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Competing Interests: Declaration of interests Bourdin A: GSK—non-financial support during the conduct of the study; Acceleron Pharma, Actelion, Galapagos, Merck Sharp & Dohme, Nuvaira, Pulmonx, United Therapeutics, Vertex Pharmaceuticals—other; Boehringer Ingelheim—grants, personal fees; AstraZeneca, Chiesi, GSK, Regeneron Pharmaceuticals Inc., Sanofi—personal fees. Bergougnoux A: no conflict of interest. Lahmar Z: no conflict of interest.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease involving airway closure and parenchyma destruction (emphysema). Cardiovascular diseases are the main causes of morbi-mortality in COPD and, in particular, hypertension and heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link has currently been established between the onset of COPD, elevated blood pressure (BP) and systemic vascular impairment (endothelial dysfunction). Thus, we aimed to characterize BP and vascular function and remodeling in a rat model of exacerbated emphysema focusing on the role of sympathetic hyperactivity. Emphysema was induced in male Wistar rats by four weekly pulmonary instillations of elastase (4UI) and exacerbation by a single dose of lipopolysaccharides (LPS). Five weeks following the last instillation, in vivo and ex vivo cardiac and vascular functions were investigated. Exacerbated emphysema induced cardiac dysfunction (HFpEF) and a BP increase in this COPD model. We observed vasomotor changes and hypotrophic remodeling of the aorta without endothelial dysfunction. Indeed, changes in contractile and vasorelaxant properties, though endothelium-dependent, were pro-relaxant and NO-independent. A β1-receptor antagonist (bisoprolol) prevented HFpEF and vascular adaptations, while the effect on BP increase was partial. Endothelial dysfunction would not trigger hypertension and HFpEF in COPD. Vascular changes appeared as an adaptation to the increased BP. The preventing effect of bisoprolol revealed a pivotal role of sympathetic hyperactivation in BP elevation. The mechanistic link between HFpEF, cardiac sympathetic activation and BP deserves further studies in this exacerbated-emphysema model, as well as in COPD patients.

Chronic obstructive pulmonary disease (COPD) is a clinical entity of increasing significance. COPD involves abnormalities of the airways and, in emphysema, parenchymal pulmonary destruction. Cardiovascular disease has emerged as a significant comorbidity to COPD. Heart failure with preserved ejection fraction (HFpEF) appears to be particularly associated with COPD-emphysema. Traditional treatments have shown limited efficacy in improving COPD-associated HFpEF. This lack of therapeutic efficacy highlights the need to identify potential mechanisms that link COPD-emphysema to HFpEF. Therefore, we aimed to study the delayed cardiac physiological impacts in a rat model with acute exacerbated emphysema. Emphysema was induced by four weekly 4 units elastase (ELA) intratracheal pulmonary instillations and exacerbation by one final additional lipolysaccharide (LPS) instillation in male Wistar rats. At 5 weeks after the ELA and LPS exposure, in vivo and ex vivo pulmonary and cardiac measurements were performed. Experimental exacerbated emphysema resulted in decreased pulmonary function and exercise intolerance. Histological analysis revealed parenchymal pulmonary destruction without signs of inflammation or cardiac fibrosis. In vivo cardiac functional analysis revealed diastolic dysfunction and tachycardia. Ex vivo analysis revealed a cellular cardiomyopathy with decreased myofilament Ca 2+ sensitivity, cross-bridge cycling kinetics, and increased adrenergic PKA (protein kinase A)-dependent phosphorylation of troponin-I. Experimental exacerbated emphysema was associated with exercise intolerance that appeared to be secondary to increased β-adrenergic tone and subsequent cardiac myofilament dysfunction. A β 1 -receptor antagonist treatment (bisoprolol) started 24 hours after ELA-LPS instillation prevented in vivo and ex vivo diastolic dysfunction. These results suggest that novel treatment strategies targeted to the cardiac myofilament may be beneficial to combat exacerbated emphysema-associated HFpEF.

Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air-liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin-8 (IL-8; a T1-cytokine), IL-25, IL-33, and thymic stromal lymphopoietin (T2-alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL-25 and IL-8 levels were highest in asthma ALI-subnatants, whereas IL-33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1-high/T2-high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in-culture T2-alarmin levels, irrespective of the T2-alarmin considered. The epithelial ALI-T2 signature was more frequently high in patients with a BEC > 300/mm 3 . Despite removal from an in vivo environment for ≥2 months, ALIs release disease-specific cytokine "cocktails" into their subnatants, suggesting continued persistence of alarmin orientation in differentiated cell line environments., (© 2023 Wiley-VCH GmbH.)

