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Chronic obstructive pulmonary disease (COPD) is a main cause of death due to interplaying factors, including comorbidities that interfere with symptoms and response to therapy. It is now admitted that COPD management should be based on clinical symptoms and health status and should consider the heterogeneity of patients’ phenotypes and treatable traits. This precision medicine approach involves a regular assessment of the patient's status and of the expected benefits and risks of therapy. The cornerstone of COPD pharmacological therapy is inhaled long-acting bronchodilation. In patients with persistent or worsened symptoms, factors likely to interfere with treatment efficacy include the patient's non-adherence to therapy, treatment preference, inhaler misuse and/or comorbidities, which should be systematically investigated before escalation is considered. Several comorbidities are known to impact symptoms, physical and social activity and lung function. The possible long-term side-effects of inhaled corticosteroids contrasting with their over-prescription in COPD patients justify the regular assessment of their benefits and risks, and de-escalation under close monitoring after a sufficient period of stability is to be considered. While commonly used in clinical trials, the relevance of routine blood eosinophil counts to guide therapy adjustment is not fully clear. Patients’ characteristics, which define phenotypes and treatable traits and thus guide therapy, often change during life, forming the basis of the concept of clinical trajectory. The application of individual trajectory-based management of COPD in clinical practice therefore implies that the benefit:risk ratio is regularly reviewed according to the evolution of the patient's traits over time to allow optimised therapy adjustments., In the current era of precision medicine, COPD management needs to be regularly adjusted based on the patient's personal clinical trajectory, i.e. the evolution of their treatable traits over time. https://bit.ly/3kxVgC7

Introduction: Dyspnoea is one of the most common symptoms in chronic obstructive pulmonary disease (COPD) and has been associated with poor clinical outcomes. Aims and objectives: To investigate relationships between dyspnoea severity, baseline characteristics and outcomes in patients with COPD. Methods: Data from two 1-year, randomized trials (NCT00168844; NCT00168831) of tiotropium Respimat® 5 µg and placebo were pooled. This retrospective analysis assessed characteristics and outcomes of patients by Baseline Dyspnea Index score. Results: Of 1317 patients, 337 (26%) had mild or no dyspnoea at baseline, 743 (56%) moderate dyspnoea and 237 (18%) severe dyspnoea (Table). Baseline demographic characteristics were similar across dyspnoea categories. However, higher levels of dyspnoea correlated with more advanced COPD (GOLD Stage), and greater use of short-acting bronchodilators and inhaled corticosteroids. Patients with severe dyspnoea reported more exacerbations within the past year. Increasing dyspnoea at baseline correlated with greater risk of moderate–severe (P=0.0005) and severe (P=0.0198) exacerbations during the study. Tiotropium reduced moderate–severe exacerbation risk and significantly improved FEV1 and FVC across all dyspnoea categories. Conclusions: Patients with more severe dyspnoea had more advanced COPD, and a higher risk of exacerbation. Tiotropium improved outcomes regardless of baseline dyspnoea severity.

Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

Resume Introduction Les immunodepressions congenitales et acquises peuvent se compliquer d’atteintes respiratoires touchant les voies aeriennes distales. L’objectif de cet article est de faire une mise au point sur les atteintes des voies aeriennes distales rencontrees lors des principales causes d’immunodepression. Etat des connaissances Les deficits immunitaires communs d’expression variable se compliquent frequemment d’atteintes bronchiolaires et de dilatations des bronches d’origine infectieuse. Des bronchiolites folliculaires ou granulomateuses d’etiologie non infectieuse peuvent egalement survenir. La bronchiolite obliterante est la premiere cause de mortalite apres la premiere annee post-greffe chez les patients ayant eu une transplantation pulmonaire. Elle peut survenir chez les patients ayant eu une allogreffe de cellules souches hematopoietiques, en particulier en cas de reaction du greffon contre l’hote. Perspectives et conclusions Les atteintes des voies aeriennes distales ont une expression et une physiopathologie variables selon la cause de l’immunodepression. Une meilleure comprehension de ces pathologies pourrait permettre le developpement de therapeutiques ciblees.

Chronic obstructive pulmonary disease (COPD) is a risk factor of post-operative complications after lung cancer resection. The influence of the "frequent exacerbator (FE)" phenotype (at least three exacerbations per year) is unknown. Postoperative outcomes of frequent exacerbators (POFE) was a prospective observational study of patients with COPD undergoing lung resection for cancer. The inclusion criteria were: age40 years, FEV1/FVC70%, non-urgent surgery for lung cancer, filled out self-questionnaires. The primary outcome was assessment of postoperative pulmonary complications (purulent tracheobronchitis, atelectasis, pneumonia, acute respiratory failure, need of mechanical ventilation). Secondary outcomes encompassed the prevalence of the FE phenotype and its impact on postoperative complications. A total of 682 patients were screened from June 2014 to October 2015. 93 patients with COPD were included, 21 (23%) were FE. Postoperative tracheobronchitis, atelectasis pneumonia or respiratory failure (isolated or associated) occurred in 47%, 48%, 26%, and 38% of patients, respectively. Non-invasive and invasive mechanical ventilation were necessary in 4 (4%) and 22 (23%) patients. Purulent tracheobronchitis, pneumonia and hypercapnia (this last requiring noninvasive mechanical ventilation) were more frequent in FE (p = 0.043, 0.042, 0.015); however the number of patients wth at least one respiratory complication was not different (76% vs. 52%, p = 0.056). In all patients, multivariate logistic regression identified two independent factors of postoperative respiratory complications: male sex (OR 10.6 [95% CI 1.97-57.6], p = 0.006) and the FE phenotype (OR 6.33 [1.04-38.39], p = 0.045). Occurrence of postoperative complications in patients with COPD is high. FE phenotype is an independent risk factor.

