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Maud Koopman,1– 3 Frits ME Franssen,1– 3 Swetlana Gaffron,4 Henrik Watz,5 Thierry Troosters,6,7 Judith Garcia-Aymerich,8– 10 Pierluigi Paggiaro,11 Eduard Molins,12 Miguel Moya,12 Lindy van Burk,13 Dieter Maier,14 Esther Garcia Gil,12 Emiel FM Wouters,1,3,15 Lowie EGW Vanfleteren,16 Martijn A Spruit1– 3 1Department of Research and Development, CIRO+, Center of Expertise for Chronic Organ Failure, Horn, the Netherlands; 2NUTRIM, School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht, the Netherlands; 3Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands; 4Viscovery Software GmbH, Vienna, Austria; 5Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6Department of Rehabilitation Sciences, KU Leuven – University of Leuven, Leuven, Belgium; 7Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium; 8Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; 9Universitat Pompeu Fabra (UPF), Barcelona, Spain; 10CIBER Epidemiología y Salud Publica (CIBERESP), Madrid, Spain; 11Department of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Pisa, Italy; 12AstraZeneca, Barcelona, Spain; 13AstraZeneca, Den Haag, the Netherlands; 14Biomax Informatics AB, Planegg, 82152, Germany; 15Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 16COPD Center, Sahlgrenska University Hospital, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenCorrespondence: Maud Koopman, CIRO+, Center of Expertise for Chronic Organ Failure, Hornerheide 1, Horn, 6085 NM, the Netherlands, Email maudkoopman@gmail.comRationale: 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.Keywords: COPD, hyperinflation, physical activity

Afroditi K Boutou,1,2,* Yogini Raste,1,* Heleen Demeyer,3 Thierry Troosters,3 Michael I Polkey,1 Ioannis Vogiatzis,4,5 Zafeiris Louvaris,4 Roberto A Rabinovich,6 Thys van der Molen,7 Judith Garcia-Aymerich,8–10 Nicholas S Hopkinson1 On behalf of the PROactive consortium1National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK; 2Department of Respiratory Medicine, “G. Papanikolaou” Hospital, Thessaloniki, Greece; 3Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences and Respiratory Division, University Hospital Leuven, Leuven, Belgium; 4First Department of Respiratory Medicine, National & Kapodistrian University of Athens, Athens, Greece; 5Department of Sport, Exercise and Rehabilitation, Northumbria University, Newcastle, UK; 6ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK; 7Department of General Practice, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 8ISGlobal, Barcelona, Spain; 9Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 10Universitat Pompeu Fabra (UPF), Barcelona, SpainCorrespondence: Afroditi K BoutouDepartment of Respiratory Medicine, “G. Papanikolaou” Hospital, Exohi, Thessaloniki 57010, GreeceTel +30 231 330 7277Email afboutou@yahoo.com*These authors contributed equally to this workPurpose: Longitudinal data on the effect of time and environmental conditions on physical activity (PA) among COPD patients are currently scarce, but this is an important factor in the design of trials to test interventions that might impact on it. Thus, we aimed to assess the effect of time and climate conditions (temperature, day length and rainfall) on progression of PA in a cohort of COPD patients.Patients and methods: This is a prospective, multicenter, cohort study undertaken as part of the EU/IMI PROactive project, in which we assessed 236 COPD patients simultaneously wearing two activity monitors (Dynaport MiniMod and Actigraph GT3X). A multivariable generalized linear model analysis was conducted to describe the effect of the explanatory variables on PA measures, over three time points (baseline, 6 and 12 months).Results: At 12 months (n=157; FEV1% predicted=57.7±21.9) there was a significant reduction in all PA measures (Actigraph step count (4284±3533 vs 3533±293)), Actigraph moderate- to vigorous-intensity PA ratio (8.8 (18.8) vs 6.1 (15.7)), Actigraph vector magnitude units (374,902.4 (265,269) vs 336,240 (214,432)), MiniMod walking time (59.1 (34.9) vs 56.9 (38.7) mins) and MiniMod PA intensity (0.183 (0) vs 0.181 (0)). Time had a significant, negative effect on most PA measures in multivariable analysis, after correcting for climate factors, study center, age, FEV1% predicted, 6MWD and other disease severity measures. Rainfall was the only climate factor with a negative effect on most PA parameters.Conclusion: COPD patients demonstrate a significant decrease in PA over 1 year follow-up, which is further affected by hours of rainfall, but not by other climate considerations.Keywords: physical activity, chronic obstructive pulmonary disease, elapsed time, climate