Objective: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology., Methods: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort., Results: Unsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits., Conclusions: This study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies., Competing Interests: Marina Pretolani’s institution has received funding from AstraZeneca. Camille Taillé reports grants or personal fees from Sanofi, GlaxoSmithKline, AstraZeneca and Novartis, outside the submitted work. Patrick Berger reports grants or personal fees from AstraZeneca, Novartis Boehringer Ingelheim, Sanofi, Circassia, Menarini and AstraZeneca outside the submitted work. Arnaud Bourdin reports grants or personal fees from GlaxoSmithKline, Nuvaira, Pulmonx, Actelion, MSD, United Therapeutic, Vertex, Acceleron, Galapagos, AstraZeneca, Boehringer Ingelheim, Chiesi and Sanofi-Regeneron outside the submitted work. Rania Dagher, Chia-Chien Chiang, Jennifer Kearley and Daniel Muthas are employees and shareholders of AstraZeneca. Jingya Wang, Roland Kolbeck and Alison A. Humbles were previous employees of AstraZeneca. An European patent under the reference EP 22 305 676.3 was submitted on May 6, 2022. There are no additional patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Dagher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Mucus is known to play a pathogenic role in muco-obstructive lung diseases, but little is known about the determinants of mucus rheology. The purpose of this study is to determine which sputum components influence sputum rheology in patients with muco-obstructive lung diseases., Methods: We performed a cross sectional prospective cohort study. Spontaneous sputum was collected from consecutive patients with muco-obstructive lung diseases. Sputum rheology was assessed using the Rheomuco® rheometer (Rheonova, Grenoble); the elastic modulus G', viscous modulus G″, and the critical stress threshold σc were recorded. Key quantitative and qualitative biological sputum components were determined by cytology, nucleic acid amplification tests and mass spectrometry., Results: 48 patients were included from January to August 2019. Among them, 10 had asthma, 14 COPD and 24 non-CF bronchiectasis (NCFB). The critical stress threshold σc predicted a sputum eosinophilia superior to 1.25% with 89.19% accuracy (AUC = 0.8762). G' and G″ are positively correlated with MUC5AC protein concentration ((rho = 0.361; P = .013) and (rho = 0.335; P = .021), respectively). σc was positively correlated with sputum eosinophilia (rho = 0.394; P = .012), MUC5B (rho = 0.552; P < .001) and total protein (rho = 0.490; P < .001) concentrations. G' and G″ were significantly higher in asthma patients (G' = 14.49[7.18-25.26]Pa, G'' = 3.0[2.16-5.38]Pa) compared to COPD (G' = 5.01[2.94-6.48]Pa, P = .010; G'' = 1.45[1.16-1.94]Pa, P = .006) and to NCFB (G' = 4.99[1.49-10.49]Pa, P = .003; G'' = 1.46[0.71-2.47]Pa, P = .002)., Conclusion: In muco-obstructive lung diseases, rheology predicts sputum eosinophilia and is correlated with mucin concentrations, regardless of the underlying disease., Clinical Trial Registration: (registrar, website, and registration number), where applicable NCT04081740., Competing Interests: Declaration of competing interest Dr. Suehs reports grants from Astra Zeneca, outside the submitted work. Dr Patarin is a full-time employee of Rheonova. Rheonova designed and built the rheometer used in this study. Pr. Molinari reports personal fees from Astra Zeneca, grants from GSK, outside the submitted work. Pr. Bourdin reports grants, personal fees, non-financial support and other from Astra Zeneca, grants, personal fees and other from GSK, grants, personal fees, non-financial support and other from Boeringher Ingelheim, personal fees, non-financial support and other from Novartis, personal fees and other from Teva, personal fees and other from Regeneron, personal fees, non-financial support and other from Chiesi Farmaceuticals, personal fees, non-financial support and other from Actelion, other from Gilead, personal fees and non-financial support from Roche, outside the submitted work. The remaining authors (MV, JV, CH, AP, EML, IV, JC) have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Discriminating asthma from chronic obstructive pulmonary disease (COPD) using medico-administrative databases is challenging but necessary for medico-economic analyses focusing on respiratory diseases. Artificial intelligence (AI) may improve dedicated algorithms., Objectives: To assess performance of different AI-based approaches to distinguish asthmatics from COPD patients in medico-administrative databases where the clinical diagnosis is absent. An "Asthma COPD Overlap" category was defined to further test whether AI can detect complexity., Methods: This study included 178,962 patients treated by two "R03" treatment prescriptions at least from January 2016 to December 2018 and managed by either a general practitioner and/or a pulmonologist participating in a permanent longitudinal observatory of prescription in ambulatory medicine (LPD). Clinical diagnoses are available in this database and were used as gold standards to develop diagnostic rules. Three types of AI approaches were explored using data restricted to demographics and treatment dispensations: multinomial regression, gradient boosting and recurrent neural networks (RNN). The best performing model (based on metric properties) was then applied to estimate the size of asthma and COPD populations based on a database (LRx) of treatment dispensations between July, 2018 and June, 2019., Results: The best models were obtained with the boosting approach and RNN, with an overall accuracy of 68%. Performance metrics were better for asthma than COPD. Based on LRx data, the extrapolated numbers of patients treated for asthma and COPD in France were 3.7 and 1.2 million, respectively. Asthma patients were younger than COPD patients (mean, 49.9 vs. 72.1 years); COPD occurred mostly in men (68%) compared to asthma (33%)., Conclusion: AI can provide models with acceptable accuracy to distinguish between asthma, ACO and COPD in medico-administrative databases where the clinical diagnosis is absent. Deep learning and machine learning (RNN) had similar performances in this regard., (© 2022. The Author(s).)

Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air−liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air−liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery.

Competing Interests: Conflicts of Interest None.

Obstructive lung diseases, such as chronic obstructive pulmonary disease, asthma, or non-cystic fibrosis bronchiectasis, share some major pathophysiological features: small airway involvement, dysregulation of adaptive and innate pulmonary immune homeostasis, mucus hyperproduction, and/or hyperconcentration. Mucus regulation is particularly valuable from a therapeutic perspective given it contributes to airflow obstruction, symptom intensity, disease severity, and to some extent, disease prognosis in these diseases. It is therefore crucial to understand the mucus constitution of our patients, its behavior in a stable state and during exacerbation, and its regulatory mechanisms. These are all elements representing potential therapeutic targets, especially in the era of biologics. Here, we first briefly discuss the composition and characteristics of sputum. We focus on mucus and mucins, and then elaborate on the different sample collection procedures and how their quality is ensured. We then give an overview of the different direct analytical techniques available in both clinical routine and more experimental settings, giving their advantages and limitations. We also report on indirect mucus assessment procedures (questionnaires, high-resolution computed tomography scanning of the chest, lung function tests). Finally, we consider ways of integrating these techniques with current and future therapeutic options. Cystic fibrosis will not be discussed given its monogenic nature.

Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.

Evidence highlights the concept of multiple trajectories leading to COPD. Early-life events (i.e., in utero lung development) may influence the maximally attained lung function and increase the risk to develop COPD. Human pluripotent stem cells (hiPSC) represent a unique opportunity to model lung development. We generated hiPSC lines from four highly characterized COPD patients with early onset and severe phenotype. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai Virus. The cell lines had normal karyotype, expressed pluripotency hallmarks, and differentiated into the three primary germ layers. These lines offer a tool to study early-life origins of COPD., (Copyright © 2021 CHU de Montpellier. Published by Elsevier B.V. All rights reserved.)

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.

The natural history of COPD is complex, and the disease is best understood as a syndrome resulting from numerous interacting factors throughout the life cycle with smoking being the strongest inciting feature. Unfortunately, diagnosis is often delayed with several longitudinal cohort studies shedding light on the long 'preclinical' period of COPD. It is now accepted that individuals presenting with different COPD phenotypes may experience varying natural history of their disease. This includes its inception, early stages and progression to established disease. Several scenarios regarding lung function course are possible, but it may conceptually be helpful to distinguish between individuals with normal maximally attained lung function in their early adulthood who thereafter experience faster than normal FEV 1 decline, and those who may achieve a lower than normal maximally attained lung function. This may be the main mechanism behind COPD in the latter group, as the decline in FEV 1 during their adult life may be normal or only slightly faster than normal. Regardless of the FEV 1 trajectory, continuous smoking is strongly associated with disease progression, development of structural lung disease and poor prognosis. In developing countries, factors such as exposure to biomass and sequelae after tuberculosis may lead to a more airway-centred COPD phenotype than seen in smokers. Mechanistically, COPD is characterized by a combination of structural and inflammatory changes. It is unlikely that all patients share the same individual or combined mechanisms given the heterogeneity of resultant phenotypes. Lung explants, bronchial biopsies and other tissue studies have revealed important features. At the small airway level, progression of COPD is clinically imperceptible, and the pathological course of the disease is poorly described. Asthmatic features can further add confusion. However, the small airway epithelium is likely to represent a key focus of the disease, combining impaired subepithelial crosstalk and structural/inflammatory changes. Insufficient resolution of inflammatory processes may facilitate these changes. Pathologically, epithelial metaplasia, inversion of the goblet to ciliated cell ratio, enlargement of the submucosal glands and neutrophil and CD8-T-cell infiltration can be detected. Evidence of type 2 inflammation is gaining interest in the light of new therapeutic agents. Alarmin biology is a promising area that may permit control of inflammation and partial reversal of structural changes in COPD. Here, we review the latest work describing the development and progression of COPD with a focus on lung function trajectories, exacerbations and survival. We also review mechanisms focusing on epithelial changes associated with COPD and lack of resolution characterizing the underlying inflammatory processes., (© 2021 Asian Pacific Society of Respirology.)