Background Azithromycin reduces exacerbations in cystic fibrosis (CF) patients. Our aim was to investigate its association with nontuberculous mycobacteria isolation and macrolide susceptibility. Methods From 2006 to 2010, all adult CF subjects at Cochin Hospital (Paris, France) harboring at least one positive NTM isolate were identified (Cases). In a nested case–control study, each Case was individually matched for age and gender with up to 4 CF adults with no NTM isolate (Controls). Clinical data at the time of first NTM isolate (index date) in Cases were compared with those of Controls using multivariate conditional regression analysis. Results CF subjects with positive NTM isolates (Cases, n =41) were matched to 155 Controls. Among Cases, 48.7% had isolates from Mycobacterium avium complex and 58.5% from Mycobacterium abscessus complex, and 31 Cases fulfilled the 2007 American Thoracic Society criteria for NTM infection (ATS+ Cases). Cases and ATS+ Cases were more likely to have low body mass index and colonization with Aspergillus fumigatus . Azithromycin was associated with a two-fold reduction in NTM isolates. Only one M. avium complex isolate had acquired macrolide resistance. Conclusion These data suggest that azithromycin is a primary prophylaxis for NTM infection in CF adults.

Background and Aims Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients is associated with worse long-term pulmonary disease and shorter survival, and chronic Pa infection (CPA) is associated with reduced lung function, faster rate of lung decline, increased rates of exacerbations and shorter survival. By using exome sequencing and extreme phenotype design, it was recently shown that isoforms of dynactin 4 (DCTN4) may influence Pa infection in CF, leading to worse respiratory disease. The purpose of this study was to investigate the role of DCTN4 missense variants on Pa infection incidence, age at first Pa infection and chronic Pa infection incidence in a cohort of adult CF patients from a single centre. Methods Polymerase chain reaction and direct sequencing were used to screen DNA samples for DCTN4 variants. Results A total of 121 adult CF patients from the Cochin Hospital CF centre have been included, all of them carrying two CFTR defects: 103 developed at least 1 pulmonary infection with Pa, and 68 patients of them had CPA. DCTN4 variants were identified in 24% (29/121) CF patients with Pa infection and in only 17% (3/18) CF patients with no Pa infection. Of the patients with CPA, 29% (20/68) had DCTN4 missense variants vs 23% (8/35) in patients without CPA. Interestingly, p.Tyr263Cys tend to be more frequently observed in CF patients with CPA than in patients without CPA (4/68 vs 0/35), and DCTN4 missense variants tend to be more frequent in male CF patients with CPA bearing two class II mutations than in male CF patients without CPA bearing two class II mutations (P = 0.06). Conclusions Our observations reinforce that DCTN4 missense variants, especially p.Tyr263Cys, may be involved in the pathogenesis of CPA in male CF.

International audience; Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes. @ERSpublications ATS/ERS statement: which types of research will have the greatest future impact on patient-centred outcomes in COPD? http://ow.ly/I54Hb

Bronchial artery embolization is the recommended therapy for massive hemoptysis in patients with cystic fibrosis (CF). We report on two cases of multiple renal infarcts and renin-associated hypertension and hypokalemia occurring in CF adults after bronchial artery embolizations. These complications were presumably related to crossing of small calibrated microspheres through arteriovenous anastomoses. Although hypokalemia resolved rapidly, hypertension persisted at least 6 months and its control required multiple antihypertensive agents. Physicians should be aware of this potentially severe, but previously unreported, complication of bronchial artery embolization.

SUMMARY Bevacizumab is an antiangiogenic targeted therapy approved for the treatment of patients with advanced non-small-cell lung cancer other than predominantly squamous cell histology in addition to platinum-based chemotherapy. The safety of bevacizumab has been assessed in studies across most cancer types and bevacizumab is generally well tolerated. Some specific issues associated with the use of bevacizumab in lung cancer are discussed in this report (pulmonary hemorrhage, brain metastases or concurrent thoracic radiotherapy) as well as frequent and clinically relevant adverse events and their management. Oncologists and pulmonologists should be aware of such events and their management since the prescription of bevacizumab concerns many patients and the future use in maintenance therapy will be associated with prolonged treatment.

SummaryAsthma is a disease characterized by inflammation which affects both proximal and distal airways. We evaluated the prevalence of small airway obstruction (SAO) in a group of clinically stable asthmatics with both normal forced expiratory volume in the first second (FEV1) and normal FEV1/forced vital capacity (FVC) and treated with an association of inhaled corticosteroids (ICSs) and long acting β2-agonists (LABAs). Clinical evaluation included the measurement of dyspnea, asthma control test and drug compliance.The prevalence of SAO was estimated by spirometry and plethysmography and defined by the presence of one or more of the following criteria: functional residual capacity (FRC) > 120% predicted (pred), residual volume (RV) > pred + 1.64 residual standard deviation (RSD), RV/total lung capacity (TLC) > pred + 1.64 RSD, forced expiratory flow (FEF)25–75% 10%.Among the 441 patients who were included, 222 had normal FEV1 and FEV1/FVC. At least one criteria of SAO was found in 115 (52%) mainly lung hyperinflation (39% based on high FRC, RV or RV/TLC) and more rarely distal airflow limitation (15% based on FEF25–75% or FEF50%) or expiratory trapping (10% based on increased SVC − FVC). In the patients with only SAO (no PAO), there was no relationship between SAO, asthma history and the scores of dyspnea, asthma control or drug compliance.These results suggest that in asthmatics with normal FEV1 and FEV1/FVC, treated with ICSs and LABAs, SAO is found in more than half of the patients indicating that the routinely used lung function tests can underestimate dysfunctions occurring in the small airways.