Christian R Osadnik,1–4,* Matthias Loeckx,1,5,6,* Zafeiris Louvaris,1,7 Heleen Demeyer,1,6 Daniel Langer,1,6 Fernanda M Rodrigues,1,6 Wim Janssens,6,8 Ioannis Vogiatzis,7,9 Thierry Troosters1,6 1Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium; 2Department of Physiotherapy, Monash University, Melbourne, Victoria, Australia; 3Monash Lung and Sleep, Monash Health, Melbourne, Victoria, Australia; 4Institute for Breathing and Sleep, Melbourne, Victoria, Australia; 5Department of Physiotherapy, LUNEX International University of Health, Exercise and Sports, Differdange, Luxembourg; 6Respiratory Division, University Hospitals, KU Leuven, Leuven, Belgium; 7Faculty of Physical Education and Sports Sciences, National and Kapodistrian University of Athens, Athens, Greece; 8Department of Chronic Disease, Metabolism and Aging, KU Leuven, Leuven, Belgium; 9Department of Sport, Exercise and Rehabilitation, Northumbria University Newcastle, Newcastle upon Tyne, UK *These authors contributed equally to this work Purpose: Pulmonary rehabilitation (PR) enhances exercise tolerance in patients with COPD; however, improvements in physical activity (PA) are not guaranteed. This study explored the relationship between baseline exercise tolerance and changes in PA after PR.Materials and methods: Patient data from prospective clinical trials in the PR settings of Athens and Leuven (2008–2016) were analyzed. Validated PA monitors were worn for 1 week before and after a 12-week program. The proportion of patients who improved PA levels ≥1,000 steps/day (“PA responders”) after PR was compared between those with initial 6-minute walk distance [6MWDi]

Henrik Watz,1 Thierry Troosters,2 Kai M Beeh,3 Judith Garcia-Aymerich,4–6 Pierluigi Paggiaro,7 Eduard Molins,8 Massimo Notari,9 Antonio Zapata,10 Diana Jarreta,8 Esther Garcia Gil8 1Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 2Department of Rehabilitation Sciences, Pulmonary Rehabilitation and Respiratory Division, University Hospital Leuven, KU Leuven, Leuven, Belgium; 3insaf Respiratory Research Institute GmbH, Wiesbaden, Germany; 4Barcelona Institute of Global Health (ISGlobal), Barcelona, Spain; 5Universitat Pompeu Fabra (UPF), Barcelona, Spain; 6CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 7Department of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Pisa, Italy; 8AstraZeneca PLC, Barcelona, Spain; 9A. Menarini Farmaceutica Internazionale S.R.L., Firenze, Italy; 10Laboratorios Menarini, S.A., Badalona, Spain Abstract: 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

Carlos A Camillo,1,2 Daniel Langer,1,2 Christian R Osadnik,1,3–5 Lisa Pancini,2 Heleen Demeyer,1,2 Chris Burtin,1,6 Rik Gosselink,1,2 Marc Decramer,2 Wim Janssens,2 Thierry Troosters1,2 1KU Leuven, Department of Rehabilitation Sciences, Leuven, Belgium; 2University Hospital Leuven, Respiratory Division and Rehabilitation, Leuven, Belgium; 3Monash University, Department of Physiotherapy, Melbourne, VIC, Australia; 4Institute for Breathing and Sleep, Melbourne, VIC, Australia; 5Monash Health, Monash Lung and Sleep, Melbourne, VIC, Australia; 6Hasselt University, Rehabilitation Research Centre, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium Abstract: The impact of rehabilitation-induced changes in 6-minute walk distance (6MWD) on the survival of patients with chronic obstructive pulmonary disease (COPD) has not been fully elucidated. This study sought to determine the association of baseline 6MWD and its changes after pulmonary rehabilitation (PR) with 5-year survival in patients with COPD. Patients who were referred to a 12-week outpatient PR program were followed up for 5 years postcompletion, and survival status was verified. Survival was analyzed according to four groups based upon initial 6MWD (6MWDi) and its changes (Δ6MWD) after PR (Group 1: 6MWDi ≥350 m and Δ6MWD ≥30 m; Group 2: 6MWDi ≥350 m and Δ6MWD 30 m after PR are associated with worse 5-year survival in patients with COPD. Keywords: pulmonary disease, chronic obstructive, exercise training, mortality, 6-minute walk test, minimally important difference

