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Clémence Martin,1,2 Pierre-Régis Burgel,1,2 Nicolas Roche1,2 1AP-HP Centre, Hôpital Cochin, Service de Pneumologie, Paris, France; 2Université de Paris, Institut Cochin, INSERM UMR 1016, Paris, FranceCorrespondence: Nicolas RocheService de Pneumologie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, Paris, F-75014, FranceTel +33 1 58 41 21 53Fax +33 1 58 41 22 60Email nicolas.roche@aphp.frAbstract: Current pharmacological treatments for chronic obstructive pulmonary disease (COPD) are mostly limited to inhaled bronchodilators and corticosteroids. Azithromycin can contribute to exacerbation prevention. Roflumilast, a phosphodiesterase (PDE) 4 inhibitor administered orally, also prevents exacerbations in selected patients with chronic bronchitis, recurrent exacerbations, severe airflow limitation and concomitant therapy with long-acting inhaled bronchodilators. This outcome likely results from anti-inflammatory effects since PDE4 is expressed by all inflammatory cell types involved in COPD. The use of this agent is, however, limited by side-effects, particularly nausea and diarrhea. To address remaining unmet needs and enrich therapeutic options for patients with COPD, inhaled dual PDE3/4 inhibitors have been developed, with the aim of enhancing bronchodilation through PDE3 inhibition and modulating inflammation and mucus production though PDE4 inhibition, thus producing a potentially synergistic effect on airway calibre. Experimental preclinical data confirmed these effects in vitro and in animal models. At present, RPL554/ensifentrine is the only agent of this family in clinical development. It decreases sputum markers of both neutrophilic and eosinophilic inflammation in patients with COPD. Clinical Phase II trials confirmed its bronchodilator effect and demonstrated clinically meaningful symptom relief and quality of life improvements in these patients. The safety profile appears satisfactory, with less effects on heart rate and blood pressure than salbutamol and no other side effect. Altogether, these data suggest that ensifentrine could have a role in COPD management, especially in addition to inhaled long-acting bronchodilators with or without corticosteroids since experimental studies suggest potentiation of ensifentrine effects by these agents. However, results from ongoing and future Phase III studies are needed to confirm both beneficial effects and favourable safety profile on a larger scale and assess other outcomes including exacerbations, lung function decline, comorbidities and mortality.Keywords: COPD, phosphodiesterase inhibitors, bronchodilation, inflammation, mucus, epithelium

Faustine Dalon,1 Nicolas Roche,2 Manon Belhassen,1 Maëva Nolin,1 Hervé Pegliasco,3 Gaëtan Deslée,4 Bruno Housset,5 Philippe Devillier,6 Eric Van Ganse1,7–81Pharmacoepidemiology Department, PELyon, Lyon, France; 2Respiratory Medicine, Cochin Hospital, AP-HP and Paris Descartes University (EA2511), Sorbonne Paris Cité, Paris, France; 3Pulmonary Department, European Hospital, Marseille, France; 4Pulmonary Department, INSERM U1250, Maison Blanche University Hospital, Reims, France; 5Pulmonary Department, CHI de Créteil, University Paris Est Créteil, Créteil, France; 6Department of Airway Diseases, UPRES EA 220, Foch Hospital, Paris-Saclay University, Suresnes, France; 7EA 7425 Hesper Health Services and Performance Research, Claude-Bernard University, Lyon, France; 8Respiratory Medicine, Croix-rousse Hospital, Lyon, FranceCorrespondence: Faustine DalonPELyon, 11 Rue Guillaume Paradin, Lyon 69008, FranceTel +33 47 877 1024Fax +33 47 877 8660Email faustine.dalon@univ-lyon1.frPurposes: Following a hospitalization for COPD, dual and triple therapies were compared in terms of persistence and relations with outcomes (exacerbations, health care resource use and costs).Methods: This was a historical observational database study. All patients aged ≥45 hospitalized