STAT, Paris, France; 10Service de pneumologie, polyclinique Les Fleurs, Ollioules, France; 11Pulmonary Dpt, Bichat Hospital, AP-HP, Paris, France; 12Respiratory and Intensive Care Medicine Dpt, Cochin Hospital, AP-HP and Paris Descartes University (EA2511), Sorbonne Paris Cité, Paris, France *These authors contributed equally to this work Abstract: In patients with COPD, there is controversy regarding the association of blood eosinophil (Eos) levels with 1) exacerbation frequency and 2) the effect of inhaled corticosteroids for prevention of exacerbations. To determine whether Eos define subgroups of patients exhibiting attributes of COPD clinical phenotypes, we compared clinical features and mortality rates in COPD patients from the Initiatives BPCO French cohort categorized using different thresholds of blood Eos levels. The following data were collected at inclusion: medical and smoking history, occupational exposures, dyspnea, cough and sputum production, exacerbations in the previous year, history of allergy and asthma, nasal symptoms, body mass index, St George Respiratory Questionnaire (SGRQ) total score, post-bronchodilator spirometry, comorbidities, and medications. Three-year survival between groups was compared using Kaplan–Meier analysis. Three sets of analyses were performed to compare patients with ≥2% versus

Gaëtan Deslee,1 Pierre-Régis Burgel,2 Roger Escamilla,3 Pascal Chanez,4 Isabelle Court-Fortune,5 Pascale Nesme-Meyer,6 Graziella Brinchault-Rabin,7 Thierry Perez,8 Gilles Jebrak,9 Denis Caillaud,10 Jean-Louis Paillasseur,11 Nicolas Roche2On behalf of the Initiatives BPCO Scientific Committee 1Department of Respiratory Diseases, INSERM UMR 903, Maison Blanche Hospital, University Hospital of Reims, Reims, 2Department of Respiratory Diseases, Cochin Hospital, AP-HP and University Paris Descartes, Sorbonne Paris Cité, Paris, 3Department of Respiratory Diseases, Larrey Hospital, Toulouse, 4Department of Respiratory Diseases, APHM, INSERM U1077, CNRS UMR 7733 Aix Marseille Université, Marseille, 5Department of Respiratory Diseases, University Hospital of St Etienne, 6Department of Respiratory Diseases, La Croix Rousse Hospital, Lyon, 7Department of Respiratory Diseases, Pontchaillou Hospital, University Hospital of Rennes, Rennes, 8Department of Respiratory Diseases, Calmette Hospital, University Hospital of Lille, Lille, 9Department of Respiratory Diseases, Bichat Hospital, AP-HP, Paris, 10Department of Respiratory Diseases, Gabriel Montpied Hospital, University Hospital of Clermont-Ferrand, Clermont-Ferrand, 11EFFI-STAT, Paris, FranceBackground: Cough and sputum production are frequent in chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the relationship between cough and sputum production and health-related quality of life in COPD.Methods: A cross-sectional study was conducted in the French Initiatives COPD cohort and assessed cough and sputum production within the past 7 days using the cough and sputum assessment questionnaire (CASA-Q), health-related quality of life, spirometry, smoking status, dyspnea, exacerbations, anxiety and depression, and comorbidities.Results: One hundred and seventy-eight stable COPD patients were included (age, 62 [56–69] years, 128 male, forced expiratory volume in 1 second [FEV1]: 57 [37–72] % predicted) (median [Q1–Q3]). In univariate analyses, health-related quality of life (Saint George’s respiratory questionnaire total score) was associated with each CASA-Q domain and with chronic bronchitis, exacerbations, dyspnea, FEV1, depression, and anxiety. All four domains introduced separately were independently associated with health-related quality of life. When introduced together in multivariate analyses, only the cough impact domain remained independently associated with health-related quality of life (R2=0.60). With chronic bronchitis (standard definition) instead of the CASA-Q, the R2 was lower (R2=0.54).Conclusion: This study provides evidence that current cough in the previous 7 days is an important determinant of health-related quality of life impairment in stable COPD patients.Keywords: signs and symptoms, respiratory, sputum, questionnaires, dyspnea, multivariate analysis

