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Maud Koopman,1– 3 Rein Posthuma,1– 3 Lowie EGW Vanfleteren,4 Sami O Simons,2,3 Frits ME Franssen1– 3 1Research and Development, Ciro+, Horn, the Netherlands; 2NUTRIM, Institute of Nutrition and Translational Research in Metabolism, University Maastricht, Maastricht, the Netherlands; 3Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands; 4COPD Center, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, SwedenCorrespondence: Frits ME Franssen, CIRO+, Hornerheide 1, Horn, 6085, NM, the Netherlands, Email fritsfranssen@ciro-horn.nlAbstract: Lung hyperinflation (LH) is a common clinical feature in patients with chronic obstructive pulmonary disease (COPD). It results from a combination of reduced elastic lung recoil as a consequence of irreversible destruction of lung parenchyma and expiratory airflow limitation. LH is an important determinant of morbidity and mortality in COPD, partially independent of the degree of airflow limitation. Therefore, reducing LH has become a major target in the treatment of COPD over the last decades. Advances were made in the diagnostics of LH and several effective interventions became available. Moreover, there is increasing evidence suggesting that LH is not only an isolated feature in COPD but rather part of a distinct clinical phenotype that may require a more integrated management. This narrative review focuses on the pathophysiology and adverse consequences of LH, the assessment of LH with lung function measurements and imaging techniques and highlights LH as a treatable trait in COPD. Finally, several suggestions regarding future studies in this field are made.Keywords: COPD, hyperinflation, treatable trait, emphysema, phenotype

Maria Minter,1,2 Jenny van Odijk,1 Hanna Augustin,1 Felipe VC Machado,3,4 Frits ME Franssen,5,6 Martijn A Spruit,5,6 Lowie EGW Vanfleteren1,5 1Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 405 30, Sweden; 2Department of Lung Medicine, Angered Hospital, SV Hospital Group, Angered, 424 22, Sweden; 3Rehabilitation Research Center (REVAL), Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium; 4Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; 5Department of Research and Development, Ciro, Horn, the Netherlands; Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands; 6Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Faculty of Health, Medicine, and Life Sciences, Maastricht University Medical Centre+, Maastricht, the NetherlandsCorrespondence: Maria Minter, Department of Lung Medicine, Angered Hospital, SV Hospital Group, Angered, 424 22, Sweden, Email maria.minter@gu.seBackground: Alterations in body weight and composition are common in patients with chronic obstructive pulmonary disease (COPD) and are independent predictors for morbidity and mortality. Low vitamin D status is also more prevalent in patients with COPD compared to controls and has been related to lower lung function, muscle atrophy and impaired musculoskeletal function. This study aimed to evaluate the association between vitamin D levels and status with body composition (BC), as well as with its changes over time.Patients and Methods: Patients with COPD and controls without COPD, participating in the Individualized COPD Evaluation in relation to Ageing (ICE‐Age) study, a prospective observational study, were included. Plasma 25-hydroxyvitamin D (25(OH)D) was measured at baseline and BC was measured by dual‐energy X‐ray absorptiometry scan, at baseline and after two years of follow-up. Multiple linear regression analyses were performed to assess the relationships between 25(OH)D (nmol/l) and longitudinal changes in BMI, fat-free mass index (FFMI), fat mas index (FMI) and bone mineral density (BMD).Results: A total of 192 patients with COPD (57% males, mean ± SD age, 62 ± 7, FEV1, 49 ± 16% predicted) and 199 controls (45% males, mean ± SD age 61 ± 7) were included in this study. Vitamin D levels were significantly lower in patients with COPD (64 ± 26 nmol/L, 95% CI 60– 68 nmol/L versus 75 ± 25 nmol/L, 95% CI 72– 79 nmol/L) compared to controls. Both patients and controls presented a significant decline in FFMI and T-score hip, but vitamin D level or status did not determine differences in BC or changes in BC over time in either COPD or controls.Conclusion: Vitamin D status was not associated with BC or longitudinal changes in BC. However, vitamin D insufficiency and low BMD were more prevalent in patients with COPD compared to controls.Keywords: chronic obstructive pulmonary disease, body composition, vitamin D, longitudinal changes, fat-free mass, bone mineral density