Introduction: Long acting bronchodilators are nowadays the central treatment for management of stable COPD. Several combinations exist within the market with different formulation devices. This article reviews a recent dual combination of glycopyrronium and formoterol fumarate in an innovative pMDI-fixed dual combination, Bevespi® Aerosphere., Areas Covered: This article explored the literature to understand the place of this novel combination and unique delivery drug device in today's therapeutic arsenal. Clinical efficacy and safety have been evaluated through the different clinical trials published in public databases., Expert Opinion: Within the fixed-dose combinations, Glycopyrrolate and formoterol fumarate offer a credible unique pMDI option to be given twice a day. LABA-LAMA offers an ICS-free alternative in COPD pharmacology which represents an important treatment option given the current debate over whether or not, maintenance triple therapy combined with ICS are benefic in the long term.

The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke (CS), the major risk factor for developing chronic obstructive pulmonary disease (COPD). CS leads to bronchial epithelial damage on ciliated, goblet, and club cells, which could involve calcium (Ca 2+ ) signaling. Ca 2+ is a key messenger involved in virtually all fundamental physiological functions, including mucus and cytokine secretion, cilia beating, and epithelial repair. In this study, we analyzed Ca 2+ signaling in air-liquid interface-reconstituted bronchial epithelium from control subjects and smokers (with and without COPD). We further aimed to determine how smoking impaired Ca 2+ signaling. First, we showed that the endoplasmic reticulum (ER) depletion of Ca 2+ stores was decreased in patients with COPD and that the Ca 2+ influx was decreased in epithelial cells from smokers (regardless of COPD status). In addition, acute CS exposure led to a decrease in ER Ca 2+ release, significant in smoker subjects, and to a decrease in Ca 2+ influx only in control subjects. Furthermore, the differential expression of 55 genes involved in Ca 2+ signaling highlighted that only ORAI3 expression was significantly altered in smokers (regardless of COPD status). Finally, we incubated epithelial cells with an ORAI antagonist (GSK-7975A). GSK-7975A altered Ca 2+ influx and ciliary beating, but not mucus and cytokine secretion or epithelial repair, in control subjects. Our data suggest that Ca 2+ signaling is impaired in smoker epithelia (regardless of COPD status) and involves ORAI3. Moreover, ORAI3 is additionally involved in ciliary beating.

Introduction: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD)., Methods: In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 μg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) and peak change from baseline in FEV 1 within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed., Results: For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of - 50 mL) for peak FEV 1 (least squares mean [LSM] difference - 3.4 mL, 97.5% confidence interval [CI] - 32.8, 25.9) but not for trough FEV 1 (LSM difference - 87.2 mL; - 117.0, - 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups., Conclusions: Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV 1 , but not for morning pre-dose trough FEV 1 . GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles., Trial Registration: NCT03162055 (Clinicaltrials.gov) FUNDING: AstraZeneca.

