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Purpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD)., Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV 1 ]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression., Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV 1 , RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV 1 ., Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality., Trial Registration: NCT01245933., Competing Interests: Dr Gabor Kovacs reports grants, personal fees and/or non-financial support from Janssen, Astra Zeneca, Boehringer Ingelheim, Bayer, GSK, MSD, Chiesi, Vitalaire, Ferrer, and AOP, outside the submitted work. Dr Horst Olschewski reports personal fees from Iqvia, MSD, Janssen, Pfizer, Astra Zeneca, GSK, Boehringer; department director for Ludwig Boltzmann Institute for Lung Vascular Research, outside the submitted work. Dr Hans-Ulrich Kauczor reports non-financial support from Bayer and Siemens; grants from BMBF, during the conduct of the study; grants and/or personal fees from Siemens, Philips, Boehringer Ingelheim, Sanofi, Median, outside the submitted work. Dr Mark Wielpütz reports grants from Vertex and Boehringer, outside the submitted work. Professor Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study; personal fees from GSK, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, and Chiesi, outside the submitted work. Professor Jürgen Behr reports personal fees from Astra-Zeneca, Boehringer-Ingelheim, BMS, Ferrer, Novartis, Roche, Sanofi-Genzyme, Janssen, and Johnson&Johnson, outside the submitted work. Dr Robert Bals reports grants from German Ministery of Education and Science (BMBF), during the conduct of the study; grants from DFG, Schwiete Stiftung, Krebshilfe, personal fees from Boehringer Ingelheim, CSL Behring, outside the submitted work. Professor Claus Vogelmeier reports grants and/or personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, Nuvaira, Roche, and Sanofi, outside the submitted work. The authors declare that they have no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Stoleriu et al.)

Background: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the "real-life" COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study., Methods: The analysis was based on data from visits 1-5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1-4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation., Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV 1 , 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV 1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation., Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction., Competing Interests: Dr Robert Bals reports grants from BMBF, during the conduct of the study; personal fees/grants from CSL Behring, DFG, GSK, and Schwiete Stifung, outside the submitted work. Prof. Dr Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study; personal fees from AstraZeneca, Berlin-Chemie, Chiesi, GSK, Novartis, outside the submitted work. Prof. Dr Klaus Rabe reports personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie, Chiesi Pharmaceuticals, GSK, CSL Behring, Sanofi & Regeneron and shareholder of rnatics, outside the submitted work. Dr Claus Vogelmeier reports personal fees and/or grants from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, MedUpdate, Menarini, Novartis, Nuvaira, Roche, and Sanofi, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Alter et al.)

Introduction: COPD is a leading cause of morbidity and mortality globally. Management is complex and costly. Although international quality standards for diagnosis and management exist, opportunities remain to improve outcomes, especially in reducing avoidable hospitalisations., Objective: To estimate the potential health and economic impact of improved adherence to guideline-recommended care for prevalent, on-treatment COPD populations in four high-income settings., Methods: A disease simulation model was developed to evaluate the impact of theoretical improvements to COPD management, comparing outcomes for usual care and policy scenarios for interventions that reduce avoidable hospitalisations: 1) increased attendance (50% vs 31-38%) of early follow-up review after severe exacerbation hospitalisation; 2) increased access (30% vs 5-10%) to an integrated disease management (IDM) programme that provides guideline adherent care., Results: For cohorts of 100,000 patients, Policy 1 yielded additional life years (England: 523; Germany: 759; Canada: 1316; Japan: 512) and lifetime cost savings (-£2.89 million; -€6.58 million; -$40.08 million; -¥735.58 million). For Policy 2, additional life years (2299; 3619; 3656) and higher lifetime total costs (£38.15 million; €35.58 million; ¥1091.53 million) were estimated in England, Germany and Japan, and additional life years (4299) and cost savings (-$20.52 million) in Canada. Scenarios found that the cost impact depended on the modelled intervention effect size., Conclusion: Interventions that reduce avoidable hospitalisations are estimated to improve survival and may generate cost savings. This study provides evidence on the theoretical impact of policies to improve COPD care and highlights priority areas for further research to support evidence-based policy decisions., Competing Interests: The study design, data gathering, data analysis, results and interpretation were carried out independently by the authors who declare that the source of funding has not led to any competing or conflicting interests. AstraZeneca reviewed the manuscript for medical and scientific accuracy. EA reports that Aquarius received funding for their company to do the research and their company has received funding for other projects relating to COPD and respiratory conditions from grants and commercial contracts (including AstraZeneca which funded the project in question). Outside of the submitted work, TW reports receiving consulting fees and/or fees for attending lectures, meetings and conferences and/or travel expenses and/or research grants from My mhealth, AstraZeneca, GlaxoSmithKline, Synairgen, Bergenbio, UCB, UKRI, NIHR, Valneva, OM Pharma, Boehringer Ingelheim, Roche, Chiesi, Teva and Nutricia. TW is a founder, director and shareholder of My mhealth. TW has served on monitoring boards for trials sponsored by Synairgen and Valneva, and has applied for patents with GlaxoSmithKline and My mhealth. HW reports receiving consulting fees and/or fees/honoraria for attending/presenting lectures, meetings and conferences and/or travel expenses and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Bayer, GlaxoSmithKline and Veronapharma. HW has served on monitoring boards for AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Bayer and GlaxoSmithKline. MB reports receiving consulting fees and/or fees/honoraria for attending/presenting lectures, meetings and conferences and/or travel expenses and/or grants from AstraZeneca, GlaxoSmithKline, Pfizer, Sanofi, Covis, Grifols, Boehringer Ingelheim, Valeo, The Lung Association of Saskatchewan, Alberta Lung and NWT, CIHR, Alberta Innovates, Novartis and Mereo. MB has a leadership or fiduciary role in the Canadian Thoracic Society and Alberta Health Services. CL reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer, grants from Ontario Ministry of Health and Canadian Institutes of Health Research and personal fees from GSK, Valeo, Teva and Covis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Adams et al.)