Thierry Perez,1 Pierre Régis Burgel,2 Jean-Louis Paillasseur,3 Denis Caillaud,4 Gaetan Deslée,5 Pascal Chanez,6 Nicolas Roche2 For the INITIATIVES BPCO Scientific Committee 1Clinique des Maladies Respiratoires, CHRU de Lille, Université Lille Nord de France, Lille, 2Service de Pneumologie, Groupe Hospitalier Cochin Broca Hotel Dieu, AP HP et Université René Descartes, 3EFFI-STAT, Paris, 4Service de Pneumologie, Hôpital Gabriel Montpied, CHU de Clermont Ferrand, Clermont Ferrand, 5Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, 6Département des Maladies respiratoires, AP-HM, Université de Méditerranée, Marseille, France Background: Assessment of dyspnea in COPD patients relies in clinical practice on the modified Medical Research Council (mMRC) scale, whereas the Baseline Dyspnea Index (BDI) is mainly used in clinical trials. Little is known on the correspondence between the two methods.Methods: Cross-sectional analysis was carried out on data from the French COPD cohort Initiatives BPCO. Dyspnea was assessed by the mMRC scale and the BDI. Spirometry, plethysmography, Hospital Anxiety-Depression Scale, St George’s Respiratory Questionnaire, exacerbation rates, and physician-diagnosed comorbidities were obtained. Correlations between mMRC and BDI scores were assessed using Spearman’s correlation coefficient. An ordinal response model was used to examine the contribution of clinical data and lung function parameters to mMRC and BDI scores.Results: Data are given as median (interquartile ranges, [IQR]). Two-hundred thirty-nine COPD subjects were analyzed (men 78%, age 65.0 years [57.0; 73.0], forced expiratory volume in 1 second [FEV1] 48% predicted [34; 67]). The mMRC grade and BDI score were, respectively, 1 [1–3] and 6 [4–8]. Both BDI and mMRC scores were significantly correlated at the group level (rho =-0.67; P

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV 1 ) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV 1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation ( n  = 5) or death ( n  = 4). Absolute increase in ppFEV 1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV 1 in the youngest age quartile was almost twice that of the oldest quartile ( P  < 0.001); body mass index < 18.5 kg/m 2 was found in 38.6% at initiation versus 11.3% at 12 months ( P  = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D 3 , were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Background: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates., Methods: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021., Results: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV 1 ) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation., Conclusion: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest related to the work submitted for publication., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV 1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV 1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV 1 (ppFEV 1 ) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV 1  = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV 1 was +15.1 (+13.8 to +16.4; P  < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P  < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively ( P  < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV 1 ) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV 1 ., Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV 1 <40 or ppFEV 1 ≥90 in comparison with those with ppFEV 1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers., Results: 827 patients were classified into 3 subgroups according to ppFEV 1 at treatment initiation (ppFEV 1 <40, n = 121; ppFEV 1 [40-90[, n = 609; ppFEV 1 ≥90, n = 97). Treatment discontinuation rate was higher in ppFEV 1 <40 patients (28.9%) than in those with ppFEV 1 [40-90[(16.4%) or ppFEV 1 ≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV 1 occurred in the ppFEV 1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV 1 <40 (+0.5%, P = 0.03) but not in those with ppFEV 1 ≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV 1 <40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups., Conclusion: Phe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function , but the characteristics and magnitude of the response vary depending on ppFEV 1 at baseline., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest related to the work submitted for publication., (Copyright © 2020. Published by Elsevier B.V.)