Club cell secretory protein (CCSP) knockout mice exhibit increased airway neutrophilia, as found in chronic obstructive pulmonary disease (COPD). We therefore investigated whether treating COPD airway epithelia with recombinant human CCSP (rhCCSP) could dampen exaggerated airway neutrophilia.Control, smoker and COPD air-liquid interface (ALI) cultures exposed to cigarette smoke extract (CSE) were treated with and without rhCCSP. The chemotactic properties of the supernatants were assessed using Dunn chambers. Neutrophil chemotaxis along recombinant human interleukin 8 (rhIL8) gradients (with and without rhCCSP) was also determined. rhCCSP-rhIL8 interactions were tested through co-immunoprecipitation, Biacore surface plasmon resonance (SPR) and in silico modelling. The relationship between CCSP/IL8 concentration ratios in the supernatant of induced sputum from COPD patients versus neutrophilic airway infiltration assessed in lung biopsies was assessed.Increased neutrophilic chemotactic activity of CSE-treated ALI cultures followed IL8 concentrations and returned to normal when supplemented with rhCCSP. rhIL8-induced chemotaxis of neutrophils was reduced by rhCCSP. rhCCSP and rhIL8 co-immunoprecipitated. SPR confirmed this in vitro interaction (equilibrium dissociation constant=8 µM). In silico modelling indicated that this interaction was highly likely. CCSP/IL8 ratios in induced sputum correlated well with the level of small airway neutrophilic infiltration (r 2 =0.746, p<0.001).CCSP is a biologically relevant counter-balancer of neutrophil chemotactic activity. These different approaches used in this study suggest that, among the possible mechanisms involved, CCSP may directly neutralise IL8., Competing Interests: Conflict of interest: L. Knabe has nothing to disclose. Conflict of interest: A. Petit has nothing to disclose. Conflict of interest: C. Vernisse has nothing to disclose. Conflict of interest: J. Charriot has nothing to disclose. Conflict of interest: M. Pugnière has nothing to disclose. Conflict of interest: C. Henriquet has nothing to disclose. Conflict of interest: S. Sasorith has nothing to disclose. Conflict of interest: N. Molinari has nothing to disclose. Conflict of interest: P. Chanez has nothing to disclose. Conflict of interest: J-P. Berthet has nothing to disclose. Conflict of interest: C. Suehs has nothing to disclose. Conflict of interest: I. Vachier has nothing to disclose. Conflict of interest: E. Ahmed has nothing to disclose. Conflict of interest: A. Bourdin has nothing to disclose., (Copyright ©ERS 2019.)

Chronic obstructive pulmonary disease (COPD) is characterised by nonreversible proximal bronchial obstruction leading to major respiratory disability. However, patient phenotypes better capture the heterogeneously reported complaints and symptoms of COPD. Recent studies provided evidence that classical bronchial obstruction does not properly reflect respiratory disability, and symptoms now form the new paradigm for assessment of disease severity and guidance of therapeutic strategies. The aim of this review was to explore pathways addressing COPD pathogenesis beyond proximal bronchial obstruction and to highlight innovative and promising tools for phenotyping and bedside assessment. Distal small airways imaging allows quantitative characterisation of emphysema and functional air trapping. Micro-computed tomography and parametric response mapping suggest small airways disease precedes emphysema destruction. Small airways can be assessed functionally using nitrogen washout, probing ventilation at conductive or acinar levels, and forced oscillation technique. These tests may better correlate with respiratory symptoms and may well capture bronchodilation effects beyond proximal obstruction.Knowledge of inflammation-based processes has not provided well-identified targets so far, and eosinophils probably play a minor role. Adaptative immunity or specific small airways secretory protein may provide new therapeutic targets. Pulmonary vasculature is involved in emphysema through capillary loss, microvascular lesions or hypoxia-induced remodelling, thereby impacting respiratory disability., Competing Interests: Conflict of interest: T. Capron has nothing to disclose. Conflict of interest: A. Bourdin reports personal fees from Novartis, Sanofi, Genentech and Chiesi Farma, and grants and personal fees from GSK, AstraZeneca and Boeringher Ingelheim, outside the submitted work. Conflict of interest: T. Perez reports personal fees from Novartis, Chiesi and Boehringer Ingelheim, and grants from Astra Zeneca, outside the submitted work. Conflict of interest: P. Chanez reports grants and personal fees from ALK, Almirall, Boehringer Ingelheim, GSK, AstraZeneca, Novartis, TEVA and Chiesi, and grants from AMU, outside the submitted work., (Copyright ©ERS 2019.)

Background: Bronchial epithelium plays a key role in orchestrating innate and adaptive immunity. The fate of ex vivo airway epithelial cultures growing at the air liquid interface (ALI) derived from human endobronchial biopsies or brushings is not easy to predict. Calibrating and differentiating these cells is a long and expensive process requiring rigorous expertise. Pinpointing factors associated with ALI culture success would help researchers gain further insight into epithelial progenitor behavior., Methods: A successful ALI culture was defined as one in which a pseudostratified epithelium has formed after 28 days in the presence of all differentiated epithelial cell types. A 4-year prospective bi-center study was conducted with adult subjects enrolled in different approved research protocols., Results: 463 consecutive endobronchial biopsies were obtained from normal healthy volunteers, healthy smokers, asthmatic patients and smokers with COPD. All demographic variables, the different fiber optic centers and culture operators, numbers of endo-bronchial biopsies and the presence of ciliated cells were carefully recorded. Univariate and multivariate models were developed. A stepwise procedure was used to select the final logistic regression model. ALI culture success was independently associated with the presence of living ciliated cells within the initial biopsy (OR = 2.18 [1.50-3.16], p < 0.001)., Conclusion: This finding highlights the properties of the cells derived from the epithelium dedifferentiation process. The preferential selection of samples with ciliated beating cells would probably save time and money. It is still unknown whether successful ALI culture is related to indicators of general cell viability or a purported stem cell state specifically associated with ciliated beating cells.