Rein Posthuma,1– 3 Lowie EGW Vanfleteren,4,5 Swetlana Gaffron,6 Anouk W Vaes,1 Frits ME Franssen,1– 3 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; 4COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden; 5Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6Viscovery Software GmbH, Vienna, AustriaCorrespondence: Rein Posthuma, CIRO+, Center of expertise for chronic organ failure, Hornerheide 1, Horn, 6085 NM, the Netherlands, Email reinposthuma@ciro-horn.nlPurpose: Long-acting bronchodilators (LABD), in general, reduce respiratory symptoms, improve exercise endurance time and pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, there might be heterogeneity in improvement for several outcomes on an individual level. Therefore, we aimed to profile the multidimensional response in patients receiving tiotropium/olodaterol (T/O) using self-organizing maps (SOM).Materials and Methods: This is a secondary analysis of the TORRACTO study: a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effects of T/O (2.5/5 and 5/5 μg) compared with placebo after 6 and 12 weeks of treatment in patients with COPD. In the current study, we used endurance time, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), inspiratory capacity (IC) at rest and IC at isotime (ICiso) to identify clusters by means of SOM in patients treated with T/O.Results: Six clusters with distinct response profiles were generated at week 12 in COPD patients receiving T/O (n = 268). Patients in cluster 1 improved significantly on all outcomes, whilst cluster 5 showed strong improvement in endurance time (357s); contrarily, FEV1, FVC, ICrest and ICiso decreased when compared to baseline.Conclusion: Individual responses on endurance time and pulmonary function after 12 weeks of T/O are heterogeneous. This study identified clusters in COPD patients with markedly different multidimensional response on LABD.Keywords: COPD, long-acting bronchodilators, outcomes

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

Sanjay Ramakrishnan,1– 3 Wim Janssens,4 Pierre-Regis Burgel,5 Marco Contoli,6 Frits ME Franssen,7 Neil J Greening,8 Timm Greulich,9 Iwein Gyselinck,4 Andreas Halner,1 Arturo Huerta,10 Rebecca L Morgan,11 Jennifer K Quint,12 Lowie EGW Vanfleteren,13 Kristina Vermeersch,4 Henrik Watz,14 Mona Bafadhel1 1Respiratory Medicine Unit, Nuffield Department of Medicine - Experimental Medicine, University of Oxford, Oxford, UK; 2 National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), University of Oxford, Oxford, UK; 3School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; 4Department of Respiratory Diseases, UZ Leuven, Research Group BREATHE, KU Leuven, Leuven, Belgium; 5Faculty of Medicine, University of Paris and INSERM 1016 Institut Cochin, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; 6Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, Netherlands; 8Department of Respiratory Sciences, NIHR Leicester Biomedical Research Centre (Respiratory), Glenfield Hospital, Leicester, UK; 9Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps University, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 10Pulmonary and Critical Care Division, Clinica Sagrada Familia, IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; 11Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada; 12National Heart & Lung Institute, Imperial College, London, UK; 13COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Department of Internal Medicine and Clinical Nutrition at Institute of Medicine, SU Sahlgrenska, Göteborg, Sweden; 14Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, GermanyCorrespondence: Mona BafadhelRespiratory Medicine Unit, Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxford, UKTel +44 1865 612898Email mona.bafadhel@ndm.ox.ac.ukBackground: 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.Keywords: COPD, disease exacerbation, hospitalisation, patient care, consensus development, expert opinion

Rob Janssen,1 Emiel FM Wouters,2 Wim Janssens,3 Willeke F Daamen,4 Paul Hagedoorn,5 Hugo AJM de Wit,6 Jef Serré,3 Ghislaine Gayan-Ramirez,3 Frits ME Franssen,2 Niki L Reynaert,2 Jan H von der Thüsen,7 Henderik W Frijlink5 1Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands; 3Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium; 4Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; 5Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, Groningen, University of Groningen, Groningen, The Netherlands; 6Department of Clinical Pharmacy, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; 7Department of Pathology, Erasmus Medical Center, Rotterdam, The NetherlandsCorrespondence: Rob JanssenDepartment of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Weg Door Jonkerbos 100, Nijmegen, SZ 6532, The NetherlandsEmail rob.janssen@cwz.nlAbstract: Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.Keywords: collagen, copper, desmosine, elastin, emphysema, fibulin-5, heparin, lysyl oxidase, lysyl oxidase-like protein 1, tropoelastin

