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Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function. The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988). Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer–Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer–Lemeshow test all p>0.05). The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.

Background: The lifetime risk of developing clinical COPD among smokers ranges from 13% to 22%. Identifying at-risk individuals who will develop overt disease in a reasonable timeframe may allow for early intervention. We hypothesised that readily available clinical and physiological variables could help identify ever-smokers at higher risk of developing chronic airflow limitation (CAL)., Methods: Among 2273 Lovelace Smokers' Cohort (LSC) participants, we included 677 (mean age 54 years) with normal spirometry at baseline and a minimum of three spirometries, each 1 year apart. Repeated spirometric measurements were used to determine incident CAL. Using logistic regression, demographics, anthropometrics, smoking history, modified Medical Research Council dyspnoea scale, St George's Respiratory Questionnaire, comorbidities and spirometry, we related variables obtained at baseline to incident CAL as defined by the Global Initiative for Chronic Obstructive Lung Disease and lower limit of normal criteria. The predictive model derived from the LSC was validated in subjects from the COPDGene study., Results: Over 6.3 years, the incidence of CAL was 26 cases per 1000 person-years. The strongest independent predictors were forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) <0.75, having smoked ≥30 pack-years, body mass index (BMI) ≤25 kg·m 2 and symptoms of chronic bronchitis. Having all four predictors increased the risk of developing CAL over 6 years to 85% (area under the receiver operating characteristic curve (AUC ROC) 0.84, 95% CI 0.81-0.89). The prediction model showed similar results when applied to subjects in the COPDGene study with a follow-up period of 10 years (AUC ROC 0.77, 95% CI 0.72-0.81)., Conclusion: In middle-aged ever-smokers, a simple predictive model with FEV 1 /FVC, smoking history, BMI and chronic bronchitis helps identify subjects at high risk of developing CAL., Competing Interests: Conflict of interest: The authors declare that they have no potential conflicts of interest to disclose. F. Polverino is a Section Editor of the European Respiratory Journal., (Copyright ©The authors 2023.)

Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world., Competing Interests: Conflict of interest: There was no external funding for the submitted work. D.D. Sin reports receipt of honorarium from AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim for giving talks on COPD, and participation on an advisory board for an NHLBI-sponsored trial. A. Agusti reports grants from AstraZeneca, GlaxoSmithKline, Menarini, Sanofi and Chiesi, and receipt of consulting fees and honoraria for presentations from AstraZeneca, GlaxoSmithKline, Chiesi, Menarini, Sanofi and Zambon. F.J. Martinez reports grants from AstraZeneca, Chiesi, GlaxoSmithKline and Sanofi/Regeneron, receipt of consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Bering, GlaxoSmithKline, Novartis, Polarean, Pulmonx, Sanofi, Regeneron, Sunovion, Teva, Theravance and UptoDate, honoraria for presentations from AstraZeneca and GlaxoSmithKline, and advisory board participation with MedTronic and GlaxoSmithKline. A. Anzueto reports receipt of consulting fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Viatix/Theravance. B.R. Celli reports receipt of consulting fees from GlaxoSmithKline, AstraZeneca, Axios, Menarini and Sanofi, honoraria for presentations from GlaxoSmithKline, AstraZeneca, Menarini, Chiesi and Regeneron, travel support from GlaxoSmithKline and Sanofi, and advisory board participation for AstraZeneca Therapeutics, Sanofi Aventis and Vertx. D. Halpin reports receipt of honoraria for presentations from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, Sanofi, Berlin-Chemie and Menarini, travel support from Menarini, and advisory board participation with Chiesi, GlaxoSmithKline and Inogen. M.K. Han reports grants from the NIH, Sanofi, Novartis, Nuvaira, Sunovion, Gala Therapeutics, COPD Foundation, AstraZeneca, American Lung Association, Boehringer Ingelheim and Biodesix, consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pulmonox, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, United Therapeutics, Regeneron, Altesa Biopharma and Amgen, honoraria for presentations from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medscape, Integrity and NACE, royalties from UptoDate, Norton Publishing and Penguin Random House, advisory board membership for Novartis and Medtronic, leadership roles with the COPD Foundation (board), COPD Foundation (scientific advisory committee), ALA (advisory committee), American Thoracic Society (journal editor), ALA (volunteer spokesperson), GOLD (scientific committee) and Emerson School Board, Ann Arbor, MI, stock or stock options from Meissa Vaccines and Altesa BioPharma, writing support from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca and Novartis, and other personal fees from Medscape and Integrity. A. Papi reports grants from Chiesi, AstraZeneca, GlaxoSmithKline, Sanofi and Agenzia Italiana del Farmaco (AIFA), receipt of consulting fees from Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Avillion and Elpen Pharmaceuticals, honoraria for presentations from Chiesi, AstraZeneca, GlaxoSmithKline, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion and Elpen Pharmaceuticals, and advisory board participation for Chiesi, AstraZeneca, GlaxoSmithKline, MSD, Novartis, Sanofi, Iqvia, Avillion and Elpen Pharmaceuticals. I. Pavord reports grants from Chiesi, receipt of consulting fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi, Teva, Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, RespiVert and Schering-Plough, and honoraria for presentations from Aerocrine BB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva. N. Roche reports grants from Boehringer Ingelheim, Novartis, GlaxoSmithKline and Pfizer, receipt of consulting fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva and Bayer, and honoraria for presentations from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva, Zambon and MSD. D. Singh reports receipt of consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Bering, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona, outside of the submitted work. R. Stockley reports receipt of consulting fees from Vertex, CSL Bering and Mereo Biopharma, and data safety monitoring board participation with Syneos. J. Wedzicha reports grants from AstraZeneca, Boehringer, Chiesi, GlaxoSmithKline, Novartis, Genentech and 37Clinical, receipt of consulting fees from AstraZeneca, Epiendo, GlaxoSmithKline, Gilead, Novartis, Pieris and Pulmatrix, honoraria for presentations from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Recipharm and Novartis, and data safety monitoring board participation with Virtus. C. Vogelmeier reports grants from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols and, Novartis, and personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, MedUpdate, Aerogen, Roche, Sanofi and Insmed, outside of the submitted work. J. Bourbeau reports grants from the Canadian Institute of Heath Research (CIHR), Réseau en santé respiratoire du FRQS, McGill University, McGill University Health Centre Foundation, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Grifols, Novartis, Sanofi and Trudell Canada Ltd, and receipt of honoraria from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Trudell and COVIS Pharma for presentations, outside of the submitted work. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Competing Interests: Conflict of interest: A. Agustí is Chair of the Board of Directors of GOLD (no payment received), and reports grants or contracts from AZ, GSK, Chiesi and Menarini, consultancy fees from AZ, GSK, Chiesi, Menarini, Zambon, MSD and Sanofi, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AZ, GSK, Chiesi, Menarini and Zambon, outside the submitted work. B.R. Celli reports support for the present work from Chiesi Farmaceutici; grants or contracts from GlaxoSmithKline, AstraZeneca, Menarini, Sanofi Aventis and Axios, consultancy fees from GlaxoSmithKline, AstraZeneca and Sanofi Aventis, payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline, AstraZeneca, Menarini, Chiesi and Regeneron, support for attending meetings and/or travel from GlaxoSmithKline and Sanofi Aventis, and participation on a data safety monitoring board or advisory board for AZ Therapeutics, Sanofi Aventis and Vertex, outside the submitted work. G.J. Criner reports support for the present work from GlaxoSmithKline; grants or contracts from ALung Technologies Inc., American College of Radiology, American Lung Association, AstraZeneca, BioScale Inc., Boehringer Ingelheim, BREATH Therapeutics Inc., COPD Foundation, Coridea/ZIDAN, Corvus, Dr Karen Burns of St Michael's Hospital, Fisher & Paykel Healthcare Ltd, Galapagos NV, GlaxoSmithKline, Kinevent, Lungpacer Medical Inc., National Heart, Lung, and Blood Institute, Nurvaira Inc., Patient-Centered Outcomes Research Institute, Pulmonary Fibrosis Foundation, PulmonX, Respironics Inc., Respivant Sciences, Spiration Inc., Steward St Elizabeth's Medical Center of Boston Inc. and Veracyte Inc., and personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, CSA Medical, EOLO Medical, Gala Therapeutics, GlaxoSmithKline, Helios Medical, Ion, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Olympus, PulmonX, Respironics Inc., Respivant Sciences, The Implementation Group and Verona Pharma, outside the submitted work. D. Halpin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, Sanofi and Menarini, support for attending meetings and/or travel from Menarini, and participation on a data safety monitoring board or advisory board with Chiesi, outside the submitted work. A. Anzueto reports consultancy fees from GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Viatrix Pharma, outside the submitted work. P. Barnes reports grants or contracts from AstraZeneca and Boehringer Ingelheim, consultancy fees from AstraZeneca, Boehringer Ingelheim, Novartis, Teva and Epi-Endo, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Novartis