Background: To examine trends in mortality, costs and in-hospital management and outcomes of severe COPD exacerbations admitted in France., Methods: Patients hospitalized from 2007 to 2012 with COPD exacerbation as the primary diagnosis were identified from the exhaustive French medico-administrative hospitalizations database records. Four groups of severe COPD exacerbations were defined: hospitalisation in a general ward (GW) without acute respiratory failure (ARF), GW with ARF, ICU without invasive mechanical ventilation (MV), and ICU with MV., Results: A 15.48 % increase in admissions from 113 276 in 2007 to 133 497 in 2012 was recorded. Age (+9.9 months), gender (-2.5 % of male) and length of stay (-0.29 day) slightly changed while the number of ICU admissions increased markedly (+41.78 %). In-hospital mortality rates increased (+8.06 %, p < .001) and followed seasonal variations peaking in winter. Total hospitalizations costs increased from 602 to 678 millions euros (+12.6 %). Pneumonia-related mortality increased (+37.2 %). A progressive replacement of chest X-ray by CT scan was observed (-41.3 % vs +31.7 %) while fewer spirometries (-13.7 %) and bronchoscopies (-22.6 %) were performed., Conclusion: The incidence of severe COPD exacerbations and the proportion of ICU-managed patients are still increasing in France. Rising total costs and mortality rates especially related to pneumonia advocate for rethinking COPD management plans., Trial Registration: Not applicable.

Impaired airway homeostasis in chronic obstructive pulmonary disease (COPD) could be partly related to club cell secretory protein (CCSP) deficiency. We hypothesize that CCSP G38A polymorphism is involved and aim to examine the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms. CCSP genotype and CCSP levels in serum and sputum were assessed in 66 subjects with stable COPD included in a 1-yr observational study. Forty-nine of them had an exacerbation. In an in vitro study, the impact on the CCSP promoter of 38G wild-type or 38A variant was assessed. BEAS-2B cells were transfected by either the 38G or 38A construct, in the presence/absence of cigarette smoke extract (CSE) or lipopolysaccharides (LPS). Cotransfections with modulating transcription factors, p53 and Nkx2.1, identified by in silico analysis by using ConSite and TFSEARCH were conducted. A allele carrier COPD patients had lower serum and sputum CCSP levels, especially among active smokers, and a decreased body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) score. In vitro, baseline CCSP transcription levels were similar between the wild and variant constructs. CSE decreased more profoundly the CCSP transcription level of 38A transfected cells. The opposite effect was observed with p53 cotransfection. LPS stimulation induced CCSP repression in 38A promoter transfected cells. Cotransfection with Nkx2.1 significantly activated the CCSP promoters irrespective of the polymorphism. Circulating CCSP levels are associated with smoking and the CCSP G38A polymorphism. CSE, LPS, and the Nkx2.1 and p53 transcription factors modulated the CCSP promoter efficiency. The 38A polymorphism exaggerated the CCSP repression in response to p53 and CSE., (Copyright © 2016 the American Physiological Society.)

Background: Club cell secretory protein (CCSP) is a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking., Objective: We investigated the effect of CCSP as a therapeutic strategy to restore the balance between injury and repair in COPD simultaneously, validating an ex vivo air-liquid interface (ALI) culture of human bronchial epithelial cells., Methods: Endobronchial biopsy specimens (EBBs) were obtained from 13 patients with COPD, eight smokers, and eight control subjects. Morphometric analysis of the initial EBBs was performed. ALI cultures derived from the same EBBs were exposed to cigarette smoke extract (CSE) with or without exogenous recombinant human CCSP (rhCCSP) supplementation. CCSP and IL-8 concentrations were assessed at steady state and after CSE exposure., Results: Morphometric analysis of the initial EBBs showed increased cell density but decreased immunostaining of CCSP+ cells in EBBs of patients with COPD (P = .03 vs control subjects). At steady state, lower CCSP (P = .04) and higher IL-8 levels (P < .0001) were found in COPD ALI epithelium. Exogenous rhCCSP supplementation dampened CSE-induced IL-8-release in patients with COPD and returned to levels similar to those of smokers and control subjects (P = .0001). A negative correlation was found between IL-8-release in ALI and CCSP+ cell density in initial biopsy specimens (P = .0073)., Conclusions: In vitro, rhCCSP exogenous supplementation can reverse CSE-induced IL-8 release in biopsy specimens from patients with COPD, indicating a potential use of this strategy in vivo.