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation. Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting. Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations. Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV 1 (ppFEV 1 ) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV 1 (+3.67%), an increase in body mass index (+0.73 kg/m 2 ), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV 1 , without improvement in body mass index or decrease in intravenous antibiotic courses. Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Background: In patients with chronic obstructive pulmonary disease, all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease. Treatment recommendations are mostly built on results from randomized controlled trials (RCTs) whose methodology ensure internal validity. However, their relevance may be compromised by the lack of generalizability, due to poor representability of study populations compared to real-life patients. In order to delimit to whom the results of studies on current and future treatments apply, we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aiming at decreasing exacerbation risk., Methods: We used the Initiatives-BPCO database, a French cohort of 1309 real-life COPD patients monitored in academic centers. We identified industry-sponsored phase III and IV trials that enrolled more than 500 patients, lasted at least one year and used exacerbations related endpoints. Eligibility criteria were extracted from each trial and applied to the patients., Results: The eligibility criteria of 16 RCTs were applied to the 1309 patients. The most discriminating eligibility criteria were FEV1, minimum exacerbation rate in the previous year and smoking history, responsible for the exclusion of 39.9, 36.7 and 16.8% of patients, respectively. Altogether, 2.3 to 46.7% of our patients would have satisfied all eligibility criteria., Conclusion: These analyses confirm that an important gap exists between real-life patients and clinical trials populations in COPD, which limits the relevance of results and therefore should be considered when grading levels of evidence and designing future studies.

Our goal was to identify subgroups of adults with cystic fibrosis (CF) at low risk of death within 10 years.Factor analysis for mixed data followed by Ward's cluster analysis was conducted using 25 variables from 1572 French CF adults in 2005. Rates of death by subgroups were analysed over 10 years. An algorithm was developed using CART (classification and regression tree) analysis to provide rules for the identification of subgroups of CF adults with low rates of death within 10 years. This algorithm was validated in 1376 Canadian CF adults.Seven subgroups were identified by cluster analysis in French CF adults, including two subgroups with low (∼5%) rates of death at 10 years: one subgroup (22% of patients) was composed of patients with nonclassic CF, the other subgroup (17% of patients) was composed of patients with classic CF but low rates of Pseudomonas aeruginosa infection and diabetes. An algorithm based on CART analysis of data in 2005 allowed us to identify most French adults with low rates of death. When tested using data from Canadian CF adults in 2005, the algorithm identified 287 out of 1376 (21%) patients at low risk (10-year death: 7.7%).Large subgroups of CF adults share low risk of 10-year mortality., Competing Interests: Conflict of interest: P-R. Burgel reports grants and personal fees from Boehringer Ingelheim, and personal fees from AstraZeneca, Chiesi, GSK, Novartis, Vertex, Zambon and MSD, outside the submitted work. Conflict of interest: L. Lemonnier has nothing to disclose. Conflict of interest: C. Dehillotte has nothing to disclose. Conflict of interest: J. Sykes has nothing to disclose. Conflict of interest: S. Stanojevic has nothing to disclose. Conflict of interest: A.L. Stephenson receives a stipend from Cystic Fibrosis Canada for her work as Director of the Canadian CF Registry, outside the submitted work. Conflict of interest: J-L. Paillasseur has nothing to disclose., (Copyright ©ERS 2019.)