Spencer J Keene,1–3 Rachel E Jordan,1 Frits ME Franssen,3,4 Frank de Vries,2,5 James Martin,1 Alice Sitch,1,6 Alice Margaret Turner,1 Andrew P Dickens,1 David Fitzmaurice,7 Peymane Adab1 1Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; 2Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands; 3Ciro, Horn, the Netherlands; 4Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands; 5Utrecht Institute for Pharmaceutical Sciences Utrecht University, Utrecht, The Netherlands; 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK; 7Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UKCorrespondence: Rachel E JordanInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UKTel +44 0121 414 6775Email r.e.jordan@bham.ac.ukBackground: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation.Objectives: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods.Patients and methods: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots.Results: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69–0.79). Similar performance was found for 1- (AUC= 0.73; 0.66–0.80) and 2-year mortality (0.72; 0.67–0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70–1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45–1.13) and 2-year (0.79; 0.57–1.01) mortality.Discussion: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks.Keywords: pulmonary disease, chronic obstructive, mortality, prognosis, validation studies

Frits ME Franssen1,2, Peter Alter,3 Nadav Bar,4 Birke J Benedikter5,6, Stella Iurato,7 Dieter Maier,8 Michael Maxheim,3 Fabienne K Roessler,4 Martijn A Spruit,1–2,9 Claus F Vogelmeier,3 Emiel FM Wouters1,2, Bernd Schmeck3,5 On behalf of the SysMed-COPD consortium 1Department of Research and Education, CIRO, Horn, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Chemical Engineering, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 5Institute for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 6Department of Medical Microbiology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands; 7Viscovery Software GmbH, Vienna, Austria; 8Biomax Informatics AG, Planegg, Germany; 9REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, BelgiumAbstract: Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.Keywords: chronic obstructive pulmonary disease, personalized medicine, systems medicine, review

Dionne CW Braeken,1–3 Gernot GU Rohde,2 Frits ME Franssen,1,2 Johanna HM Driessen,3–5 Tjeerd P van Staa,3,6 Patrick C Souverein,3 Emiel FM Wouters,1,2 Frank de Vries3,4,7 1Department of Research and Education, CIRO, Horn, 2Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, 3Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, 4Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre (MUMC+), Maastricht, 5Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht, the Netherlands; 6Department of Health eResearch, University of Manchester, Manchester, 7MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, UK Background: Smoking increases the risk of community-acquired pneumonia (CAP) and is associated with the development of COPD. Until now, it is unclear whether CAP in COPD is due to smoking-related effects, or due to COPD pathophysiology itself. Objective: To evaluate the association between COPD and CAP by smoking status. Methods: In total, 62,621 COPD and 191,654 control subjects, matched by year of birth, gender and primary care practice, were extracted from the Clinical Practice Research Datalink (2005–2014). Incidence rates (IRs) were estimated by dividing the total number of CAP cases by the cumulative person-time at risk. Time-varying Cox proportional hazard models were used to estimate the hazard ratios (HRs) for CAP in COPD patients versus controls. HRs of CAP by smoking status were calculated by stratified analyses in COPD patients versus controls and within both subgroups with never smoking as reference. Results: IRs of CAP in COPD patients (32.00/1,000 person-years) and controls (6.75/1,000 person-years) increased with age and female gender. The risk of CAP in COPD patients was higher than in controls (HR 4.51, 95% CI: 4.27–4.77). Current smoking COPD patients had comparable CAP risk (HR 0.92, 95% CI: 0.82–1.02) as never smoking COPD patients (reference), whereas current smoking controls had a higher risk (HR 1.23, 95% CI: 1.13–1.34) compared to never smoking controls. Conclusion: COPD patients have a fourfold increased risk to develop CAP, independent of smoking status. Identification of factors related with the increased risk of CAP in COPD is warranted, in order to improve the management of patients at risk. Keywords: COPD, respiratory infections, incidence, smoking risk

This article proposes a survey of two great scholars’ in Arabic literature correspondances: a European of the 20th century, Seeger Adrianus Bonebakker, who is of special interest for us because he bequeathed all of his great library, personal notes and correspondance to the Università Ca’ Foscari, and a subject of study of the former, Ḫalīl b. Aybak al-Ṣafadī, great littérateur and scholar of the first century of the Mamluk period. Letters sent and received are preserved in both cases and are primary sources on their network, but also on their personal life, personnality and methodology.