for COPD between 2007 and 2015 were identified in a 1/97th, random sample of French claims data. Patients receiving dual therapy within 60 days after hospitalization were compared to patients receiving triple therapy, after propensity score matching on disease severity.Results: Of the 3,089 patients hospitalized for COPD, 1,538 (49.8%) received either dual or triple therapy in the 2 months following inclusion, and 1,500 (48.6%) had at least 30 days of follow-up available; 846 (27.4%) received dual therapy, and 654 (21.2%) received triple therapy. After matching, the number of exacerbations was 2.4 per year in the dual vs 2.3 in the triple group (p=0.45). Among newly treated patients (n=206), persistence at 12 months was similar in the dual and triple groups (48% vs 41%, respectively, p=0.37). As compared to patients on dual therapy, more patients on triple therapy received oral corticosteroids (49.1 vs 40.4%, p=0.003) or were hospitalized for any reason (67%vs 55.8%, p=0.0001) or for COPD (35.3 vs 25.1%, p=0.0002) during follow-up. Cost of care was higher for patients on triple than for those on dual therapy (€11,877.1 vs €9,825.1, p=0.01).Conclusion: Following hospitalizations for COPD, patients on dual and triple therapy experienced recurrent exacerbations, limited adherence to therapies and high cost of care. Patients on triple therapy appeared more severe than those on dual therapy, as reflected by exacerbations and health care resource use.Keywords: COPD, therapy, persistence, exacerbations, health care resource use

Omar S Usmani,1 Nicolas Roche,2 Martin Jenkins,3 Neda Stjepanovic,4 Peter Mack,5 Wilfried De Backer6 1National Heart and Lung Institute (NHLI), Imperial College London, and Royal Brompton Hospital, London, UK; 2Respiratory Medicine, Cochin Hospital, University Paris Descartes, Paris, France; 3AstraZeneca, Cambridge, UK; 4AstraZeneca, Gothenburg, Mölndal, Sweden; 5AstraZeneca, Durham, NC, USA; 6Department of Pulmonary Medicine, Faculty of Medicine, University of Antwerp, Antwerp, BelgiumCorrespondence: Wilfried De BackerDepartment of Pulmonary Medicine, Faculty of Medicine, University of Antwerp, Lange Lozanastraat 142, Antwerp 2018, BelgiumTel +32 468 195206Email wilfried.debacker@uantwerpen.beAbstract: Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug–drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.Keywords: Aerosphere, BGF MDI, co-suspension delivery technology, FRI, GFF MDI, metered dose inhaler

Thibaud Soumagne,1 Alicia Guillien,2 Nicolas Roche,3 Isabella Annesi-Maesano,4 Pascal Andujar,5,6 Lucie Laurent,1 Stéphane Jouneau,7,8 Martial Botebol,9 Jean-Jacques Laplante,10 Jean-Charles Dalphin,1,11 Bruno Degano12,13 1Service de Pneumologie, Oncologie Thoracique et Allergologie Respiratoire, CHU de Besançon, Besançon, France; 2Equipe d’Epidémiologie Environnementale, Institute for Advanced Biosciences, Centre de Recherche UGA, INSERM U1209, CNRS UMR 5309, Grenoble, France; 3Service de Pneumologie, Groupe Hospitalier Cochin, Site Val de Grâce, AP-HP and Université Paris Descartes (EA2511), Sorbonne-Paris-Cité, Paris, France; 4Epidemiology of Allergic and Respiratory Diseases UMR-S 707 Inserm/UPMC, Université Paris 6, Paris, France; 5Centre Hospitalier Intercommunal de Créteil, Service de Pathologie Professionnelle et de l’Environnement, Créteil, France; 6Université Paris-Est Créteil, Faculté de Médecine, Créteil, France; 7Service de Pneumologie, CHU de Rennes, Rennes, France; 8Univ Rennes, CHU Rennes, Inserm, EHESP, Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) – UMR-S 1085, Rennes, France; 9Fédération des Maisons de Santé Comtoises (FéMaSaC), Beure, France; 10Mutualité Sociale Agricole (MSA), Besançon, France; 11UMR CNRS Chrono Environnement, Université de Franche-Comté, Besançon, France; 12Service Hospitalier Universitaire Pneumologie Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble, Alpes, France; 13Université Grenoble Alpes, INSERM U 