Background: In patients with COPD, inhalation ability should be assessed when considering inhaler choice. To evaluate whether the soft mist inhaler (SMI) is suitable for COPD patients irrespective of inhalation ability, the TRONARTO study investigated the efficacy of dual long-acting bronchodilator therapy delivered via the Respimat ® SMI on lung function in patients with COPD stratified by inhalation ability. Tiotropium/olodaterol delivered via the SMI was effective both in patients with peak inspiratory flow (PIF) <60 L/min and PIF ≥60 L/min, measured against medium-low resistance., Methods: This congress compilation summarizes post hoc analyses from the TRONARTO study presented at the annual American Thoracic Society 2022 and European Respiratory Society 2022 meetings. These analyses evaluated PIF in over 200 patients, with PIF measurements taken daily at home for 4 weeks, and in the clinic at baseline, Weeks 2 and 4., Results: Overall, 57.9% of patients had a PIF range (difference between lowest and highest PIF measurements) <20 L/min (12.4% of patients had PIF range <10 L/min). At-home PIF range decreased over the study period, suggesting that inhaler training/repeated PIF measurements may help to make patients' inspiratory effort more consistent. Some patient characteristics correlated with lower PIF (female gender, shorter stature, more severe disease, worse airflow obstruction) and lower PIF range (more severe disease). PIF measurements differed between medium-low and high-resistance settings, highlighting the importance of measuring PIF at the resistance of a patient's inhaler. PIF correlated poorly with spirometry measurements., Conclusion: As indicated in COPD management guidelines, choice of inhaler is essential to optimize pharmacologic therapies for COPD. Poor inspiratory ability should be viewed as a treatable trait that can help to inform inhaler choice. Inhaler training and consideration of PIF (if patients use a dry powder inhaler) can reduce patient-to-inhaler mismatch, with potential consequences for health status and exacerbation risk., Competing Interests: MBD reports research grants from the National Institutes of Health, Department of Defense, American Lung Association, Boehringer Ingelheim, Midmark and Teva unrelated to this work. He reports personal consulting fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Teva, Midmark, Verona, Optimum Patient Care, Chiesi, Becker Pharma and Polarean unrelated to this work. HW reports grants, personal fees and other support from Boehringer Ingelheim during the conduct of the study. Outside the submitted work, HW received grants, personal fees and other support from AstraZeneca, Chiesi, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, and Novartis. JR is an employee of Syneos Health working on behalf of Boehringer Ingelheim. AG, RE-S and AS are employees of Boehringer Ingelheim. DAM reports fees for advisory boards from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Teva, Theravance, Verona and Viatris; royalties from Salem Media Group – COPD: Answers to Your Questions (2015); work with pharmaceutical companies on the use of BDI/TDI; participation in speaker’s bureau for AstraZeneca, Boehringer Ingelheim and Teva; and https://www.donaldmahler.com – an educational website for those with COPD and their families. The authors report no other conflicts of interest in this work., (© 2023 Mahler et al.)

Background: Multimorbidity plays an important role in chronic obstructive pulmonary disease (COPD) but is also a feature of ageing. We estimated to what extent increases in the prevalence of multimorbidity over time are attributable to COPD progression compared to increasing patient age., Methods: Patients with COPD from the long-term COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort with four follow-up visits were included in this analysis. At each visit, symptoms, exacerbation history, quality of life and lung function were assessed, along with the comorbidities heart failure (HF), coronary artery disease (CAD), peripheral arterial disease (PAD), hypertension, sleep apnea, diabetes mellitus, hyperlipidemia, hyperuricemia and osteoporosis. Using longitudinal logistic regression analysis, we determined what proportion of the increase in the prevalence of comorbidities could be attributed to patients' age or to the progression of COPD over visits., Results: Of 2030 patients at baseline, 878 completed four follow-up visits (up to 4.5 years). CAD prevalence increased over time, with similar effects attributable to the 4.5-year follow-up, used as indicator of COPD progression, and to a 5-year increase in patients' age. The prevalence of HF, diabetes, hyperlipidemia, hyperuricemia, osteoporosis and sleep apnea showed stronger contributions of COPD progression than of age; in contrast, age dominated for hypertension and PAD. There were different relationships to patients' characteristics including BMI and sex. The results were not critically dependent on the duration of COPD prior to enrolment, or the inclusion of patients with all four follow-up visits vs those attending only at least one of them., Conclusion: Analyzing the increasing prevalence of multimorbidity in COPD over time, we separated age-independent contributions, probably reflecting intrinsic COPD-related disease progression, from age-dependent contributions. This distinction might be useful for the individual assessment of disease progression in COPD., Competing Interests: Dr Franziska C Trudzinski reports personal fees from Novartis AG, non-financial support from CSL Behring, personal fees from Boehringer Ingelheim, personal fees from GlaxoSmithKline, personal fees from Chiesi, outside the submitted work. Professor Dr Robert Bals reports grants from BMBF, grants from Marburg University, during the conduct of the study; grants, personal fees from Various, outside the submitted work. Prof Dr Stefan Andreas reports grants from Boehringer, personal fees from Altana, Boehringer, AZ, GSK, Chiesi, GSK, Novartis, Menerini, outside the submitted work. Professor Dr Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study. Dr Antonia Sassmann-Schweda reports Contractual payments for conduction of study visits; payments were made to Research Center Borstel, Center for Clinical Studies from Philipps University of Marburg, during the conduct of the study. Professor Dr Joachim H Ficker reports personal fees, non-financial support from CSL Behring, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Boehringer, personal fees from Pfizer, outside the submitted work; Prof Dr Claus F Vogelmeier reports personal fees from Aerogen, grants, personal fees from AstraZeneca, grants, personal fees from Boehringer Ingelheim, grants, personal fees from CSL Behring, grants, personal fees from Chiesi, grants, personal fees from GlaxoSmithKline, grants, personal fees from Grifols, personal fees from Menarini, grants, personal fees from Novartis, personal fees from Nuvaira, personal fees from MedUpdate, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Alter et al.)