Background: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma.Objective: To evaluate safety and tolerability of tiotropium delivered via the Respimat (R) device, compared with placebo, each as add-on to at least ICS therapy, in a pooled sample of adults with symptomatic asthma at different treatment steps.Methods: Data were pooled from seven Phase H and III, randomised, double-blind, parallel-group trials of 12-52 weeks' treatment duration, which investigated once-daily tiotropium Respimat (R) (5 mu g, 2.5 mu g) versus placebo as add-on to different background maintenance therapy including at least ICS. Adverse events (AEs) including serious AEs were assessed throughout treatment + 30 days after the last dose of trial medication.Results: Of 3474 patients analysed, 2157 received tiotropium. The percentage of patients with AEs was comparable between treatment groups: tiotropium 5 mu g, 60.8%; placebo 5 mu g pool, 62.5%; tiotropium 2.5 mu g, 57.1%; placebo 2.5 mu g pool, 55.1%. Consistent with the disease profile, the most frequent AEs overall were asthma, decreased peak expiratory flow rate (both less frequent with tiotropium) and nasopharyngitis. Overall incidence of dry mouth, commonly associated with use of anticholinergics, was low: tiotropium 5 mu g, 1.0%; placebo 5 mu g pool, 0.5%; tiotropium 2.5 mu g, 0.4%; placebo 2.511g pool, 0.5%. The percentage of cardiac disorder AEs was comparable between tiotropium and placebo: tiotropium 5 jig, 1.4%; placebo 5 mu g pool, 1.4%; tiotropium 2.5 mu g, 14, 1.4%; placebo 2.5 mu g pool, 1.1%. The proportions of patients with serious AEs were balanced across groups: tiotropium 5 mu g, 4.0%; placebo 5 mu g pool, 4.9%; tiotropium 2.5 mu g, 2.0%; placebo 2.5 mu g pool, 33%.Conclusion: Tiotropium Respimat (R) demonstrated safety and tolerability comparable with those of placebo, as add-on to at least ICS therapy, at different treatment steps in adults with symptomatic asthma. (C) 2016 Elsevier Ltd. All rights reserved.

Resume Introduction Les exacerbations de bronchopneumopathie chronique obstructive (BPCO) sont une cause de souffrance pour les patients et une charge pour la societe. Leur prevention constitue un enjeu individuel et collectif. Cet article issu des travaux d’un groupe d’experts reunis en mai 2011 vise a mettre en exergue leur importance. Etat des connaissances En l’absence de critere facilement quantifiable, la definition des exacerbations varie dans la litterature, rendant leur identification difficile et influencant les resultats des etudes. Les exacerbations augmentent la mortalite, le risque de maladie cardiovasculaire et la survenue d’exacerbations. Elles accelerent le declin du VEMS, et contribuent a diminuer la masse musculaire. Elles handicapent le patient et degradent sa qualite de vie en limitant ses activites physiques quotidiennes et favorisant l’anxiete et la depression. Elles sont causes d’absenteisme au travail. Leur cout represente environ 60 % du cout de la BPCO. Perspectives Une identification precoce avec des criteres simples, eventuellement associes a des phenotypes particuliers de patients, pourrait permettre de mieux les prevenir et eviter les hospitalisations. Conclusions Les exacerbations ne doivent pas etre banalisees ni prises a la legere, en raison de leur impact immediat et differe. Leur prevention est un enjeu fondamental.

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results.

Eosinophilic pleural effusions have multiple aetiologies. We report on the case of a 40-year-old man who experienced an eosinophilic pleural effusion with blood hypereosinophilia that occurred nine weeks after a treatment with valproic acid was introduced. Usual aetiologies of eosinophilic pleural effusion were excluded. Once valproic acid was discontinued, both pleural effusion and blood eosinophilia decreased rapidly. The persistence of a residual pleural effusion required the introduction of oral corticosteroids, which resulted in the effusion disappearing completely and rapidly. Valproic acid is a rare cause of eosinophilic pleural effusion. The effusion usually regresses when treatment is discontinued but short-term oral corticotherapy may be necessary in order to heal the patient.

Resume La BPCO est aujourd’hui un enjeu majeur de sante publique avec une prevalence de 7,5 % en France. L’evaluation la plus precise des symptomes est au cœur d’une demarche clinique rationnelle afin d’evaluer au mieux l’impact des traitements. Malgre une comprehension des mecanismes physiopathologiques de plus en plus approfondie, les options therapeutiques restent limitees et beaucoup de patients demeurent symptomatiques. L’analyse des sous types phenotypiques et la selection de groupes de patients permet d’envisager des therapeutiques specifiques, plus adaptees a chaque patient.