Nini H Jonkman,1 Heleen Westland,1 Jaap CA Trappenburg,1 Rolf HH Groenwold,2 Erik WMA Bischoff,3 Jean Bourbeau,4 Christine E Bucknall,5 David Coultas,6 Tanja W Effing,7 Michael J Epton,8 Frode Gallefoss,9 Judith Garcia-Aymerich,10–12 Suzanne M Lloyd,13 Evelyn M Monninkhof,2 Huong Q Nguyen,14 Job van der Palen,15,16 Kathryn L Rice,17 Maria Sedeno,4 Stephanie JC Taylor,18 Thierry Troosters,19 Nicholas A Zwar,20 Arno W Hoes,2 Marieke J Schuurmans1 1Department of Rehabilitation, Nursing Science and Sports, 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands; 4Respiratory Epidemiology and Clinical Research Unit, Department of Medicine, McGill University Health Center, McGill University, Montreal, QC, Canada; 5Department of Respiratory Medicine, Glasgow Royal Infirmary, Glasgow, UK; 6Veterans Administration Portland Health Care System and Oregon Health & Science University, Portland, OR, USA; 7Department of Respiratory Medicine, Repatriation General Hospital, Adelaide, SA, Australia; 8Canterbury District Health Board, Respiratory Services, Christchurch Hospital, Christchurch, New Zealand; 9Department of Pulmonary Medicine, Sorlandet Hospital, Kristiansand, Norway; 10Centre for Research in Environmental Epidemiology CREAL, 11Pompeu Fabra University, 12CIBER Epidemiología y Salud Pública CIBERESP, Barcelona, Spain; 13Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK; 14Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA; 15Department of Research Methodology, Measurement and Data Analysis, University of Twente, 16Department of Clinical Epidemiology, Medisch Spectrum Twente, Enschede, the Netherlands; 17Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Minneapolis Veterans Affairs Health Care Service and University of Minnesota, Minneapolis, MN, USA; 18Centre for Primary Care and Public Health, Queen Mary University of London, London, UK; 19Department of Rehabilitation Sciences, Catholic University of Leuven, Leuven, Belgium; 20School of Public Health and Community Medicine, UNSW Australia, Sydney, NSW, Australia Background: Self-management interventions are considered effective in patients with COPD, but trials have shown inconsistent results and it is unknown which patients benefit most. This study aimed to summarize the evidence on effectiveness of self-management interventions and identify subgroups of COPD patients who benefit most.Methods: Randomized trials of self-management interventions between 1985 and 2013 were identified through a systematic literature search. Individual patient data of selected studies were requested from principal investigators and analyzed in an individual patient data meta-analysis using generalized mixed effects models.Results: Fourteen trials representing 3,282 patients were included. Self-management interventions improved health-related quality of life at 12 months (standardized mean difference 0.08, 95% confidence interval [CI] 0.00–0.16) and time to first respiratory-related hospitalization (hazard ratio 0.79, 95% CI 0.66–0.94) and all-cause hospitalization (hazard ratio 0.80, 95% CI 0.69–0.90), but had no effect on mortality. Prespecified subgroup analyses showed that interventions were more effective in males (6-month COPD-related hospitalization: interaction P=0.006), patients with severe lung function (6-month all-cause hospitalization: interaction P=0.016), moderate self-efficacy (12-month COPD-related hospitalization: interaction P=0.036), and high body mass index (6-month COPD-related hospitalization: interaction P=0.028 and 6-month mortality: interaction P=0.026). In none of these subgroups, a consistent effect was shown on all relevant outcomes.Conclusion: Self-management interventions exert positive effects in patients with COPD on respiratory-related and all-cause hospitalizations and modest effects on 12-month health-related quality of life, supporting the implementation of self-management strategies in clinical practice. Benefits seem similar across the subgroups studied and limiting self-management interventions to specific patient subgroups cannot be recommended. Keywords: chronic obstructive pulmonary disease, individual patient data meta-analysis, self-management, subgroup analysis