Introduction: We studied the pattern changes over time of medication prescriptions for COPD and their conformity with French and international recommendations using data from patients in the prospective French cohort "Initiatives BPCO"., Method: Eight hundred and forty-six patients have been included during a first period from August, 2001 till May 2006 (n=425) and a second period from June, 2006 till June, 2012 (n=421). The pivotal date was based on the tiotropium availability in France., Results: During period 1, we recruited older patients (average 65 vs 64 years), less often women (19 vs 26 %) and having less severe airflow obstruction (mean FEV1 48 vs 54 %). The ICS prescriptions decreased in mild COPD, but there was no change for inhaled long-acting beta-2 agonist (LABA) (68 %). The use of LABA+LAMA association without ICS increased from 0.9 to 7 %, but remained lower than the fixed LABA+ICS association (26 %), less often prescribed than the triple association LABA+ICS+LAMA (32.5 % in period 2). The use of long-acting bronchodilators increased from 68 to 80 % between both periods. Vaccinations and rehabilitation remained insufficiently prescribed. LAMA had been added but did not appear to replace other drugs., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Some studies suggest that asthma-COPD overlap syndrome (ACOS) is associated with worse outcomes than chronic obstructive pulmonary disease (COPD). The goal of this study was to further explore the clinical characteristics and survival of patients with ACOS identified in a real-life cohort of patients with COPD., Methods: Data from the French COPD cohort 'INITIATIVES BronchoPneumopathie Chronique Obstructive' (n = 998 patients) were analyzed to assess the frequency of ACOS defined as a physician diagnosis of asthma before the age of 40 years and to analyze its impact. Univariate analyses were performed to assess the relationship between ACOS and sociodemographic characteristics, risk factors (smoking, occupational exposure, atopic diseases), symptoms (chronic bronchitis, dyspnea-modified Medical Research Council scale and baseline dyspnea index), quality of life (QoL), mood disorders, exacerbations, comorbidities, lung function, prescribed treatment, and survival., Results: ACOS was diagnosed in 129 patients (13%). In multivariate analyses, ACOS was associated negatively with cumulative smoking (odds ratio [OR]: 0.992; 95% CI 0.984-1.000 per pack-year) and positively with obesity: OR: 1.97 [1.22-3.16], history of atopic disease (hay fever: OR: 5.50 [3.42-9.00] and atopic dermatitis: OR 3.76 [2.14-6.61]), and drug use (LABA + ICS: 1.86 [1.27-2.74], antileukotrienes 4.83 [1.63-14.34], theophylline: 2.46 [1.23-4.91], and oral corticosteroids: [2.99;.1.26-7.08]). No independent association was found with dyspnea, QoL, exacerbations, and mortality., Conclusions: Compared to 'pure' COPD patients, patients with ACOS exhibit lower cumulative smoking, suffer more from obesity and atopic diseases, and use more asthma treatments. Disease severity (dyspnea, QoL, exacerbations, comorbidities) and prognosis (mortality) are not different from 'pure' COPD patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: This study evaluated a standardized procedure aiming at early detection of COPD in a consecutive population of employees visiting occupational medicine., Methods: A total of 2818 employees were included by 22 occupational physicians in 5 centers. Respiratory symptoms, smoking status, occupational exposures and socioprofessional categories were collected. Subjects with at least one symptom and/or risk factor underwent spirometry., Results: In this population aged 39±12 years, 2603 patients were free of known asthma or COPD. The presence of at least one symptom was observed in 23.6 % of employees and was significantly associated with smoking status, occupational exposure to organic dust, gas fumes and vapors, and agriculture (P<0.0001). Airflow obstruction (FEV1/FVC < 0.70) was detected in 1.7 % of 1605 employees who underwent spirometry. With the inclusion of known COPD subjects (n=22), the prevalence reached 2.38 %. COPD was significantly associated with smoking intensity. Information on subsequent diagnosis was obtained in only two cases. The quality of spirometry was inadequate in 30 % of cases. Thirty-three percent of detected COPD subjects did not report any respiratory symptoms., Conclusion: The strategy used in this study (specific questionnaire plus spirometry) allowed detection of a few cases of previously undiagnosed COPD. Occupational physicians need specific training in spirometry and a better follow-up of care pathways is required to obtain diagnostic confirmation., (Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objective: The "Pas à Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients., Setting: Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population., Design: A prospective national epidemiological study was performed., Subjects: A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included., Intervention and Main Outcome Measure: PA was recorded during seven consecutive days using a pedometer to measure daily step numbers., Results: Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA., Conclusions: Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD., Methods: The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George's Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up., Results: Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75-1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters., Conclusions: Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients.