Resume L’histoire naturelle de la bronchopneumopathie chronique obstructive (BPCO) se caracterise par une progression plus ou moins rapide de l’obstruction bronchique, une alteration de la qualite de vie et un risque accru de mortalite. Les symptomes de la BPCO sont domines par la toux, l’expectoration et la dyspnee dont la presence et l’intensite sont variables et inconstantes d’un sujet a l’autre au cours de l’evolution de la maladie. Les symptomes et l’histoire naturelle de la BPCO sont la resultante de lesions des voies respiratoires associant des modifications structurales et une inflammation qui debutent et predominent au niveau des voies aeriennes distales (VAD). Cet article examine les relations entre les symptomes et l’histoire naturelle de la BPCO a la lumiere des grandes etudes de cohorte publiees dans la litterature. Le role des VAD dans l’apparition et l’intensite des symptomes et l’histoire naturelle de la BPCO est difficile a preciser. Nous avons tente de cerner ce role a la lumiere des travaux ayant etudie soit les relations entre les lesions anatomopathologiques des VAD et le phenotype clinique des patients, soit les formes precoces de BPCO ou l’atteinte des VAD est predominante. Ces donnees suggerent l’interet de therapeutiques ciblant precocement les modifications structurales et l’inflammation des VAD chez les patients atteints de BPCO.

The natural history of cystic fibrosis (CF) may be associated both with acute respiratory complications (respiratory exacerbations, haemoptysis, pneumothorax) and with non-respiratory complications (distal intestinal obstruction syndrome, dehydration) that may result in hospitalizations. The aim of this article is to describe the main therapeutic approaches that are adopted in the management of acute complications occurring in CF adults, and to discuss indications for admission of these patients to intensive care units. Adult CF patients admitted to intensive care unit often benefit from antibiotic courses adapted to their chronic bronchial infection, especially when the hospitalization is related to respiratory disease (including haemoptysis and pneumothorax). Nutritional support, including hypercaloric diet, control of hyperglycemia and pancreatic enzyme supplementation is warranted. The recommended therapy for major haemoptysis is bronchial artery embolization. Patient with significant pneumothorax should have a chest tube inserted, while the treatment of distal intestinal obstruction syndrome will most often be medical. In case of respiratory failure, non-invasive ventilation is the preferred mode of ventilatory support because invasive ventilation is associated with poor outcomes. Therapeutic options should always have been discussed between the patient, family members and the CF medical team to allow for informed decision making.

To the Editors: Chronic obstructive pulmonary disease (COPD) is characterised by progressive and poorly reversible airflow obstruction due to small airway disease and emphysema. Cigarette smoking is the major cause of COPD, but the disease also occurs in nonsmokers. In nonsmokers, environmental factors ( e.g. second-hand smoking and inhalation of toxic gas), genetic factors ( e.g. the rare α1-antitrypsin deficiency) and infectious factors ( e.g. HIV infection) have been implicated in the pathogenesis of the disease. We report on two cases of COPD with emphysema in nonsmokers with long-standing undiagnosed coeliac disease. A 71-yr-old female was referred to our hospital (Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France) for dyspnoea and cough, which had evolved over 5 yrs. She had suffered from alternating diarrhoea and constipation for many years, ascribed to functional bowel disease. She had never been exposed to inhaled toxics and had never smoked. Examination revealed a body mass index (BMI) of 18 kg·m−2 and a chest computed tomography (CT) image revealed pulmonary distension and emphysema (fig. 1). Spirometry revealed severe airflow limitation (table 1). Serum α1-antitrypsin was normal. Treatment with long-acting bronchodilators was initiated. After 7 yrs of follow-up, the patient complained of progressive weight loss (BMI 15 kg·m−2 …

Two strategies are possible for targeting distal airways in asthma. The first one is systemic, with the delivery of medications either orally or intravenously. Montelukast is the only oral drug that has demonstrated its efficacy on distal airways by reducing lung hyperinflation. The second possible strategy is to deliver inhaled medications using ultrafine particles. Studies performed with formoterol-HFA solution (Formoair Modulite), the only available long-acting beta2 agonist with ultrafine particles have shown a non-inferior bronchodilator effect and a good tolerance as compared to inhaled long acting beta2 agonists with non-ultrafine particles. Studies performed with BDP-HFA alone (QVAR) or combined BDP-HFA/formoterol (Fostair) with ultrafine particles have mostly demonstrated their clinical non- inferiority on bronchodilation, quality of life, and symptoms in asthmatic subjects as compared to non-ultrafine inhaled medications. With the exception of a few studies, most publications have been performed in a limited number of patients and for only short durations. The available studies have not yet demonstrated a long-term benefit in terms of additional clinical efficacy of these ultrafine inhaled medications on symptoms, control and exacerbations of asthma.

The aims of the present study were to identify prognostic factors for systemic sclerosis (SSc)-related interstitial lung disease and to clarify the possible causative role of manometric oesophageal involvement. Consecutive SSc patients underwent pulmonary function tests and oesophageal manometry. They were included in the study if pulmonary function tests were repeated12 months after baseline. The primary end-point was a decrease ofor=10% of the predicted value in forced vital capacity (FVC). The secondary end-points were a decrease ofor=15% pred in lung carbon monoxide diffusing capacity (D(L,CO)) and a decrease ofor=20% pred in FVC. Of the 105 patients (45 diffuse SSc; median disease duration 2.0 yrs), 23 (23%) had a FVC of80% pred, 60 (59%) had a D(L,CO) of80% pred and 57 (54%) showed severe oesophageal hypomotility at baseline. Over 72+/-46 months, 29 (28%) patients displayed a decrease ofor=10% pred in FVC, 39 (40%) of 98 patients displayed D(L,CO) decline and 19 (18%) patients displayed a decrease ofor=20% pred in FVC. On multivariate analysis, diffuse SSc was a significant predictor for a decrease ofor=10% pred in FVC (p = 0.01). No other predictor of a decrease in pulmonary function was identified. Only diffuse SSc was predictive of a decrease in pulmonary function in this early-SSc cohort. This does not support preliminary data suggestive of a causative role of oesophageal involvement.