Background: COPD is largely under-diagnosed and once diagnosed usually at a late stage. Early diagnosis is thoroughly recommended but most attempts failed as the disease is marginally known and screening marginally accepted. It is a rare cause of concern in primary care and spirometry is not very common. Exhaled carbon monoxide (eCO) is a 5-seconds easy-to-use device dedicated to monitor cigarette smoke consumption. We aimed to assess whether systematic eCO measurement in primary care is a useful tool to improve acceptance for early COPD diagnosis., Methods: This was a two-center randomized controlled trial enrolling 410 patients between March and May, 2013. Whatever was the reason of attendance to the clinic, all adults were proposed to measure eCO during randomly chosen days and outcomes were compared between the two different groups of patients (performing and not performing eCO). Primary outcome was the rates of acceptance for COPD screening., Results: Rate of acceptance for COPD screening was 28% in the eCO group and 26% in the other (P = 0.575). These rates increased to 48 and 51% in smokers (current and former). eCO significantly increased the rate of clinics during which a debate on smoking was initiated (42 vs. 24%, P = 0.001). eCO at 2.5 ppm was the discriminative concentration for identifying active smokers (ROC curve AUC: 0.935). Smoking was the only independent risk factor associated with acceptance for early COPD screening (OR = 364.6 (82.5-901.5) and OR = 78.5 (18.7-330.0) in current and former smokers, respectively) while eCO measurement was not., Conclusions: Early COPD diagnosis is a minor cause of concern in primary care. Systematic eCO assessment failed to improve acceptance for early COPD screening.

Objectives: to understand epidemiological trends in severe COPD exacerbations through analyzes of hospitalizations and deaths during three consecutive years in a French administrative region area., Methods: Medico-administrative records of hospitalizations for COPD exacerbations were sorted from 2010 to 2012 using selected International Classification of Diseases (ICD10) codes. Four groups of hospitalization for COPD severe exacerbations were elicited leading to hospitalizations (general ward without respiratory failure, general ward with acute respiratory distress, ICU without mechanical ventilation, ICU with mechanical ventilation)., Results: Data extraction identified 5007, 4986 and 5359 admissions related to 4136, 4155 and 4460 patients in 2010, 2011 and 2012, respectively. Marked seasonal variations were observed. Duration of stay (median (IQR), 7 (7) vs 9 (8) vs 10 (9) vs 14 (16) days, P < .001), death rates (3.6% vs 14.2% vs 14.4% vs 21.2%, P < .01), number of co-morbid conditions (median (IQR), 2 (2) vs 2 (2) vs 4 (5) vs 4 (4.5), P < .01), type of institution (64.9% in public institution vs 79.9% vs 87.8% vs 76.6%, P < .01) were significantly associated with the hospitalization group and more than 8% of admissions led to death (3% to 24%). Age, type of institution and past hospitalizations were independent risk factors for deaths. Readmissions were infrequent but mainly related to the worsening of the co-morbid conditions., Conclusion: COPD severe exacerbations are frequent and lead to an important numbers of deaths related to the severity of acute respiratory failure and the number of co-morbid conditions.

Background: Small airways are regarded as the elective anatomic site of obstruction in most chronic airway diseases. Expiratory computed tomography (CT) is increasingly used to assess obstruction at this level but there is no consensus regarding the best quantification method. We aimed to evaluate software-assisted CT quantification of air trapping for assessing small airway obstruction and determine which CT criteria better predict small airway obstruction on single breath nitrogen test (SBNT)., Methods: Eighty-nine healthy volunteers age from 60 to 90 years old, underwent spirometrically-gated inspiratory (I) and expiratory (E) CT and pulmonary function tests (PFTs) using SBNT, performed on the same day. Air trapping was estimated using dedicated software measuring on inspiratory and expiratory CT low attenuation area (LAA) lung proportion and mean lung density (MLD). CT indexes were compared to SBNT results using the Spearman correlation coefficient and hierarchical dendrogram analysis. In addition, receiver operating characteristic (ROC) curve analysis was performed to determine the optimal CT air-trapping criterion., Results: 43 of 89 subjects (48,3%) had dN2 value above the threshold defining small airway obstruction (i.e. 2.5% N2/l). Expiratory to inspiratory MLD ratio (r = 0.40) and LAA for the range -850 -1024 HU (r = 0.29) and for the range -850 -910 HU (r = 0.37) were positively correlated with SBNT results. E/I MLD was the most suitable criterion for its expression. Expiratory to inspiratory MLD ratio (E/I MLD) showed the highest AUC value (0.733) for small airway obstruction assessment., Conclusion: Among all CT criteria, all correlating with small airway obstruction on SBNT, E/I MLD was the most suitable criterion for its expression in asymptomatic subjects with mild small airway obstruction, Trial Registration: Registered at Clinicaltrials.gov, identifier: NCT01230879.