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. A comprehensive and detailed understanding of COPD care pathways from pre-diagnosis to acute care is required to understand the common barriers to optimal COPD care across diverse health systems., Methods: Country-specific COPD care pathways were created for four high-income countries using international recommendations and country-specific guidelines, then populated with published epidemiological, clinical, and economic data. To refine and validate the pathways, semi-structured interviews using pre-prepared discussion guides and country-specific pathway maps were held with twenty-four primary and secondary care respiratory healthcare professionals. Thematic analysis was then performed on the interview transcripts., Results: The COPD care pathway showed broad consistency across the countries. Three key themes relating to barriers in optimal COPD management were identified across the countries: journey to diagnosis, treatment, and the impact of COVID-19. Common barriers included presentation to healthcare with advanced COPD, low COPD consideration, and sub-optimal acute and chronic disease management. COVID-19 has negatively impacted disease management across the pathway but presents opportunities to retain virtual consultations. Structural factors such as insurance and short duration of appointments also impacted the diagnosis and management of COPD., Conclusion: COPD is an important public health issue that needs urgent prioritization. The use of Evidenced Care Pathways with decision-makers can facilitate evidence-based decision making on interventions and policies to improve care and outcomes for patients and reduce unnecessary resource use and associated costs for the healthcare provider/payer., Competing Interests: AM, RGA, YM, AR (at the time of the project), GW (at the time of the project), and EA work at Aquarius Population Health and have received consultancy fees from other pharmaceutical and MedTech companies unrelated to this work. Outside of the submitted work, TW reports receiving consulting fees and/or fees for attending lectures, meetings and conferences and/or travel expenses and/or research grants from My mhealth, AstraZeneca, GlaxoSmithKline, Synairgen, Bergenbio, UCB, UKRI, NIHR, Valneva, OM Pharma, Boehringer Ingelheim, Roche, Chiesi, Teva and Nutricia. TW is a founder, director and shareholder of My mhealth. TW has served on monitoring boards for trials sponsored by Synairgen and Valneva, and has applied for patents with GlaxoSmithKline and My mhealth. HW reports receiving consulting fees and/or fees/honoraria for attending/presenting lectures, meetings and conferences and/or travel expenses and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Bayer, GlaxoSmithKline and Verona Pharma. HW has served on monitoring boards for AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Bayer and GlaxoSmithKline. JS reports receiving consulting fees and/or fees/honoraria for attending/presenting lectures, meetings and conferences from AstraZeneca, Chiesi, Teva and Mundipharma. JS has received payment for expert testimony from Bush and Co Ltd. MB reports receiving consulting fees and/or fees/honoraria for attending/presenting lectures, meetings and conferences and/or travel expenses and/or grants from AstraZeneca, GlaxoSmithKline, Pfizer, Sanofi, Covis, Grifols, Boehringer Ingelheim, Valeo, The Lung Association of Saskatchewan, Alberta Lung and NWT, CIHR, Alberta Innovates, Novartis and Mereo. MB has a leadership or fiduciary role in the Canadian Thoracic Society and Alberta Health Services. GW reports receiving grants or contracts from Adelphi Values PROVE. MI reports no conflicts of interest. No other conflicts of interest were declared., (© 2022 Meiwald et al.)

Competing Interests: Mustafa Abdo and Frauke Pedersen report no relevant conflicts of interest. Frederik Trinkmann reports grants from Chiesi for the conduct of the study. He also received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi Aventis, all outside the submitted work. Felix Herth and Klaus F. Rabe report no relevant conflict of interest. Anne-Marie Kirsten reports grants from Chiesi for the conduct of the study. Henrik Watz reports grants from Chiesi for the conduct of the study. Grants, personal fees and non-financial support from AZ, grants, personal fees and non-financial support from GSK, grants, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from BI, outside the submitted work. The authors report no other conflicts of interest in this work.

Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD., Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups., Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients., Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy., Clinical Trial Registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344., Competing Interests: Maud Koopman reports no real or perceived conflict of interest. Frits M.E. Franssen reports grants and personal fees from AstraZeneca and Novartis; personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and TEVA, outside the submitted work. Swetlana Gaffron works at Viscovery. Viscovery provides analysis services to Ciro+. Henrik Watz reports personal fees from AZ, during the conduct of the study; grants and/or personal fees from AZ, GSK, Chiesi, Boehringer Ingelheim Novartis, and Menarini, outside the submitted work. Thierry Troosters reports personal fees from AstraZeneca, Boehringer Ingelheim, and Chiesi, outside the submitted work. Judith Garcia-Aymerich reports consulting and lecture fees from AstraZeneca (outside the submitted work) and lecture fees from Esteve and Chiesi (outside the submitted work). Pierluigi Paggiaro reports grants and/or personal fees from ALK, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Guidotti, Menarini, and Mundipharma, outside the submitted work. Eduard Molins, Miguel Moya, Lindy van Burk, and Esther Garcia Gil are AstraZeneca employees. Dieter Maier works at Biomax. Biomax provides data management and analysis services to CIRO+. Emiel F.M. Wouters reports no real or perceived conflict of interest. Lowie E.G.W. Vanfleteren reports grants and/or personal fees from AstraZeneca, Novartis, GSK, Chiesi, Menarini, Pulmonx, Fisher&Paykel, and Boehringer, outside the submitted work. Martijn A. Spruit reports grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, GSK, Boehringer Ingelheim, AstraZeneca, TEVA, and Chiesi, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Koopman et al.)

Background: Patients with chronic obstructive pulmonary disease (COPD) often have osteoporosis and diabetes as comorbid conditions. Anti-diabetic medication, including metformin, has protective effects on osteoporosis in experimental studies. We therefore studied whether patients with COPD receiving anti-diabetic medication had a lower osteoporosis prevalence in a large COPD cohort, COSYCONET., Methods: Assessment of osteoporosis was based on patients' reports of physician-based diagnoses and the presence of disease-specific medication. The predictive value of physical characteristics, lung function, comorbidities, cardiovascular medication, and the use of anti-inflammatory diabetes medication, including metformin, sulfonylureas, glinides or DPP4I, was evaluated using logistic regression analysis. ClinicalTrials.gov: NCT01245933., Results: In total, 2222 patients were eligible for analysis (863 [39%] female, mean age 65 y), 515 of whom had higher symptoms and exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D). Osteoporosis was present in 15.8% of the overall cohort, and in 24.1% of GOLD D patients. Regression analyses identified the following as associated with osteoporosis (p < 0.05): female sex, higher age, lower body-mass index, asthma, higher air trapping, oral steroids, and cardiovascular medication. Although oral anti-diabetic medication was overall not associated with a lower prevalence of osteoporosis (p = 0.131), anti-inflammatory anti-diabetic medication (p = 0.009) and metformin-containing therapy (p = 0.039) were. This was driven by GOLD D patients., Conclusion: In a large COPD cohort, anti-inflammatory diabetes therapy, including metformin, was associated with a lower prevalence of osteoporosis, especially in patients with higher symptoms and exacerbations. These findings suggest a protective effect of common anti-diabetic medication on osteoporosis, possibly as a result of attenuated systemic inflammation., Competing Interests: Professor Joachim H Ficker reports personal fees from Boehringer-Ingelheim, AstraZeneca, and GSK; personal fees, non-financial support from CSL Behring and Novartis, outside the submitted work. Professor Jürgen Behr reports personal fees from Boehringer-Ingelheim, AstraZeneca, and Novartis, outside the submitted work. Professor Robert Bals reports COSYCONET is supported by the German Centre for Lung Research (DZL), grant number 82DZLI05A2 (COSYCONET), the BMBF, grant number 01GI0881 and also received unrestricted grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, GlaxoSmithKline GmbH&Co. KG, Grifols Deutschland GmbH, and Novartis Deutschland GmbH. Professor Bals also reports grants, and/or personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Novartis, CSL Behring, German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Sander Stiftung, Schwiete Stiftung, Krebshilfe, and Mukoviszidose eV, outside the submitted work. Professor Claus F Vogelmeier reports personal fees, and/or grants from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, and MedUpdate, outside the submitted work. The authors declare that they have no other competing interests., (© 2021 Kahnert et al.)