Fiona AHM Cleutjens,1 Frits ME Franssen,1 Martijn A Spruit,1 Lowie EGW Vanfleteren,1 Candy Gijsen,1 Jeanette B Dijkstra,2 Rudolf WHM Ponds,2 Emiel FM Wouters,1,3 Daisy JA Janssen1 1Department of Research and Education, CIRO, Centre of Expertise for Chronic Organ Failure, Horn, 2Department of Medical Psychology, Maastricht UMC+/School for Mental Health and Neurosciences (MHeNS), 3Department of Respiratory Medicine, Maastricht UMC+, Maastricht, the Netherlands Abstract: Impaired cognitive function is increasingly recognized in COPD. Yet, the prevalence of cognitive impairment in specific cognitive domains in COPD has been poorly studied. The aim of this cross-sectional observational study was to compare the prevalence of domain-specific cognitive impairment between patients with COPD and non-COPD controls. A neuropsychological assessment was administered in 90 stable COPD patients and 90 non-COPD controls with comparable smoking status, age, and level of education. Six core tests from the Maastricht Aging Study were used to assess general cognitive impairment. By using Z-scores, compound scores were constructed for the following domains: psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility. General cognitive impairment and domain-specific cognitive impairment were compared between COPD patients and controls after correction for comorbidities using multivariate linear and logistic regression models. General cognitive impairment was found in 56.7% of patients with COPD and in 13.3% of controls. Deficits in the following domains were more often present in patients with COPD after correction for comorbidities: psychomotor speed (17.8% vs 3.3%; P

Dionne CW Braeken,1,2 Sarah Houben-Wilke,1 Dionne E Smid,1 Gernot GU Rohde,2 Jesse JC Drijkoningen,2 Emiel FM Wouters,1,2 Martijn A Spruit,1 Frits ME Franssen1,2 1Department of Research and Education, CIRO, Horn, the Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands Background: Spontaneous sputum production occurs in a subset of COPD patients; however, its clinical relevance has not been established. Differences in health status and clinical outcomes between patients with and without positive sputum cultures are unknown.Objective: To compare clinical characteristics and health status of spontaneous sputum producers with a positive culture (SC+) and negative culture (SC-) with nonsputum producers (NP) in a cohort of COPD patients referred for pulmonary rehabilitation.Methods: In total, 518 clinically stable patients with mild-to-very severe COPD were recruited (mean age: 64.1±9.1 years, 55.6% males, forced expiratory volume in 1 second 48.6%±20.0% predicted). Health status was measured using COPD Assessment Test, St George’s Respiratory Questionnaire, and the Clinical COPD Questionnaire. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Exercise capacity was measured using the 6-minute walking distance. Spontaneously expectorated sputum was cultured for microbiology.Results: Almost one-third of patients spontaneously produced sputum (n=164, 31.7%). Despite comparable lung function, SC+ reported more frequent exacerbations than NP (≥2 exacerbations

Francesca de Blasio,1 Francesco de Blasio,2,3 Giulia Miracco Berlingieri,2 Andrea Bianco,3,4 Marta La Greca,1 Frits M E Franssen,5 Luca Scalfi1 1Department of Public Health, Medical School, “Federico II” University of Naples, 2Respiratory Medicine and Pulmonary Rehabilitation Section, Clinic Center, Private Hospital, Naples, 3Department of Medicine and Health Sciences “V Tiberio”, University of Molise, Campobasso, 4Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy; 5Department of Research and Education, CIRO, Horn, the NetherlandsBackground: Multifrequency bioelectrical impedance analysis (MF-BIA) is a technique that measures body impedance (Z) at different frequencies (5, 10, 50, 100, and 250 kHz). Body composition may be estimated using empirical equations, which include BIA variables or, alternatively, raw BIA data may provide direct information on water distribution and muscle quality.Objectives: To compare raw MF-BIA data between COPD patients and controls and to study their relationship with respiratory and functional parameters in COPD patients.Methods: MF-BIA was performed (Human Im-Touch analyzer) in 212 COPD patients and 115 age- and BMI-matched controls. Fat-free mass (FFM) and fat mass were estimated from BIA data, and low- to high-frequency (5 kHz/250 kHz) impedance ratio was calculated. Physical fitness, lung function and respiratory muscle strength were also assessed in COPD patients.Results: After adjusting for age, weight, and body mass index, FFM and the 5/250 impedance ratio were lower in COPD patients (P