and Teva, outside the submitted work. J. Bourbeau reports grants or contracts from Canadian Institute of Heath Research (CIHR), Réseau en santé respiratoire du FRQS, McGill University, McGill University Health Centre Foundation, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Grifols, Novartis, Sanofi and Trudell Canada Ltd, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca Canada Ltd, COVIS Pharma Canada Ltd, GlaxoSmithKline Canada Ltd, Pfizer Canada Ltd and Trudell Canada Ltd, outside the submitted work. M.K. Han reports grants or contracts from NIH, Sanofi, Novartis, Nuvaira, Sunovion, Gala Therapeutics, COPD Foundation, AstraZeneca, American Lung Association, Boehringer Ingelheim and Biodesix, royalties or licences from Uptodate, Norton Publishing and Penguin Random House, consultancy fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, United Therapeutics, Regeneron, Altesa BioPharma and Amgen, payment or honoraria for lectures, presentations, manuscript writing or educational events from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medscape, Integrity and NACE, participation on a data safety monitoring board or advisory board with Novartis and Medtronic, leadership or fiduciary roles with COPD Foundation, COPD Foundation Scientific Advisory Committee, ALA advisory committee, American Thoracic Society (journal editor), ALA (volunteer spokesperson), GOLD scientific committee and Emerson School Board, stock or stock options with Meissa Vaccines and Altesa BioPharma, receipt of equipment, materials, drugs, medical writing, gifts or other services from GSK, Boehringer Ingelheim, AstraZeneca and Novartis, and personal fees from Medscape and Integrity, outside the submitted work. F.J. Martinez reports grants or contracts from AstraZeneca, Chiesi, GSK and Sanofi/Regeneron, consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis, Polarean, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and UpToDate, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca, and participation on a data safety monitoring board or advisory board for MedTronic and GSK, outside the submitted work. M. Montes de Oca reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline and AstraZeneca, outside the submitted work. K. Mortimer has contributed to advisory boards for AstraZeneca and GlaxoSmithKline, outside the submitted work. A. Papi reports grants or contracts from Chiesi, AstraZeneca, GSK, Sanofi and Agenzia Italiana del Farmaco (AIFA), consultancy fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Avillion and Elpen Pharmaceuticals, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion and Elpen Pharmaceuticals, and participation on a data safety monitoring board or advisory board for Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, Iqvia, Avillion and Elpen Pharmaceuticals, outside the submitted work. I. Pavord reports speaker fees from Aerocrine AB, speaker and consultancy fees from Almirall and Novartis, speaker fees, payments for organization of educational events, consultancy fees and international scientific meeting sponsorship from AstraZeneca, GSK, Regeneron Pharmaceuticals, Inc., Sanofi and Teva, speaker fees, consultancy fees and international scientific meeting sponsorship from Boehringer Ingelheim, speaker fees, consultancy fees, research grants and international scientific meeting sponsorship from Chiesi, consultancy fees from Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, RespiVert and Schering-Plough, and consultancy fees and international scientific meeting sponsorship from Napp Pharmaceuticals, outside the submitted work. N. Roche reports grants or contracts from Boehringer Ingelheim, Novartis, GSK and Pfizer, consultancy fees from Boehringer Ingelheim, GSK, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva and Bayer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, GSK, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva, Zambon and MSD, outside the submitted work. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim and GSK, outside the submitted work. D. Singh reports consultancy fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona, outside the submitted work. R. Stockley reports consultancy fees from CSL Behring and Mereo Biopharma, and participation on a data safety monitoring board or advisory board for Kamada and Syneos, outside the submitted work. J.A. Wedzicha reports grants or contracts from AstraZeneca, Boehringer, Chiesi, GSK, Novartis, Genentech and 37Clinical, consultancy fees from AstraZeneca, Epiendo, GSK, Gilead, Novartis, Pieris and Pulmatrix, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK, Boehringer, Recipharm and Novartis, and participation on a data safety monitoring board or advisory board for Virtus, outside the submitted work. C.F. Vogelmeier reports grants or contracts from German Ministry of Education and Science (BMBF), AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols and Novartis, consultancy fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini, Novartis and Nuvaira, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini, Novartis, Roche and Sanofi, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose.