Background: Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood., Methods: TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat ® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV 1 ) area under the curve 0-3 hours (FEV 1 AUC 0-3h ) and trough FEV 1 ., Results: Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF <60 L/min, 55; PIF ≥60 L/min, 51) and 107 received placebo (PIF <60 L/min, 55; PIF ≥60 L/min, 52). For FEV 1 AUC 0-3h , the adjusted mean change from baseline versus placebo was 336 mL (95% confidence interval [CI] 246-425 mL; P<0.0001) in the PIF <60 L/min group and 321 mL (95% CI 233-409 mL; P<0.0001) in the PIF ≥60 L/min group. For trough FEV 1 , the adjusted mean change from baseline versus placebo was 201 mL (95% CI 117-286 mL; P<0.0001) in the PIF <60 L/min group and 217 mL (95% CI 135-299 mL; P<0.0001) in the PIF ≥60 L/min group., Conclusion: In the TRONARTO study, which included patients with moderate-to-severe COPD and varying inspiratory flow abilities, treatment with tiotropium/olodaterol resulted in significant lung function improvements versus placebo. This SMI can be used irrespective of the PIF that a patient can generate., Competing Interests: Donald A. Mahler, M.D., FCCP reports fees for advisory boards from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Teva, Theravance, and Verona; royalties from Salem Media Group – COPD: Answers to Your Questions (2015); work with pharmaceutical companies on the use of BDI/TDI; and participation in speaker’s bureau for AstraZeneca, Boehringer Ingelheim and Teva; and https://www.donaldmahler.com – an educational website for those with COPD and their families. Andrea Ludwig-Sengpiel reports investigator fees from Boehringer Ingelheim, paid to her institution during the conduct of the study; investigator fees from AstraZeneca, GlaxoSmithKline, Sanofi, Teva, Avillion, IONIS, Gossamer, Chiesi, Verona, Insmed and Novartis paid to her institution. Gary T. Ferguson reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Teva Pharmaceuticals, Novartis, AstraZeneca, Pearl Therapeutics, Sunovion, Verona, Theravance, Mylan, Verona, and GlaxoSmithKline; grants and personal fees from Sanofi, grants from Altavant, Chiesi, and Knopp; personal fees from DevPro, Galderma, Ionis, and Orpheris, outside the submitted work. Alberto de la Hoz, John Ritz and Asif Shaikh are all employees of Boehringer Ingelheim. Henrik Watz reports grants from Boehringer Ingelheim for conductance of the study paid to his institution, consulting fees, honoraria payments, support for attending meetings and participation on a data safety monitoring or advisory board from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Novartis, Takeda, Verona Pharma, and GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2021 Mahler et al.)

Rationale: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma., Objective: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing., Methods: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma., Results: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman's coefficient = -0.42, p < 0.001), RV% (-0.32, p = 0.02)., Conclusion: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients., Competing Interests: Mustafa Abdo reports no conflict of interest. Frederik Trinkmann received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi aventis, all outside the submitted work. Anne-Marie Kirsten, Heike biller and Frauke Pedersen report no conflict of interest. Erika von Mutius reports personal fees from Pharmaventures, personal fees from OM Pharma S. A., personal fees from Springer-Verlag GmbH, personal fees from Elsevier GmbH and Elsevier Ltd., personal fees from Peptinnovate Ltd., personal fees from Turun Yliopisto, personal fees from Tampereen Yliopisto, personal fees from Helsingin Yliopisto, personal fees from European Respiratory Society, personal fees from Deutsche Pharmazeutische Gesellschaft e. V., personal fees from Massachusetts Medical Society, personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from Böhringer Ingelheim International GmbH, personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Georg Thieme Verlag, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; In addition, Dr. von Mutius has a patent LU101064 - Barn dust extract for the prevention and treatment of diseases pending, a patent EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to ProtectImmun GmbH, a patent EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to ProtectImmun GmbH, a patent number EP1637147: Stable dust extract for allergy protection licensed to ProtectImmun GmbH, and a patent EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to ProtectImmun GmbH. Matthias V. Kopp, Gesine Hansen, Benjamin Waschki, Klaus F. Rabe and Henrik Watz reports no relevant conflict of interest. Thomas Bahmer reports grants from BMBF: Unrestricted research grant for the German Center for Lung Research (DZL), during the conduct of the study; personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Novartis, and personal fees from Roche, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Abdo et al.)

Background: In COPD patients of GOLD groups A and B, a high degree of treatment with inhaled corticosteroids (ICS) has been reported, which is regarded as overtreatment according to GOLD recommendations. We investigated which factors predict ICS use and which relationship it has to clinical and functional outcomes, or healthcare costs., Methods: We used pooled data from visits 1 and 3 of the COSYCONET cohort (n=2741, n=2053, interval 1.5 years) including patients categorized as GOLD grades 1-4 and GOLD group A or B at both visits (n=1080). Comparisons were performed using ANOVA, and regression analyses using propensity matching and inverse probability weighting to adjust for differences between ICS groups. These were defined as having ICS at both visits (always) vs no ICS at both visits (never). Measures were divided into predictors of ICS treatment and outcomes., Results: Among 1080 patients, 608 patients were eligible for ICS groups (n=297 never, n=311 always). Prior to matching, patients with ICS showed significantly (p<0.05 each) impaired lung function, symptoms and exacerbation history. After matching, the outcomes generic quality of life and CO diffusing capacity were increased in ICS patients (p<0.05 each). Moreover, costs for respiratory medication, but not total health care costs, were significantly elevated in the ICS group by 780€ per year., Conclusion: ICS therapy in COPD GOLD A/B patients can have small positive and negative effects on clinical outcomes and health care costs, indicating that the clinical evaluation of ICS over-therapy in COPD requires a multi-dimensional approach., Competing Interests: Professor Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study; personal fees from AstraZeneca, GSK, Novartis, and Chiesi, outside the submitted work. Professor Robert Bals reports grants from Bundesministerium für Bildung und Forschung, during the conduct of the study; outside the submitted work. Professor Claus F. Vogelmeier reports grants, personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi; grants from GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, and MeddUpdate, outside the submitted work. The authors declare that they have no other competing interests., (© 2021 Lutter et al.)