The present review is the summary of an expert workshop that took place in Vence (France) in 2007 on the role of distal airways in asthma. The evidence showing inflammation and remodelling in distal airways, and their possible involvement in asthma control and natural history, was reviewed. The usefulness and limitations of various techniques used for assessing distal airways were also evaluated, including pulmonary function tests and imaging. Finally, the available data studying the benefit of treatment better targeting distal airways in asthma was examined. It was concluded that both proximal and distal airways were involved in asthma and that distal airways were the major determinant of airflow obstruction. Inflammation in distal airways appeared more intense in severe and uncontrolled asthma. Distal airways were poorly attained by conventional aerosol of asthma medications owing to their granulometry, being composed of 3-5emsp14;μm particles. Both proximal and distal airways might be targeted either by delivering medications systemically or by aerosol of extra-fine particles. Extra-fine aerosols of long-acting β-agonists, inhaled corticosteroids or inhaled corticosteroid/long-acting β-agonist combinations have been shown in short-term studies to be not inferior to non-extra-fine aerosols of comparators. However, available studies have not yet demonstrated that extra-fine inhaled medications offer increased benefit compared with usual aerosols in asthmatic patients.

Introduction La mucoviscidose est habituellement diagnostiquee dans les premieres annees de vie. Observations Nous rapportons trois cas familiaux de mucoviscidose diagnostiques a l’âge adulte. Le premier patient, âge de 39 ans, a consulte pour une infertilite par atresie des canaux deferents ; le diagnostic de mucoviscidose a ete retenu devant la positivite du test de la sueur et la presence de deux mutations du gene CFTR. La mere de ce patient presentait des surinfections bronchiques a repetition depuis l’enfance. Le test de la sueur etait normal, la mesure de la difference de potentiel nasal transepithelial etait evocatrice de la maladie et la recherche des 33 mutations les plus frequentes de CFTR ne retrouvait qu’une seule mutation. Le sequencage complet du gene CFTR qui a montre une seconde mutation, et affirme le diagnostic de mucoviscidose a 74 ans. L’enquete familiale a revele un cas de mucoviscidose pauci-symptomatique chez un frere du cas index. Conclusions Ces observations illustrent les difficultes du diagnostic des formes attenuees de mucoviscidose a l’âge adulte. Nous discutons les modalites du diagnostic ainsi que l’interet de ce diagnostic pour adapter les therapeutiques et pour le conseil genetique.

L’impact des traitements medicamenteux sur l’histoire naturelle de la BPCO et sur ses trois principales composantes (declin du VEMS, de la qualite de vie et survie) differe selon le stade de la maladie ; la prise en charge des comorbidites est essentielle. Cette presentation reprend la litterature portant sur les strategies medicamenteuses de la BPCO et les nouvelles perspectives therapeutiques.

Resume La pleuresie eosinophile est definie par un taux de polynucleaires eosinophiles dans la plevre superieur a 10 %. Elle peut etre observee dans toutes les causes d’epanchement pleural, mais certaines etiologies, de par leur frequence ou leur potentiel de gravite, doivent systematiquement etre recherchees. La presence d’air ou de sang dans la cavite pleurale constitue la premiere cause a evoquer. Une pneumopathie bacterienne, une tuberculose et certaines parasitoses doivent etre recherchees, de meme que certaines prises medicamenteuses. Bien que souvent consideree comme marqueur de benignite, l’eosinophilie pleurale est frequemment associee a des neoplasies ou a des hemopathies. Enfin, la pleuresie eosinophile peut apparaitre dans l’evolution de certaines vascularites, comme le syndrome de Churg et Strauss, et parfois en etre une manifestation revelatrice. Nous rapportons l’observation d’un homme de 27 ans, asthmatique, qui a developpe un epanchement pleural eosinophile revelant un syndrome de Churg et Strauss devant l’association d’un asthme, d’une hypereosinophilie sanguine et sur le lavage bronchioloalveolaire, d’une myopericardite et d’anticorps anticytoplasme des polynucleaires neutrophiles (ANCA) positifs. Cette observation permet de discuter les differentes etiologies a rechercher devant un epanchement pleural eosinophile et illustre le fait qu’une pleuresie eosinophile peut etre une manifestation d’un syndrome de Churg et Strauss.