Populations with COPD demonstrate higher survival in overweight and obese compared with normal weight; the "obesity paradox". Relationships in less-severe COPD are unclear, as is the impact of cardiovascular risk, and few studies include individuals at extremes of obesity.  We examined the relationship between body mass index (BMI; defined as underweight: <20 kg·m -2 , normal: 20-25 kg·m -2 , overweight: 25- <30 kg·m -2 , obese class I: 30- <35 kg·m -2 , class II: 35- <40 kg·m -2 and class III: ≥40 kg·m -2 ), morbidity, and mortality in the SUMMIT trial population (n=16 485), characterised by moderate COPD and heightened cardiovascular risk with a substantial proportion with class III obesity. The association between BMI category and time to event was modelled via proportional hazards (reference normal weight) adjusted for demographics and cardiorespiratory disease.  Consistent with the paradox, underweight individuals demonstrated higher mortality (hazard ratio (HR) 1.31 (95% CI 1.04-1.64)), with lower mortality among overweight (HR 0.62 (95% CI 0.52-0.73)) and obese class I (HR 0.75 (95% CI 0.62-0.90)). However, mortality increased in obese class III (HR 1.36 (95% CI 1.00-1.86)). Death was primarily attributable to cardiovascular causes.  Within a large, multinational cohort with moderate COPD and increased cardiovascular risk, the phenomenon of reduced mortality with obesity did not persist at BMI >40 kg·m -2 , suggesting that obesity may not remain protective at the extremes in this population., Competing Interests: Conflict of interest: E.P. Brigham has nothing to disclose. Conflict of interest: J.A. Anderson is an employee of and owns shares in GSK. Conflict of interest: R.D. Brook reports personal fees from GSK for a steering committee during the conduct of the study. Conflict of interest: P.M.A. Calverley reports that he was a member of the SUMMIT Science Committee supported by GSK; and he was paid for the conduct of the SUMMIT study by GSK, was paid for speaking at a company meeting and for advice on study design by AstraZeneca, he advised on development of new trials and has spoken for Boehringer Ingelheim at sponsored meetings, and he has received personal fees for speaking at sponsored meeting from Novartis, outside the submitted work. Conflict of interest: B.R. Celli reports personal fees from GlaxoSmithKline during the conduct of the study; and personal fees from AstraZeneca, Sanofi Aventis, Chiesi, Novartis, Menarini and Pulmonx outside the submitted work. Conflict of interest: N.J. Cowans reports this study was funded by GlaxoSmithKline plc.; and he is an employee of Veramed Ltd, a contract research organisation undertaking contracted statistical analyses of respiratory studies funded by GlaxoSmithKline plc. Conflict of interest: C. Crim is an employee of GSK and holds GSK stocks/shares; this study was funded by GSK (NCT01313676, GSK study number 113782; Study to Understand Mortality and Morbidity In COPD Trial (SUMMIT)). Conflict of interest: J.E. Diserens reports this study was funded by GlaxoSmithKline plc.; and he is an employee of Veramed Ltd, a contract research organisation undertaking contracted statistical analyses of respiratory studies funded by GlaxoSmithKline plc. Conflict of interest: F.J. Martinez reports grants from the NHLBI during the conduct of the study; and grants from the National Institutes of Health, personal fees from Continuing Education and Forest Laboratories, other support from Janssen, and personal fees from GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, the California Society of Allergy and Immunology, Chiesi and the Puerto Rico Thoracic Society, outside the submitted work. Conflict of interest: M.C. McCormack reports support from UpToDate outside the submitted work. Conflict of interest: D.E. Newby reports grants and personal fees from GSK during the conduct of the study. Conflict of interest: J.C. Yates is an employee of and owns shares in GSK. Conflict of interest: J. Vestbo was partly reimbursed for his work as Chair of the SUMMIT Steering Committee buy GlaxoSmithKline during the conduct of the study; and reports consultancy for COPD phase 2 and 3 programmes and payment for lectures including service in speaker bureaus from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis and AstraZeneca, outside the submitted work. Conflict of interest: T.D. Wu has nothing to disclose. Conflict of interest: R.A Wise reports grants and personal fees from GlaxoSmithKline during the conduct of the study; grants and personal fees from AstraZeneca/Medimmune and Boehringer Ingelheim, personal fees from Contrafect, Pulmonx, Roche/Genentech, Spiration, Sunovion, Pearl Therapeutics, Merck, Circassia, Pneuma, Verona, Bonti, Denali, Aradigm, Mylan, Theravance, Propeller Health, Kiniksa and Syneos, outside the submitted work., (Copyright ©The authors 2021.)