Rationale: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking., Objective: To study the impact of symptom control on PA and body composition., Methods: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control., Results: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R 2 = 0.61, p < 0.001). Persistent uncontrolled asthma patients (n=64) had lower physical activity at both baseline (6614 steps/118 min) and follow-up (6195/115). Despite having stable BMI, they also had significant muscle loss (-1.2%, -0.88 kg, p<0.01) and fat accumulation (+1%, +1.1 kg, p<0.01). By contrast, temporarily uncontrolled or controlled asthma patients had higher physical activity at baseline (8670/156) and follow -up (9058/153) with almost unchanged body composition., Conclusion: Persistent uncontrolled asthma is associated with sustained physical inactivity and adverse changes in body composition that might be overlooked by relying solely on BMI. Physical activity is an independent predictor of body composition and reliable long-term marker of symptom control., Competing Interests: Mustafa Abdo reports no conflict of interest. Frederik Trinkmann received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi aventis, all outside the submitted work. Anne-Marie Kirsten, Heike biller, Frauke Pedersen and Christian Herzmann report no conflict of interest. Erika von Mutius reports personal fees from Pharmaventures, personal fees from OM Pharma S. A., personal fees from Springer-Verlag GmbH, personal fees from Elsevier GmbH and Elsevier Ltd., personal fees from Peptinnovate Ltd., personal fees from Turun Yliopisto, personal fees from Tampereen Yliopisto, personal fees from Helsingin Yliopisto, personal fees from European Respiratory Society, personal fees from Deutsche Pharmazeutische Gesellschaft e. V., personal fees from Massachusetts Medical Society, personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from Böhringer Ingelheim International GmbH, personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Georg Thieme Verlag, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; In addition, Dr. von Mutius has a patent LU101064 - Barn dust extract for the prevention and treatment of diseases pending, a patent EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to ProtectImmun GmbH, a patent EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to ProtectImmun GmbH, a patent number EP1637147: Stable dust extract for allergy protection licensed to ProtectImmun GmbH, and a patent EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to ProtectImmun GmbH. Matthias V. Kopp, Gesine Hansen, Benjamin Waschki, Klaus F. Rabe and Henrik Watz reports no relevant conflict of interest. Thomas Bahmer reports grants from BMBF: Unrestricted research grant for the German Center for Lung Research (DZL), during the conduct of the study; personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Novartis, and personal fees from Roche, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Abdo et al.)

Purpose: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations., Methods: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels., Results: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors., Conclusion: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels., Competing Interests: Dr Frederik Trinkmann reports personal fees from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma, TEVA, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Sanofi Aventis, outside the submitted work. Prof. Dr. Klaus F Rabe reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, Chiesi, Teva, Sanofi & Regeneron, Berlin Chemie, GSK, and Orion Menarini, outside the submitted work. Prof. Dr. Marina Saetta reports grants from Chiesi Farmaceutici, outside the submitted work. Prof. Dr. Jens M Hohlfeld reports personal fees from Boehringer Ingelheim for consultancy and HAL for lecture fee, grants to my institution from AstraZeneca AB, Novartis, Janssen Pharmaceutica NV, ALK, Boehringer Ingelheim, LETI, GlaxoSmithKline, GSK, Astellas Pharma, Allergopharma, and Sanofi-Aventis, personal fees for consultancy from Merck & Co, Inc., lecture fee from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Pedersen et al.)

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up., Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken., Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation., Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations., Competing Interests: Dr. Ramakrishnan reports non-financial support from AstraZeneca, PhD scholarship from Australian Government Research Training Program (RTP) and junior researcher salary support from National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), during the conduct of the study and outside the submitted work. Dr. Janssens reports grants from Chiesi, AstraZeneca and GSK, advisory board membership for Boerhinger Ingelheim, AstraZeneca, Chiesi, GSK outside the submitted work; and W. Janssens is cofounder of ARTIQ, a spinoff company of KULEUVEN. Dr. Burgel reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Pfizer, Insmed and Zambon, and grants and personal fees from GSK and Vertex, outside the submitted work. Dr. Contoli reports grants and personal fees from Chiesi, AstraZeneca and GlaxoSmithKline, personal fees from Boehringer Ingelheim, Alk-Abello, Novartis and Zambon and grants from University of Ferrara, Italy, outside the submitted work. Dr. Franssen reports grants and personal fees from AstraZeneca and Novartis, and personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline and TEVA, outside the submitted work. Dr. Greening reports grants and personal fees from GSK, personal fees and non-financial support from Chiesi, and Boehringer Ingelheim outside the submitted work. Dr. Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), grants and personal fees from Grifols and CSL-Behring and lectures and advisory boards for GSK, Novartis and Roche, outside the submitted work. Dr. Gyselinck reports other non financial support from KU-Leuven, outside the submitted work. Dr. Quint reports grants from MRC, during the conduct of the study; personal fees from GSK, grants from Asthma UK, Chiesi, MRC and The Health Foundation, grants and personal fees from AZ and BI, Bayer outside the submitted work. Dr. Vanfleteren reports grants and personal fees from AstraZeneca, personal fees from Novartis, GSK, Chiesi, Menarini, Pulmonx, Resmed, Boehringer, Verona Pharma and AGA Linde outside the submitted work. Dr. Bafadhel reports grants and personal fees from AstraZeneca, personal fees from Chiesi and GSK, grants and non-financial support from AZ, non-financial support from Chiesi and GSK and advisory board membership for Albus Health and ProAxsis, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2021 Ramakrishnan et al.)