Rationale: Little knowledge exists on structural changes and plugging in small airways in cystic fibrosis. Objective: To characterise the extent of plugging and contribution of secreted mucins to the plugs. Methods: Small airways in patients with cystic fibrosis at transplantation (n = 18) were compared with control non-smokers (n = 10). Tissue sections were stained with Alcian blue (AB)/periodic acid-Schiff (PAS), for mucins MUC5B and MUC5AC, and for neutrophils and its chemoattractant interleukin (IL) 8. Epidermal growth factor receptor (EGFR) and its ligand pro-transforming growth factor α were also identified using immunohistochemical staining. Epithelial and luminal contents were assessed morphometrically. Results: Plugs occupying >50% of total luminal volume were found in 147 of 231 (63.6%) airways in patients with cystic fibrosis, but only in 1 of 39 (2.6%) airways in controls. In the epithelium of patients with cystic fibrosis, AB/PAS, MUC5B, and MUC5AC-stained volume densities were increased 10-fold (p

Background Body composition (BC) analysis based on bioelectrical impedance analysis (BIA) provides conflicting results. The purpose of the study was to validate an equation specific for young patients with cystic fibrosis (CF), describe their BC and investigate its association with lung function. Methods Fifty-four young CF patients were evaluated by BIA and dual X-ray absorptiometry (DXA). An empirically derived CF-specific equation for fat-free mass (FFM) estimation by BIA was elaborated after stepwise multivariate regression and the agreement between BIA and DXA was assessed by Bland–Altman plots. The association between BC and lung function was investigated by regression analysis. Results The mean difference between the BIA and DXA assessment was close to zero. A total of 22.5% of patients ( n =9) presented a FFM z -score≤−2. They had a worse pulmonary function and diaphragmatic impairment. Among these 9 patients, 7 had a normal BMI z -score>−1. Conclusions BIA, based on a CF-specific equation, is a reliable method for BC assessment and allows the identification of patients at risk of nutritional degradation and bad respiratory prognosis.

Patients with chronic obstructive pulmonary disease (COPD) who were naive to anticholinergics before the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial may reflect patients seen in practice, in particular in primary care. In addition, investigating safety in these patients avoids the potential bias in patients who previously received anticholinergics and may be tolerant of their effects. The aim of this study was to evaluate whether patients naive to anticholinergic therapy who were treated with tiotropium Respimat 2.5 or 5 μg had different safety and efficacy outcomes than patients treated with tiotropium HandiHaler 18 μg. A post hoc analysis of patients who were not receiving anticholinergics before TIOSPIR (N=6,966/17,135) was conducted. Primary end points were risk of death from any cause and risk of COPD exacerbation. Secondary outcomes included severe exacerbation and major adverse cardiovascular events (MACE). Additional analysis of exacerbations was carried out in anticholinergic-naive patients with moderate (GOLD II) disease. Anticholinergic-naive patients had less severe disease than the total TIOSPIR population. Discontinuations because of anticholinergic side effects were infrequent (0.9% overall). Similar to the primary study, patients in the tiotropium Respimat groups had no difference in the risk of death or risk of any or severe exacerbation than patients treated with tiotropium HandiHaler. Risk of MACE was similar across the Respimat and HandiHaler groups. Rates of exacerbations in the subgroup of patients with moderate disease were similar across the Respimat and HandiHaler groups. Tiotropium Respimat and HandiHaler have similar safety and efficacy profiles in patients who are naive to anticholinergic therapy. Inhaled forms of the drug tiotropium are safe and effective for patients with chronic lung disease. Breathing difficulties caused by chronic obstructive pulmonary disease (COPD) can be treated using the 'anticholinergic' drug tiotropium, which works by enlarging the patient's airways. Tiotropium is available as a dry powder or aqueous solution inhaler. The inhaler was recently confirmed as safe in randomized trials, however, there were concerns that the trials did not verify safety and efficacy for patients new to anticholinergic therapy. Robert Wise at Johns Hopkins University School of Medicine in Baltimore, USA, and co-workers tested two inhaled forms of tiotropium on 6,966 COPD patients new to anticholinergics. Their results indicated both inhalers were effective and presented low risks of death, heart problems or other side effects, regardless of previous exposure to anticholinergics.

Background Tiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups. Methods TIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial. Results The substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV1 (average 24–120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: −10 [−38, 18] mL for Respimat® 5 μg and, −37 [−65, −9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not. Conclusions The TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV1, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction. Trial registration NCT01126437. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0269-4) contains supplementary material, which is available to authorized users.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g.post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host–microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways.

Resume Introduction Faire le point sur l’etat des connaissances de la litterature sur l’asthme leger (asthme intermittent et persistant leger selon le GINA). Etat des connaissances Un Groupe de Travail (11 pneumologues, 4 pediatres, 1 pharmacologue, 1 medecin generaliste) a selectionne, analyse, et resume la bibliographie sur l’epidemiologie descriptive, la physiopathologie, la clinique, et le traitement de l’asthme leger. Le point de vue du groupe de travail sur l’epidemiologie descriptive (facteurs causaux exclus) et la nature de l’inflammation bronchique a ete presente dans un premier article. Ce second article s’interesse aux signes cliniques et aux traitements medicamenteux de l’asthme leger. Perspectives L’asthme leger est plus frequent, plus symptomatique, et moins bien controle chez l’enfant que chez l’adulte. D’evolution generalement benigne, il peut parfois ( Conclusions L’asthme leger est sous-represente dans la litterature medicale et les recommandations therapeutiques au regard de sa prevalence. Les donnees presentees devraient permettre de guider les cliniciens dans leur prise en charge therapeutique de l’asthme leger.