Reports regarding gender-related differences in COPD expression have provided conflicting results. In the French Initiatives BPCO real-world cohort, which contained 688 patients (146 women) when data were extracted, women were matched with men (1:3 ratio: n = 107:275) on age (5-year intervals) and FEV1 (5% predicted intervals) and comparisons were performed using univariate logistic regressions. For a given age and level of airflow obstruction, women with COPD had higher BOD scores due to more pronounced dyspnea and lower BMI, suggesting worse prognosis, and were more likely to exhibit anxiety, suggesting the need for specific assessment and care.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies.

Background: The 6 min walk test (6MWT) provides prognostic information in various respiratory diseases, but limited data exist in cystic fibrosis (CF) adults., Methods: Consecutive CF adults who performed 6MWT at Cochin Hospital (Paris, France) over 12 years were analyzed. The cut-off 6 min walking distance (6MWD) value that best predicted a combined endpoint (death without transplant or lung transplant) was established using a receiver operating curve. Determinants of low 6MWD or of desaturation (SpO2 ≤ 90%) during 6MWT were examined using multivariate logistic regressions. Prognostic value of these variables was assessed using Kaplan-Meier and Cox analyses., Results: 6MWT was performed in 286 CF adults (median: age, 28 yr; FEV1, 45% predicted) of whom 14% (n = 40) had lung transplant and 6% (n = 18) died without transplant. 6MWD correlated with FEV1% predicted (r = 0.43; P < 0.001), but markedly differed in subjects within the same range of FEV1. A 6MWD ≤ 475 m predicted death or transplant and was mostly found in patients with FEV1 ≤ 60% predicted. Desaturation during the 6MWT occurred in 29% of patients, exclusively in subjects with FEV1 ≤ 60% predicted. Both 6MWD ≤ 475 m and desaturation during the 6MWT were independent predictors of death or transplant., Conclusion: The 6MWT provides prognostic information in CF adults, especially in subjects with FEV1 ≤ 60% predicted., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Rationale: The application of a haemostatic agent in general surgery, in addition to its effect on bleeding, also provides tissue sealing and adhesion. A sponge drug is used with some actions of resection and wide dissection, without knowledge of the eligibility of patients. In this study, we sought to identify clusters of patients for which the medicated sponge enhances tissue sealing., Methods: Observational study (ELITE), from a panel of selected surgeons from hospitals in France in several surgical areas: abdominal, gynaecology, urology and thoracic. The survey identified the criteria for using the sponge TachoSil® in their surgical practices involving n = 683 patients. A multiple correspondence analysis (MCA) followed by an ascending hierarchical classification (AHC) was used in order to identify the eligibility criteria for the application of the sponge for tissue sealing in addition to hemostasis., Results: The most relevant classification was based on 9 groups of patients for which the sponge was used. 6 of them are mainly linked with the kind of lesion, 2 with the site of application and the latest one with the type of operation., Conclusions: The ELITE study revealed that the TachoSil® sponge was used mainly during surgery, requiring a reinforcement of the resection tissue sealing. The expected objective was successfully reached in 97% of the cases.