Rationale: Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation., Objectives: We hypothesised that somatotype changes - as a surrogate of adiposity - from early adulthood follow different trajectories to reach distinct phenotypes., Methods: Using the validated Stunkard's Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory., Measurements and Main Results: At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m -2 ) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m -2 ). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and D LCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV 1 ), D LCO , more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype., Conclusions: COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD., Competing Interests: Conflict of interest: M.J. Divo has nothing to disclose. Conflict of interest: M. Marin Oto has nothing to disclose. Conflict of interest: C. Casanova Macario reports, in the last 3 years, to have received lectures and/or scientific advice from Laboratorios Bial, Boehringer Ingelheim, Gebropharma, GSK, Esteve, Menarini, Novartis and Rovi. Conflict of interest: C. Cabrera Lopez has nothing to disclose. Conflict of interest: J.P. de-Torres has nothing to disclose. Conflict of interest: J.M. Marin Trigo has nothing to disclose. Conflict of interest: C.P. Hersh reports grants from National Institutes of Health during the conduct of the study; and grants from Boehringer Ingelheim and Novartis, and personal fees from 23 and Me, outside the submitted work. Conflict of interest: A. Ezponda Casajús has nothing to disclose. Conflict of interest: C. Maguire has nothing to disclose. Conflict of interest: V.M. Pinto-Plata has nothing to disclose. Conflict of interest: F. Polverino has nothing to disclose. Conflict of interest: J.C. Ross reports grants from NIH during the conduct of the study. Conflict of interest: D. DeMeo has nothing to disclose. Conflict of interest: G. Bastarrika reports personal fees from General Electric, nonfinancial support from Siemens and grants from Guerbet, outside the submitted work. Conflict of interest: E.K. Silverman reports grants from NIH during the conduct of the study, and grants and travel support from GlaxoSmithKline outside the submitted work. Conflict of interest: B.R. Celli has nothing to disclose., (Copyright ©ERS 2020.)

Precision medicine is a patient-specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side-effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD) patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment.The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment-naive individuals at initial presentation. However, their use is more problematic during follow-up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow-up.Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow-up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This article explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations., Competing Interests: Conflict of interest: D. Singh reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Therevance and Verona, personal fees from Cipla, Genentech and Peptinnovate, outside the submitted work. Conflict of interest: A. Agusti reports personal fees from AstraZeneca, Chiesi and Nuvaira, grants and personal fees from Menarini and GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Anzueto reports grants and personal fees for consultancy from GlaxoSmithKline, personal fees for consultancy from AstraZeneca, Novartis, Boehringer Ingelheim and Sunovion Pharmaceutical, outside the submitted work. Conflict of interest: P.J. Barnes reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, personal fees from Pieris, Novartis and Teva, outside the submitted work. Conflict of interest: J. Bourbeau reports grants from CIHR, Canadian Respiratory Research Network (CRRN), Foundation of the MUHC and Aerocrine, personal fees for consultancy and lecturing from the Canadian Thoracic Society and CHEST, grants and personal fees for advisory work and lecturing from AstraZeneca, Boehringer Ingelheim, Grifols, GlaxoSmithKline, Novartis and Trudell, outside the submitted work. Conflict of interest: B.R. Celli reports grants and research support from AstraZeneca, personal fees for consulting and scientific committee membership from GlaxoSmithKline, personal fees for consulting from Boehringer Ingelheim, Novartis, Sanofi-Aventis and Menarini, outside the submitted work. Conflict of interest: G.J. Criner reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Mereo, AstraZeneca, Pulmonx, Pneumrx, Olympus, Broncus, Lungpacer, Nuvaira, ResMed, Respironics and Patara, personal fees from Verona, BTG, EOLO and NGM, grants from Alung, Fisher Paykel and Galapagos, outside the submitted work. Conflict of interest: P. Frith reports non-financial support to attend a scientific committee meeting from Global Initiative for Chronic Obstructive Lung Disease (GOLD), during the conduct of the study; personal fees for advisory board membership from AstraZeneca, personal fees and non-financial support for advisory board work, chairing independent conference organising committees and lecturing from Boehringer Ingelheim and Novartis, non-financial support for attending educational meetings from GlaxoSmithKline, non-financial support for attending committee and board meetings from Lung Foundation Australia (LFA), personal