Purpose: In the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting β 2 -agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening., Patients and Methods: The effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥2 exacerbations in the previous year and various blood eosinophil counts was assessed., Results: Overall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89-1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94-1.19]). However, in patients with a history of ≥2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81-1.41] (≥100 cells/μL) to 1.45 [0.58-3.60] (≥400 cells/μL)., Conclusion: Consistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy., Competing Interests: GTF reports grants, personal fees, and nonfinancial support from Boehringer Ingelheim and AstraZeneca; grants and personal fees from Novartis, Pearl Therapeutics, Sanofi, Sunovion, and Theravance; grants from Altavant and Forest; and personal fees from Circassia, Meda, Verona, Mylan, Innoviva, and GlaxoSmithKline, outside the submitted work. AS, KT, and AM are employees of Boehringer Ingelheim. HM reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from AstraZeneca, Novartis, and ndd Medical Technologies, Inc. outside the submitted work. HW reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Berlin-Chemie, Chiesi, GlaxoSmithKline, AstraZeneca, Menarini, Novartis, Takeda, and Roche, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Ferguson et al.)

Background: Beyond smoking, several risk factors for the development of chronic obstructive pulmonary disease (COPD) have been described, among which socioeconomic status including education is of particular interest. We studied the contribution of education to lung function and symptoms relative to smoking in a group of never-smokers with COPD compared to a group of long-time ex-smokers with COPD., Methods: We used baseline data of the COSYCONET cohort, including patients of GOLD grades 1-4 who were either never-smokers (n=150, age 68.5y, 53.3% female) or ex-smokers (≥10 packyears) for at least 10 years (n=616, 68.3y, 29.9% female). Socioeconomic status was analyzed using education level and mortality was assessed over a follow-up period of 4.5 years. Analyses were performed using ANOVA and regression models., Results: Spirometric lung function did not differ between groups, whereas CO diffusing capacity and indicators of lung hyperinflation/air-trapping showed better values in the never-smoker group. In both groups, spirometric lung function depended on the education level, with better values for higher education. Quality of life and 6-MWD were significantly different in never-smokers as well as patients with higher education. Asthma, alpha-1-antitrypsin deficiency, and bronchiectasis were more often reported in never-smokers, and asthma was more often reported in patients with higher education. Higher education was also associated with reduced mortality (hazard ratio 0.46; 95% CI 0.22-0.98)., Conclusion: Overall, in the COSYCONET COPD cohort, differences in functional status between never-smokers and long-time ex-smokers were not large. Compared to that, the dependence on education level was more prominent, with higher education associated with better outcomes, including mortality. These data indicate that non-smoking COPD patients' socioeconomic factors are relevant and should be taken into account by clinicians., Competing Interests: Johanna I Lutter reports grants from German Federal Ministry of Education and Research (BMBF) with grant number 01GI0882, during the conduct of the study. Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study. Rolf Holle reports grants from German Federal Ministry of Education and Research, during the conduct of the study. Dr. Vogelmeier stated the follwoing:Relevant financial activities outside the submitted work:Grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis and German Federal Ministry of Education and Research (BMBF) Competence Network Asthma und COPD (ASCONET). Furthermore, Dr. Vogelmeier reported personal fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, Berlin Chemie/Menarini, CSL Behring, Nuvaira, MedUpdate. Kathrin Kahnert reports personal fees from Novartis GmbH, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2020 Lutter et al.)

Introduction: Ensifentrine is an inhaled first-in-class dual inhibitor of phosphodiesterase (PDE) 3 and 4. In a four-week randomized, double-blind, placebo-controlled, parallel-group study in patients with chronic obstructive pulmonary disease (COPD), nebulized ensifentrine 0.75 to 6mg twice daily significantly improved bronchodilation and symptoms, with all doses being well tolerated. Here, we report data for a number of prespecified exploratory and post hoc endpoints from this study that help to further profile the effect of ensifentrine on symptoms., Methods: Eligible patients were males or females aged 40-75 years with COPD, post-bronchodilator forced expiratory volume in 1 second 40-80% predicted. Other than being clinically stable for at least four weeks prior to entry, there were no symptomatic inclusion or exclusion criteria. The outcome measures reported in this manuscript are the Evaluating Respiratory Symptoms [E-RS™:COPD] questionnaire total score and subscales (breathlessness, cough/sputum and chest symptoms) at Weeks 1-4, Transition Dyspnea Index (TDI) focal score at Weeks 2 and 4, and St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) total score and domain data (symptoms, activity and impacts) at Week 4., Results: There was a gradual improvement versus placebo with all ensifentrine doses for all three E-RS™:COPD subscales from Week 1 to Week 4, with the greatest ensifentrine effect on the breathlessness subscale, and all four doses superior to placebo from Week 2 onwards (p<0.05). For TDI focal score, all ensifentrine doses were superior to placebo at Weeks 2 and 4 (p<0.05). In the individual SGRQ-C domains at Week 4, ensifentrine had the greatest effect on the symptoms domain, with ensifentrine 6mg superior to placebo (p<0.05)., Conclusion: In these analyses, ensifentrine demonstrated a notable early and meaningful effect on dyspnea, with this effect observed across two different assessment tools., Competing Interests: HW reports personal fees from AstraZeneca, Bayer, BerlinChemie, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, all outside the submitted work. KR and TR are employees of Verona, the sponsor of the study. TB reports personal fees from Verona, both during the conduct of the study and outside the submitted work. DS reports personal fees from Verona during the conduct of the study. Outside the submitted work, he reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance, and Verona. The authors report no other conflicts of interest in this work., (© 2020 Watz et al.)