Background: Comorbidities are frequent in subjects with COPD, but their contribution to health-related quality of life (HRQoL) impairment is not clearly established., Methods: Cross-sectional analysis of data from the French COPD cohort Initiatives BPCO. Data were recorded in stable state and included spirometry, dyspnea (modified Medical Research Council - mMRC-scale), mood disorders (hospital anxiety-depression scale) and physician-diagnosed comorbidities including diabetes, hypertension, coronary artery disease, chronic heart failure, venous thromboembolism. HRQoL was assessed using the disease-specific St. George's Respiratory Questionnaire (SGRQ). Stepwise forward and backward multiple regression analyses were performed to examine the contribution of comorbidities to SGRQ scores., Results: Data are median [IQR]. 326 COPD subjects were analyzed: male 77%, age 65.0 [57.0; 72.0] years, FEV(1) 48.9 [34.7; 65.9]% predicted. SGRQ total score was 44.2 [30.0; 61.2]. In univariate analysis, positive correlations were found between SGRQ total scores and dyspnea and exacerbations/patient/year, whereas negative correlations were found with FEV(1). SGRQ total scores were increased in women (P = 0.06), and in subjects with low BMI, anxiety or depression (each analysis, P < 0.001), but not in subjects with cardiovascular comorbidities or diabetes. In multivariate analyses, major independent determinants of SGRQ total score included dyspnea, exacerbations/patient/year and depression. Low BMI, coronary artery disease and FEV(1) were also independently associated with SGRQ total score, but their contribution was only modest., Conclusions: These data suggest that in the presence of dyspnea and exacerbation, depression is the most important contributor to HRQoL impairment measured by SGRQ in COPD subjects, whereas other comorbidities and FEV(1) have only limited impact., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The contribution of occupational exposures to COPD and their interaction with cigarette smoking on clinical pattern of COPD remain underappreciated. The aim of this study was to explore the contribution of occupational exposures on clinical pattern of COPD., Methods: Cross-sectional data from a multicenter tertiary care cohort of 591 smokers or ex-smokers with COPD (median FEV1 49%) were analyzed. Self-reported exposure to vapor, dust, gas or fumes (VDGF) at any time during the entire career was recorded., Results: VDGF exposure was reported in 209 (35%) subjects aged 31 to 88 years. Several features were significantly associated with VDGF exposure: age (median 68 versus 64 years, p < 0.001), male gender (90% vs 76%; p < 0.0001), reported work-related respiratory disability (86% vs 7%, p < 0.001), current wheezing (71% vs 61%, p = 0.03) and hay fever (15.5% vs 8.5%, p < 0.01). In contrast, current and cumulative smoking was less (p = 0.01) despite similar severity of airflow obstruction., Conclusion: In this patient series of COPD patients, subjects exposed to VDGF were older male patients who reported more work-related respiratory disability, more asthma-like symptoms and atopy, suggesting that, even in smokers or ex-smokers with COPD, occupational exposures are associated with distinct patients characteristics.

Rationale: In COPD patients, mortality risk is influenced by age, severity of respiratory disease, and comorbidities. With an unbiased statistical approach we sought to identify clusters of COPD patients and to examine their mortality risk., Methods: Stable COPD subjects (n = 527) were classified using hierarchical cluster analysis of clinical, functional and imaging data. The relevance of this classification was validated using prospective follow-up of mortality., Results: The most relevant patient classification was that based on three clusters (phenotypes). Phenotype 1 included subjects at very low risk of mortality, who had mild respiratory disease and low rates of comorbidities. Phenotype 2 and 3 were at high risk of mortality. Phenotype 2 included younger subjects with severe airflow limitation, emphysema and hyperinflation, low body mass index, and low rates of cardiovascular comorbidities. Phenotype 3 included older subjects with less severe respiratory disease, but higher rates of obesity and cardiovascular comorbidities. Mortality was associated with the severity of airflow limitation in Phenotype 2 but not in Phenotype 3 subjects, and subjects in Phenotype 2 died at younger age., Conclusions: We identified three COPD phenotypes, including two phenotypes with high risk of mortality. Subjects within these phenotypes may require different therapeutic interventions to improve their outcome.