Iván Dueñas-Espín,1–5 Heleen Demeyer,6 Elena Gimeno-Santos,1–3 Michael I Polkey,7 Nicholas S Hopkinson,7 Roberto A Rabinovich,8 Fabienne Dobbels,9 Niklas Karlsson,10 Thierry Troosters,6,11 Judith Garcia-Aymerich1–3 On behalf of the PROactive Consortium 1ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 2Universitat Pompeu Fabra (UPF), 3CIBEREpidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 4Secretaría Nacional de Educación Superior, Ciencia, Tecnología e Innovación del Ecuador (SENESCYT), Quito, Ecuador; 5Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 6Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium; 7NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK; 8ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK; 9Department of Public Health and Primary Care, Academic Centre for Nursing and Midwifery, KU Leuven, Leuven, Belgium; 10Health Economics and Outcomes Research, AstraZeneca R&D, Mölndal, Sweden; 11Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium Background: The role of anxiety and depression in the physical activity (PA) of patients with COPD is controversial. We prospectively assessed the effect of symptoms of anxiety and depression on PA in COPD patients.Methods: We evaluated anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), PA (Dynaport® accelerometer), and other relevant characteristics in 220 COPD patients from five European countries at baseline and at 6 and 12 months of follow-up. HADS score was categorized as: no symptoms (score 0–7), suggested (8–10), and probable (>11) anxiety or depression. We estimated the association between anxiety and depression at t (baseline and 6 months) and PA at t+1 (6 and 12 months) using regression models with a repeated measures approach.Results: Patients had a mean (standard deviation) age of 67 (8) years, forced expiratory volume in 1 second 57 (20)% predicted. At baseline, the prevalence of probable anxiety and depression was 10% and 5%, respectively. In multivariable models adjusted by confounders and previous PA, patients performed 81 fewer steps/day (95% confidence interval, -149 to -12, P=0.02) per extra point in HADS-depression score. HADS-anxiety symptoms were not associated with PA.Conclusion: In COPD patients, symptoms of depression are prospectively associated with a measurable reduction in PA 6 months later. Keywords: COPD, anxiety, depression, HADS, physical activity, prospective study

Kristina Vermeersch,1 Maria Gabrovska,2 Griet Deslypere,3 Ingel K Demedts,4 Hans Slabbynck,5 Joseph Aumann,3 Vincent Ninane,2 Geert M Verleden,1 Thierry Troosters,1,6 Kris Bogaerts,7,8 Guy G Brusselle,9 Wim Janssens1 On behalf of the BACE Trial Investigators 1KU Leuven, Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Faculty of Medicine, Leuven, Belgium; 2Department of Pneumology, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; 3Department of Pneumology, Jessa Ziekenhuis, Hasselt, Belgium; 4Department of Respiratory Medicine, AZ Delta Roeselare-Menen, Roeselare, Belgium; 5Department of Respiratory Medicine, ZNA Middelheim, Antwerpen, Belgium; 6KU Leuven, Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, Leuven, Belgium; 7KU Leuven, Department of Public Health and Primary Care, I-BioStat, Leuven, Belgium; 8Hasselt University, Hasselt, Belgium; 9Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium Background: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions.Methods/design: Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge.Discussion: We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs. Keywords: COPD, acute exacerbation, macrolide antibiotics, azithromycin, physical activity, RCT