Background: A substantial prevalence of cardiovascular disease is known for COPD, but detection of its presence, relationship to functional findings and contribution to symptoms remains challenging. The present analysis focusses on the cardiovascular contribution to COPD symptoms and their relationship to the patients' diagnostic status, medication and echocardiographic findings., Methods: Patients from the COPD cohort COSYCONET with data on lung function, including FEV 1 , residual volume/total lung capacity (RV/TLC) ratio, diffusing capacity TLCO, and echocardiographic data on left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), medical history, medication, modified British Medical Research Council dyspnea scale (mMRC) and Saint Georges Respiratory Questionnaire (SGRQ) were analyzed., Results: A total of 1591 patients (GOLD 0-4: n=230/126/614/498/123) fulfilled the inclusion criteria. Ischemic heart disease, myocardial infarction or heart failure were reported in 289 patients (18.2%); 860 patients (54%) received at least one cardiovascular medication, with more than one in many patients. LVEF<50% or LVEDD>56 mm was found in 204 patients (12.8%), of whom 74 (36.3%) had neither a cardiovascular history nor medication. Among 948 patients (59.6%) without isolated hypertension, there were 21/55 (38.2%) patients with LVEF<50% and 47/88 (53.4%) with LVEDD>56 mm, who lacked both a cardiac diagnosis and medication. LVEDD and LVEF were linked to medical history; LVEDD was dependent on RV/TLC and LVEF on FEV 1 . Exertional COPD symptoms were best described by mMRC and the SGRQ activity score. Beyond lung function, an independent link from LVEDD on symptoms was revealed., Conclusion: A remarkable proportion of patients with suspicious echocardiographic findings were undiagnosed and untreated, implying an increased risk for an unfavorable prognosis. Cardiac size and function were dependent on lung function and only partially linked to cardiovascular history. Although the contribution of LV size to COPD symptoms was small compared to lung function, it was detectable irrespective of all other influencing factors. However, only the mMRC and SGRQ activity component were found to be suitable for this purpose., Competing Interests: Peter Alter, Barbara A Mayerhofer, Kathrin Kahnert, Henrik Watz, Benjamin Waschki, Frank Biertz, and Rudolf A Jörres report no conflicts of interest in this work. Stefan Andreas report grants and personal fees from Boehringer Ing and Pfizer, and personal fees from Novartis, Astra Zeneca, GSK, Chiesi, and Merini, outside the submitted work. Robert Bals report grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), during the conduct of the study, and grants and personal fees from AstraZeneca, Novartis, and Boehringer Ingelheim, and personal fees from GlaxoSmithKline, Grifols, and CSL Behring, outside the submitted work. Claus F Vogelmeier report grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis, personal fees from CSL Behring, Chiesi, Menarini, Mundipharma, Teva, and Cipla, and grants from Bayer Schering Pharma AG, MSD, and Pfizer, outside the submitted work. The authors report no other conflicts of interest regarding this work., (© 2019 Alter et al.)

Background: AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate (AB/FF) vs its monocomponents and tiotropium (TIO) in patients with moderate-to-very severe symptomatic COPD (NCT02796677)., Methods: In this 24-week, Phase III, double-dummy, active-controlled study, symptomatic patients (COPD Assessment Test score ≥10) were randomized to twice-daily AB/FF 400/12 µg, AB 400 µg, or FF 12 µg, or once-daily TIO 18 µg. Co-primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV 1 (AB/FF vs AB) and in pre-dose (trough) FEV 1 (AB/FF vs FF). Non-inferiority of AB vs TIO in pre-dose FEV 1 was also an objective. Normalized area under the curve (AUC) 0-3/3 h FEV 1 and nighttime and early morning symptoms were also assessed. A subgroup participated in a 24-hour serial spirometry sub-study., Results: A total of 1,594 patients were randomized; 566 entered the sub-study. At week 24, 1-hour post-dose FEV 1 significantly improved with AB/FF vs AB, FF, and TIO (84, 84, and 92 mL; all P <0.0001). AB/FF significantly improved trough FEV 1 vs FF (55 mL, P <0.001) and AB was non-inferior to TIO. AB/FF significantly improved AUC 0-3/3 h FEV 1 vs all comparators ( P <0.0001) and provided significant improvements in early morning symptoms vs TIO. The 24-hour spirometry demonstrated significantly greater improvements with AB/FF in AUC 12-24/12 h vs all comparators, and in AUC 0-24/24 h vs FF or TIO at week 24., Conclusion: In patients with moderate-to-very severe symptomatic COPD, twice-daily AB/FF significantly improved lung function vs monocomponents and TIO, and early morning symptom control vs TIO., Competing Interests: Disclosure SS has received grants from AstraZeneca, Dey, and Pearl Therapeutics. He has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cempra, CSL Behring, Forest, GlaxoSmithKline, Merck, Pearl Therapeutics, Pulmonx, Reckitt Benckiser, Sunovion, and Theravance. EK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl Therapeutics, Sunovion, Teva, and Theravance. He has conducted multicenter clinical trials for ~ 40 pharmaceutical companies. HW has received honoraria for consultancies, lectures, and travel support to attend scientific congresses from Almirall, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Takeda. His institution received investigator fees for participation in clinical trials from Almirall, AstraZeneca, Bayer Health Care, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis, and Takeda. GTF reports consulting and advisory board participation for AstraZeneca, Boehringer Ingelheim, Forest Laboratories, Novartis, Pearl Therapeutics, Sunovion, and Verona Pharma; consulting fees from Receptos; speaking engagements for AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Pearl Therapeutics, and Sunovion; and research grants from AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Novartis, Pearl Therapeutics, Sanofi, Sunovion, and Theravance Biopharma. RMM has received consulting fees, speaker’s fees, and travel expenses from Boehringer Ingelheim and has also received compensation for participating in advisory boards for Almirall, AstraZeneca, Boehringer Ingelheim, and Novartis. Furthermore, RMM has received compensation for participation in multicenter clinical trials in the past 5 years from several companies including Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Mundipharma, Novartis, Pearl, Roche, and Takeda. RS, EM, DJ, and EGG are employees of AstraZeneca PLC, Barcelona, Spain. The authors report no other conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses., Materials and Methods: Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR., Results: Six candidate genes were selected for further investigations: Aquaporin 3 ( AQP3 ), extracellular matrix protein 1 ( ECM1 ), four and a half LIM domain 1 ( FHL1 ), milk fat globule epidermal growth factor 8 ( MFGE8 , lactadherin), phosphodiesterase 4D-interacting protein ( PDE4DIP ), and creatine transporter SLC6A8 . All six proteins were allocated to distinct cell types by immunohistochemistry. Upon stimulation with cigarette smoke extract, human type II pneumocytes showed a dose-dependent down-regulation of MFGE8 , while ECM1 and FHL1 also tended to be down-regulated. Although present, none of the candidates was regulated by cigarette smoke extract in primary human macrophages., Discussion: MFGE8 turned out to be an interesting new candidate gene in COPD deserving further studies., Competing Interests: Disclosure The author Lena Heinbockel is supported by the Deutsche Forschungsgemeinschaft (DFG, project DR797/3-1 611672). The authors report no other conflicts of interest in this work.

Background: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy., Methods: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment., Results: Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47-0.93], p =0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47-0.83], p =0.001) compared with those in the 500 µg OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD, the difference was not significant (OR 0.76, p =0.114, and OR 0.78, p =0.091, respectively) compared with ROF 500 µg OD., Conclusion: A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD resulted in reduced treatment discontinuation and improved tolerability., Competing Interests: Disclosure NB was employed by Takeda Development Centre Europe Ltd, London, UK. The authors report no other conflicts of interest in this work.