Classification of chronic obstructive pulmonary disease (COPD) is usually based on the severity of airflow limitation, which may not reflect phenotypic heterogeneity. Here, we sought to identify COPD phenotypes using multiple clinical variables. COPD subjects recruited in a French multicentre cohort were characterised using a standardised process. Principal component analysis (PCA) was performed using eight variables selected for their relevance to COPD: age, cumulative smoking, forced expiratory volume in 1 s (FEV(1)) (% predicted), body mass index, exacerbations, dyspnoea (modified Medical Research Council scale), health status (St George's Respiratory Questionnaire) and depressive symptoms (hospital anxiety and depression scale). Patient classification was performed using cluster analysis based on PCA-transformed data. 322 COPD subjects were analysed: 77% were male; median (interquartile range) age was 65.0 (58.0-73.0) yrs; FEV(1) was 48.9 (34.1-66.3)% pred; and 21, 135, 107 and 59 subjects were classified in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1, 2, 3 and 4, respectively. PCA showed that three independent components accounted for 61% of variance. PCA-based cluster analysis resulted in the classification of subjects into four clinical phenotypes that could not be identified using GOLD classification. Importantly, subjects with comparable airflow limitation (FEV(1)) belonged to different phenotypes and had marked differences in age, symptoms, comorbidities and predicted mortality. These analyses underscore the need for novel multidimensional COPD classification for improving patient care and quality of clinical trials.

A multicentre open study to which 229 investigators participated was carried out to demonstrate the safety of cicletanine, a new therapeutic agent, in routine clinical use. Cicletanine was administered alone for three months and normalized blood pressure (less than 160/95 mmHg) in 63 p. 100 of the 1,238 hypertensive patients who entered the study. There was a significant fall of systolic arterial pressure from 178.4 +/- 14.8 to 151.8 +/- 14.2 mmHg and a similar fall of diastolic arterial pressure from 104.0 +/- 6.7 to 86.3 +/- 6.2 mmHg. The reduction of BP values was accompanied by a significant decrease of differential BP (SBP-DBP) from 72.5 to 65.8 mmHg. The initial dosage (50 mg/day) was doubled in only one-third of the patients. The mean daily dose was 66 mg. This antihypertensive effect was paralleled by a significant and major improvement of signs (dyspnoea, oedema of the lower limbs) and symptoms (mainly dizziness, headache, visual and auditory disorders, asthenia) which existed at inclusion. A modest, but significant, reduction of heart rate from 76.7 to 73.9 beats/mn was also noted. Cicletanine produced no toxic or severe adverse events. Clinical side-effects consisted of pruritus, fatigue, headache, vertigo, lower limb oedema and gastrointestinal disorders. These effects were mild and non-specific (doubtful drug imputability); each of them occurred with an incidence ranging from 4.0 to 1.0 p. 100. They were responsible for the withdrawal of about 30 patients (2.4 p. 100). No significant alteration of biochemical or haematological values was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

In a multicentre open trial involving 229 investigators, cicletanine, a new antihypertensive agent, was administered orally in doses of 50 to 100 mg/day either alone (1,238 patients) or combined with another drug (430 patients). In this second group of patients with essential hypertension whose BP had not been normalized by a beta-blocker (n = 157), a calcium inhibitor (n = 67), an angiotensin-converting enzyme inhibitor (n = 134) or an alpha-blocker (n = 7), cicletanine normalized BP (less than 160/95 mmHg) in 48.8% of the patients and significantly lowered BP values which fell from 177.7 +/- 15.9/103.3 +/- 6.3 mmHg to 157.2 +/- 17.6/88.8 +/- 8.7 mmHg. The addition of cicletanine to treatments with beta-blockers, calcium inhibitors and angiotensin-converting enzyme inhibitors normalized BP in 48%, 52% and 47% of patients respectively. A significant reduction of symptoms was noted, notably as regards headache, dizziness, palpitations, lower limb oedema, asthenia, auditory disorders and dyspnoea. The side-effects reported (headache, dizziness, gastralgia, nausea, pruritus) were minor and non-specific; they accounted for the withdrawal of only 8 patients. The only significant, though moderate, biochemical variations observed were decreases in natremia and cholesterolaemia unconfirmed by qualitative analysis. Altogether, cicletanine proved to be effective and well tolerated when administered in combination with other antihypertensive drugs belonging to three main therapeutic classes.