Aclidinium is a potent and selective muscarinic antagonist, which interacts rapidly with muscarinic receptors and shows subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)); its association rate for the M(3) receptor is similar to that of ipratropium and 2.6 times faster than that of tiotropium. Aclidinium dissociates slightly faster from M(2) and M(3) receptors than tiotropium but much more slowly than ipratropium. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Aclidinium undergoes rapid hydrolysis in the plasma into two major compounds, the alcohol (LAS34823) and the carboxylic acid (LAS34850) metabolites, resulting in low and transient systemic exposure to the active drug. The two major metabolites show no significant affinity for human muscarinic receptors. A potent bronchodilatory activity has been observed after inhaled administration of aclidinium. Clinical trials have provided evidence of sustained bronchodilation similar to that observed with tiotropium. Trial results have confirmed the positive safety profile of aclidinium, particularly in terms of a very low propensity to cause anticholinergic adverse events. Aclidinium is now moving to phase III clinical development for chronic obstructive pulmonary disease (COPD).

Smoking associated COPD progression is likely to be directly linked to differential injury and repair dynamics in small airways (SA). Although IL8 is a well-accepted marker for injured airway epithelium, Clara cells [the predominant proliferating cells in SA] and SCGB1A1 protein [their major secretory product] have only recently emerged as potential SA repair markers. We therefore postulate that the SCGB1A1/IL8 ratio in the airways of smokers would be inversely associated with physiological, radiological and clinical measures of COPD. A cross-sectional cohort of 28 smokers undergoing surgery for peripheral nodule was recruited (24M/4F, age 61 +/- 11 y, FEV1s 76 +/- 20%, smoking 40 +/- 12 p.y). SCGB1A1 and IL8 were measured by ELISA in the induced sputum (IS) 3 to 5 days prior to surgery as well as by immunohistochemistry from lung tissue (also assessed morphometrically) obtained distant to the cancer surgery site. COPD was assessed using standard clinical, functional and radiological parameters. Log-transformed IS-SCGB1A1 was linearly correlated with SCGB1A1-positive epithelial cells detected via immunohistochemistry (r = .533, p = .001), while IS-IL8 was positively related to SA infiltrating neutrophils (Elastase-positive cells). There was a striking negative correlation between IS-SCGB1A1/IL8 levels and whole airway thickness [SA < 2 mm] at morphometry (r = -0.83, p < 0.0001). IS-SCGB1A1/IL8 levels were also inversely associated with nitrogen slope [r = -0.52, p < 0.001] and HRCT SA score [r = -0.51, p < 0.001]. In a multivariate analysis the IS-SCGB1A1/IL8 ratio was a stronger predictor than both the physiological and radiological measures of SA disease assessed. The SCGB1A1/IL8 ratio measured in sputum is a potentially valuable biomarker for non-invasive assessment of SA remodelling in smokers.

The effects of inhaled corticosteroids (ICSs) have been investigated in asthma and chronic obstructive pulmonary disease (COPD) using endobronchial biopsies. In asthma, most studies have shown reductions in infiltrating eosinophils, mast cells, and T lymphocytes. Cell-associated mediators, such as cytokines derived from type 2 T-helper lymphocytes, are decreased as assessed by immunostaining and molecular biology techniques. More recently, attention has been devoted to the effect of ICSs on structural changes. In asthma, ICSs have been shown in some studies to affect collagen deposition (size of the reticular basement membrane), the number of vessels, or epithelial integrity. The correlations between those findings and various clinical and functional outcomes are far from clear. A long-term study has shown a decrease in the basement membrane size in a group of patients with asthma treated according to their level of airway hyperreactivity. In COPD, ICSs generally do not decrease neutrophils, macrophages, and CD8(+) T lymphocytes. The effects of these drugs on structural changes in COPD have not been investigated extensively. Long-term prospective studies are needed to demonstrate the potential for ICSs to affect the natural history of chronic bronchial diseases.