The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 μg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair ® dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P =0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P <0.0001). AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 ( P <0.01 and P <0.0001, respectively) and Week 8 ( P <0.05 and P <0.0001, respectively). AB/FF achieved higher step counts ( P <0.01) with fewer inactive patients ( P <0.0001) at Week 4 versus placebo. Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo. AB/FF 400/12 μg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI. A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF., Competing Interests: Disclosure Henrik Watz has received honoraria for consultancies, lectures, and travel support to attend scientific congresses from Almirall, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Takeda. His institution received investigator fees for participation in clinical trials from Almirall, AstraZeneca, Bayer Health Care, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi Aventis, Roche, and Takeda. Thierry Troosters has received grants from the Innovative Medicines Initiative Joint Undertaking and speaker fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. Kai M Beeh’s institution has received compensation for organizing or participating in advisory boards (from Almirall Hermal, Cytos, Chiesi, Boehringer Ingelheim, AstraZeneca, Mundipharma, Novartis, and Teva), has participated in scientific meetings or courses (supported by Almirall Hermal, AstraZeneca, Boehringer Ingelheim, Mundipharma, Novartis, Pfizer, and Teva) in the past 3 years, has received consulting fees (from Ablynx, Apellis Pharmaceuticals, Sterna GmbH, Chiesi, and Cytos), and has received compensation for the design, performance, or participation in single or multicenter clinical trials in the past 3 years (from Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmith-Kline, Infinity, Mundipharma, Novartis, Pfizer, Revotar Biopharmaceuticals, Sterna GmbH, Teva, and Zentiva). Judith Garcia-Aymerich’s institution has received consulting and lecture fees from AstraZeneca, and lecture fees from Esteve. Pierluigi Paggiaro is on the AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Novartis boards and has received lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratori Guidotti, Menarini, Mundipharma, Novartis, Sanofi, and Teva. Eduard Molins, Diana Jarreta, and Esther Garcia Gil are employees of AstraZeneca PLC, Barcelona, Spain. Massimo Notari is an employee of A. Menarini Farmaceutica Internazionale S.R.L., Firenze, Italy. Antonio Zapata is an employee of Laboratorios Menarini, S.A., Badalona, Spain. The authors report no other conflicts of interest in this work.

Introduction: Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear., Methods: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle-brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined., Results: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis., Conclusion: The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland-Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of -0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease characterized by nonreversible airway obstruction. Well-characterized symptoms such as exertional dyspnea and fatigue have a negative impact on patients' quality of life (QoL) and restrict physical activity in daily life. The impact of COPD symptoms on QoL is often underestimated; for example, 36% of patients who describe their symptoms as being mild-to-moderate also admit to being too breathless to leave the house. Additionally, early morning and nighttime symptoms are a particular problem. Methods are available to allow clinicians to accurately assess COPD symptoms, including patient questionnaires. Integrated approaches to COPD management, particularly pulmonary rehabilitation, are effective strategies for addressing symptoms, improving exercise capacity and, potentially, also increasing physical activity. Inhaled bronchodilators continue to be the mainstay of drug therapy in COPD, where options can be tailored to meet patients' needs with careful selection of the inhaled medication and the device used for its delivery. Overall, an integrated approach to disease management should be considered for improving QoL and subsequent patient outcomes in COPD.

There is an ongoing demand for easily accessible biomarkers related to pathophysiological processes in chronic obstructive pulmonary disease (COPD). Short-term intense exercise is known to increase the peripheral blood levels of cytokines. Therefore, we tested the potential and the repeatability of an exercise challenge to amplify seven serum biomarkers (interleukin 6 [IL6], C-reactive protein [CRP], myeloperoxidase [MPO], leukotriene B4, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and von Willebrand factor [VWF]) in smokers with and without COPD. Twenty-three smokers with moderate COPD (GOLD 2) and 23 sex- and age-matched healthy smokers underwent up to 30-minute submaximal, constant-load exercise (75% of maximum work load) on two occasions separated by 4 weeks (second challenge n=19/20). Serum samples were obtained before, 5 minutes after the start, at the end of exercise (maximum 30 minutes or until exhaustion), and after additional 20 minutes of rest. The median (interquartile range) exercise time until exhaustion in the two challenges was 10.0 (4.0) minutes and 10.0 (8.0) minutes in smokers with COPD and 22.0 (16.0) minutes and 26.5 (14.5) minutes in healthy smokers. The exercise challenge significantly increased the serum concentrations of IL6 and VWF, but decreased the concentrations of MPO. Healthy smokers showed a significantly greater increase (at the end of exercise compared to before exercise) in IL6 (P=0.01) and a larger decline (P=0.03) in MPO. The overall profile of the serum markers during the exercise challenge was shown to be repeatable in the second challenge. In summary, intense load exercise is capable of changing the concentration of inflammatory and endothelial function markers. Especially, the decline in the level of MPO, a marker closely related to cardiovascular risk, appears to be of clinical interest, as the exercise-induced decline might be related to the beneficial effects of physical activity in general.

Background: indacaterol is a novel, inhaled once-daily ultra-long-acting β(2)-agonist for the treatment of chronic obstructive pulmonary disease (COPD)., Objectives: this study compared the onset of action of single doses of indacaterol 150 and 300 μg with salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo in moderate-to-severe COPD patients., Methods: this was a multicenter, randomized, double-blind, placebo-controlled crossover study. The primary variable was forced expiratory volume in one second (FEV(1)) at five minutes postdose., Results: out of 89 patients randomized (mean age 62 years), 86 completed the study. At five minutes postdose, both indacaterol doses were statistically and clinically superior to placebo (P < 0.001), with treatment-placebo differences in FEV(1) of 100 (95% confidence interval [CI] 70-130) mL and 120 (95% CI 90-150) mL for indacaterol 150 and 300 μg, respectively. FEV(1) at five minutes postdose with both indacaterol doses was numerically higher than for salbutamol (10 and 30 mL for indacaterol 150 and 300 μg, respectively) and significantly higher than for salmeterol-fluticasone (50 mL, P = 0.003; 70 mL, P < 0.001, respectively). Moreover, both indacaterol doses showed significantly higher FEV(1) than placebo (P < 0.001) at all postdose time points. The numbers of patients with an FEV(1) increase of at least 12% and 200 mL at five minutes postdose were 16 (18.8%), 24 (27.6%), 20 (23.3%), 8 (9.1%), and 3 (3.4%) for indacaterol 150 and 300 μg, salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo, respectively., Conclusions: single doses of indacaterol 150 and 300 μg demonstrated a fast onset of action similar to that for salbutamol and faster than that for salmeterol-fluticasone.