Resume Introduction Faire le point sur l’etat des connaissances de la litterature sur l’asthme leger (asthme intermittent et persistant leger selon le GINA). Etat des connaissances Un groupe de travail (11 pneumo-logues, 4 pediatres, 1 pharmacologue, 1 medecin generaliste) a selectionne, analyse, et resume la bibliographie sur l’epidemiologie, la physiopathologie, la clinique, et le traitement de l’asthme leger. Cet article donne le point de vue du groupe de travail sur l’epidemiologie descriptive (facteurs causaux exclus) et la nature de l’inflammation bronchique. Les signes cliniques et les traitements medicamenteux feront l’objet d’une publication specifique. Perspectives L’asthme leger concerne selon les etudes 50 % a 75 % des patients asthmatiques. Le suivi des cohortes de l’enfance a l’âge adulte indique que le stade de severite reste inchange au cours du temps. D’evolution generalement benigne, l’asthme leger peut parfois ( Conclusion Les donnees presentees devraient aider les cliniciens a mieux identifier et comprendre l’asthme leger.

We retrospectively studied the outcomes of adult patients with cystic fibrosis (CF) hospitalized for severe pulmonary exacerbations (69 cases) between January 1997 and June 2001. Cases were treated either in the Pulmonary Department (n = 46) or in the intensive care unit (ICU) (n = 23) depending on severity. Noninvasive mechanical ventilation was used in 61% (14 of 23) and 33% (15 of 46) of cases treated in the ICU and the Pulmonary Department groups, respectively. Invasive ventilation was necessary in 4 of 23 cases treated in the ICU. The 1-year survival rate was 52% (12 of 23) and 91% (42 of 46) in the ICU and the Pulmonary Department groups, respectively. Lung transplantation was performed in two patients from the ICU group and in five patients from the Pulmonary Department group after hospital discharge. Factors predictive of death were prior colonization with Burkholderia cepacia and rapid decline in FEV1 before admission and severity of exacerbations (severity of hypoxemia and hypercapnia, simplified acute physiology score II and logistic organ dysfunction (LOD) scores, requirement of noninvasive mechanical ventilation, and hospitalization in the ICU) in the univariate analysis and were prior colonization with B. cepacia, the severity of hypoxemia at admission, and hospitalization in the ICU in the multivariate analysis. In 1-year survivors, pulmonary exacerbation did not affect the progression of the disease.

Background: Pressurized metered-dose inhalers (pMDIs) have traditionally used CFCs as propellants. However, the worldwide phase-out of CFCs has necessitated the development of new pMDIs that use alternative propellants. One such replacement is the hydrofluoroalkane HFA-134a. Objectives: This study sought to establish the clinical non-inferiority of a new HFA-134a-containing pMDI to a conventional dry powder inhaler (DPI) in the administration of formoterol to adult patients with moderate-to-severe, stable persistent asthma. The secondary aim was to collect safety data in a multiple-dose long-term study. Methods: During this multicenter, double-blind, parallel study, 500 patients were randomized to receive 12 µg of formoterol twice daily for 12 weeks via either an HFA pMDI or a DPI. If necessary, the dose could be increased to 24 µg twice daily. At baseline, all patients (aged 18–70 years) had an FEV1 40–80% of predicted and a documented positive response to the reversibility test. Results: After 12 weeks’ therapy, the adjusted mean morning PEFR was 343.69 l/min in the formoterol HFA pMDI group and 344.56 l/min in the formoterol DPI group. Because the lower limit of the 95% CI for the between-group difference (–11.64 l/min) was well within the non-inferiority margin (–20 l/min), the HFA device was deemed clinically non-inferior to the DPI device. This finding was confirmed when evening PEFR and FEV1 were assessed. Both formulations of formoterol were well tolerated during prolonged multiple dosing. Conclusions: This study provides evidence that the new HFA-formulated formoterol pMDI has a similar efficacy and safety profile to the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma.

Background: This study was conducted to determine whether the major nasal airway ion transport abnormalities in cystic fibrosis (that is, defective cAMP regulated chloride secretion and basal sodium hyperabsorption) are related to the clinical expression of cystic fibrosis and/or to the genotype. Methods: Nasal potential difference was measured in 79 adult patients with cystic fibrosis for whom clinical status, respiratory function, and CFTR genotype were determined. Results: In univariate and multivariate analysis, patients with pancreatic insufficiency were more likely to have low responses to low chloride (odds ratio (OR) 8.6 (95% CI 1.3 to 58.5), p = 0.03) and isoproterenol (OR 11.2 (95% CI 1.3 to 93.9), p = 0.03) solutions. Similarly, in univariate and multivariate analysis, patients with poor respiratory function (forced expiratory volume in 1 second

Resume L’enquete transversale « Compli’Asthme », realisee en 2000 avec l’appui de la visite medicale Chiesi SA aupres de 1 758 medecins francais prenant en charge des patients asthmatiques persistants (80 % de generalistes, 20 % de specialistes) permettait aux praticiens de decrire au moyen d’un questionnaire auto-administre leur perception, leurs connaissances et leur experience de l’observance therapeutique, de la corticophobie et de l’usage des dispositifs inhalateurs qu’ils prescrivent a leurs patients. La mauvaise observance therapeutique est percue par 58 a 85 % de l’echantillon comme un probleme frequent, principalement cause par l’inaptitude a utiliser le dispositif inhalateur (enfants, sujets âges) ou lie a l’oubli accidentel des medicaments (adulte, parents). Pour 58 % des medecins interroges, la corticophobie est une preoccupation frequente du patient et les principales craintes des patients sont les effets anabolisants, la peur diffuse des effets secondaires et la dependance au traitement. En cas de corticophobie, le praticien declare interroger le patient, lui donner des explications et maintenir le traitement. Quatre-vingt six pour cent des medecins ont declare prendre en compte les preferences de leurs patients lorsqu’ils prescrivaient le dispositif inhalateur, 90 % faire une demonstration du dispositif lors de la premiere prescription et 68 % refaire des demonstrations iteratives. Pour 56 a 87 % des medecins interroges, la mauvaise observance therapeutique, la corticophobie, le mauvais usage du dispositif inhalateur pouvaient etre depistes et corriges. Soixante-dix sept pour cent des medecins reconnaissaient en l’education du patient un facteur essentiel pour ameliorer l’observance therapeutique et le bon usage de l’inhalateur. En cas de mauvaise observance des traitements inhales et de mauvais usage des inhalateurs par les patients, les attitudes declarees des medecins de l’echantillon suivaient les recommandations en vigueur.