1042, Grenoble, FranceCorrespondence: Thibaud Soumagne Email thibaud_soumagne@live.frBackground: Comorbidities including cardiovascular diseases are very common in chronic obstructive pulmonary disease (COPD) secondary to tobacco smoking and contribute to the overall severity of the disease. In non-smoking COPD, which accounts for about 25% of COPD cases worldwide, current knowledge on the frequency and determinants of comorbidities remains scarce. The aims of the current study were to assess the frequency of major comorbidities and to evaluate their determinants in a group of non-selected patients with mild-to-moderate COPD who were exposed to organic dust (dairy farmers), to tobacco smoking, or to both, and in controls without COPD who were exposed to organic dust (dairy farmers), or to tobacco smoking, or to both, or who were without exposure.Patients and Methods: A total of 4665 subjects (2323 dairy farmers and 2342 non-farmers) including 355 patients with COPD and 4310 controls with normal spirometry were recruited through a large COPD screening program. Self-reported physician-diagnosed diseases with plausible links to COPD were recorded in this cross-sectional study.Results: Whatever the exposure, cardiovascular comorbidities were not more frequent in patients with COPD than their counterparts without airflow limitation. A higher risk of major cardiovascular comorbidities was associated with tobacco smoking and a lower risk was associated with exposure to organic dusts.Conclusion: Tobacco smoking (but not COPD) is associated with higher frequency of cardiovascular comorbidities. By contrast, being a dairy farmer exposed to organic dusts is associated with a lower frequency of the same comorbidities. This reinforces the crucial need for controlling established cardiovascular risk factors even in patients with mild-to-moderate COPD.Keywords: cardiovascular diseases, chronic obstructive pulmonary disease, comorbidity, diabetes mellitus, tobacco smoking

Filipe Froes,1 Nicolas Roche,2 Francesco Blasi3,4 1Chest Department, Hospital Pulido Valente, North Lisbon Hospital Center, Lisbon, Portugal; 2Department of Respiratory and Intensive Care Medicine, Cochin Hospital, Paris Descartes University, Paris, France; 3Department of Pathophysiology and Transplantation, University of Milan, 4Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS ca Granda Ospedale Maggiore Policlinico, Milan, Italy Abstract: Patients with COPD and other chronic respiratory diseases are especially vulnerable to viral and bacterial pulmonary infections, which are major causes of exacerbations, hospitalization, disease progression, and mortality in COPD patients. Effective vaccines could reduce the burden of respiratory infections and acute exacerbations in COPD patients, but what is the evidence for this? This article reviews and discusses the existing evidence for pneumococcal vaccination efficacy and its changing role in patients with chronic respiratory diseases, especially COPD. Specifically, the recent Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) showed the efficacy of pneumococcal conjugate vaccine in older adults, many of whom had additional risk factors for pneumococcal disease, including chronic lung diseases. Taken together, the evidence suggests that pneumococcal and influenza vaccinations can prevent community-acquired pneumonia and acute exacerbations in COPD patients, while pneumococcal vaccination early in the course of COPD could help maintain stable health status. Despite the need to prevent pulmonary infections in patients with chronic respiratory diseases and evidence for the efficacy of pneumococcal conjugate vaccine, pneumococcal vaccine coverage and awareness are low and need to be improved. Respiratory physicians need to communicate the benefits of vaccination more effectively to their patients who suffer from chronic respiratory diseases. Keywords: COPD, COPD exacerbation, infection, pneumococcal vaccine