FREE FULL TEXT http://erj.ersjournals.com/cgi/content/full/21/4/574; Inhaled fluticasone propionate (FP) is widely used to reduce pulmonary inflammation in chronic obstructive pulmonary disease, but the potential effects of FP on airway epithelial cells from patients with cystic fibrosis (CF) are unknown. In CF disease, a nonregulated inflammatory lung response occurs through exaggerated nuclear factor (NF)-kappaB activation and elevated pro-inflammatory cytokines production by airway epithelial cells. To determine whether FP reduces cytokine production in bronchial epithelial cells via NF-kappaB, the authors investigated the nonstimulated and the Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulated production of NF-kappaB-dependent interleukin (IL)-6, IL-8 and RANTES (regulated on activation, T-cell expressed and secreted) along with the activation of NF-kappaB in non-CF and CF human bronchial gland epithelial cells. It was demonstrated that a relevant concentration of FP (10(-8) M) inhibited constitutive and P. aeruginosa LPS-induced IL-6 and IL-8 production of non-CF and CF bronchial epithelial cells. Interestingly, the expression of two IkappaB kinases (IKK)-alpha/beta, the degradation of cytosolic IkappaB-beta inhibitor and the NF-kappaB deoxyribonucleic acid binding activity were markedly reduced after FP treatment in both CF and non-CF bronchial epithelial cells. It was shown by the authors that fluticasone propionate exerts an anti-inflammatory effect by blocking a signal transduction leading to a reduced level of IkappaB-alpha/beta kinases in bronchial epithelial cells. In particular the strong effect on the IkappaB-beta kinase, which is known to be elevated in bronchial epithelial cells in cystic fibrosis patients, was observed.

Purpose: To assess the follow-up of patients with sarcoidosis and myocardial MRI abnormalities. Materials and methods: Twelve patients with histologically proven sarcoidosis and highly suspected cardiac involvement underwent initial and 12-month follow-up cardiac assessment including cardiac MRI (T2-weighted, functional gradient echo, and T1-weighted gadoliniumdiethylenetriamine penta-acetic acid-enhanced sequences). MRI abnormalities and clinical and MRI progression were scored by two observers. Results: Six patients receiving corticosteroid therapy (including three patients with clinical cardiac involvement) were scored as having cleared or improved at MRI follow-up, while others were seen to have worsened or remained stable. The stability, improvement, or clearing of MRI findings were correlated with clinically stable, improved or cleared sarcoidosis, while a worsening at MRI follow-up was correlated with a worsening of sarcoidosis and, in one patient, was predictive of clinical cardiac involvement. Conclusion: Cardiac MRI is a useful noninvasive method for the early diagnosis and follow-up of cardiac sarcoidosis. (CHEST 2002; 122:1895–1901)

International audience; Severe emphysema is a difficult to treat condition with limited efficacy of currently available treatments. Endobronchial coil treatment (ECT) is a minimally invasive endobronchial treatment which consists of placing shape-memory nitinol coils in emphysematous lobes to enhance lung recoil and reduce lung hyperinflation at rest and during exercise [1, 2]. Randomised studies demonstrated an improvement in exercise capacity, lung function and quality of life, and showed an acceptable safety profile at 1 year [3–6]. However, to our best knowledge, longer term safety and effectiveness results beyond 1 year have not been reported thus far.REVOLENS (Réduction volumique endobronchique par spirales) (NCT01822795) is a 1:1 randomised controlled study of 100 patients (50 patients treated with coils and optimal medical management and 50 patients treated with optimal medical management only) in 10 centres across France. Patients treated with optimal medical management only were offered coil treatment after 1 year. The study protocol [7] and 1-year results [5] of the REVOLENS study have been previously described, demonstrating a decrease in lung hyperinflation and improvement in quality of life. In the present study, we analysed efficacy and safety data at 2 years in the 50 patients randomised to the ECT group.

60 Evaluation of twice-a-year antibiotic susceptibility testing for Pseudomonas aeruginosa in adult patients with cystic fibrosis P.C. Morand1,2, J. Chapron1,3, J. Loubinoux1,2, I. Honore1,3, H. Poupet2, R. Kanaan1,3, P.-R. Burgel1,3, C. Poyart1,2, D. Dusser1,3, D. Hubert3. 1Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; 2Assistance PubliqueHopitaux de Paris, Hopital Cochin, Bacteriology, Paris, France; 3Assistance Publique-Hopitaux de Paris, Hopital Cochin, Service de Pneumologie and Adult CF Centre, Paris, France