fees and non-financial support for advisory board work from CSL Behring, outside the submitted work. Conflict of interest: D.M.G. Halpin reports personal fees and non-financial support from Boehringer Ingelheim and Novartis, personal fees from AstraZeneca, Chiesi, GlaxoSmithKline and Pfizer, outside the submitted work. Conflict of interest: M. Han reports personal fees from GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca, research support from Novartis and Sunovion, outside the submitted work. Conflict of interest: M.V. López Varela has nothing to disclose. Conflict of interest: F. Martinez reports personal fees for organising CME programmes and non-financial support for travel from the American College of Chest Physicians, Continuing Education, Inova Fairfax Health System, MD Magazine, Miller Communications, National Association for Continuing Education, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Potomac, University of Alabama Birmingham, Physicians Education Resource and Canadian Respiratory Network, personal fees for advisory board and steering committee work, and lecturing, and non-financial support for travel from AstraZeneca, personal fees for advisory board and data safety and monitoring board work, and lecturing, non-financial support for travel from Boehringer Ingelheim, non-financial support for advisory board work from ProterrixBio, personal fees for organising CME programmes from Columbia University Integritas, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Academic CME, PlatformIQ, Rockpointe, Rare Disease Healthcare Communications and France Foundation, personal fees for advisory board work and non-financial support for travel from ConCert, Roche, Sunovion, Theravance and Teva, personal fees for advisory board and data safety and monitoring board work and non-financial support for travel from Genentech, personal fees for advisory board, steering committee and data safety and monitoring board work, and lecturing, and non-financial support for travel from GlaxoSmithKline, personal fees for advisory board work and lecturing, and non-financial support for travel from Novartis and Chiesi, personal fees for advisory board and steering committee work, and non-financial support for travel from Pearl Pharmaceuticals, personal fees for teleconference involvement from Unity, non-financial support for steering committee work from Afferent/Merck, Gilead, Veracyte, Prometic, Bayer and ProMedior, non-financial support for teleconferencing and steering committee work from Nitto, personal fees for consultancy and steering committee work from Patara, non-financial support for data safety and monitoring board work and steering committee from Biogen, personal fees for advisory board work and support for meeting attendance from Zambon, personal fees for editorial board work from the American Thoracic Society, grants from NIH (IPF UO1, COPD UO1/RO1), and non-financial support for consultancy from Bridge Biotherapeutics, outside the submitted work. Conflict of interest: M. Montes de Oca has nothing to disclose. Conflict of interest: A. Papi reports grants, personal fees for board membership, consultancy, lecturing and travel reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and Teva, grants, personal fees for lecturing and travel reimbursement from Menarini, personal fees for lecturing and travel reimbursement from Novartis, Zambon and Sanofi, outside the submitted work. Conflict of interest: I.D. Pavord reports personal fees for lecturing, advisory board work and travel expenses from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim and Teva, grants and personal fees for lecturing, advisory board work and travel expenses from Chiesi, personal fees for advisory board work from Sanofi/Regeneron, Merck, Novartis, Knopp and Roche/Genentech, personal fees for lecturing from Circassia and Mundipharma, grants and personal fees for advisory board work from Afferent, outside the submitted work. Conflict of interest: N. Roche reports grants and personal fees from Boehringer Ingelheim, Novartis and Pfizer, personal fees from Teva, GlaxoSmithKline, AstraZeneca, Chiesi, Mundipharma, Sanofi, Sandoz, 3M and Zambon, outside the submitted work. Conflict of interest: D.D. Sin reports grants from Merck, personal fees for advisory meetings from Sanofi-Aventis and Regeneron, grants and personal fees for lecturing and advisory board work from Boehringer Ingelheim and AstraZeneca, personal fees for lecturing and advisory board work from Novartis, outside the submitted work. Conflict of interest: R. Stockley reports personal fees for advisory board membership and lecturing from AstraZeneca, personal fees for advisory board membership from MedImmune, Almirall, Kamada, Baxter, Chiesi and Polyphor, personal fees for lecturing from Nycomed, Takeda and GlaxoSmithKline, personal fees for advisory board membership, lecturing and travel to meetings from Boehringer Ingelheim, grants and personal fees for advisory board membership, lecturing and travel to meetings from CSL Behring, outside the submitted work. Conflict of interest: J. Vestbo reports personal fees for consultancy and lecturing from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis and AstraZeneca, grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: J.A. Wedzicha reports grants and travel expenses from GlaxoSmithKline, Boehringer Ingelheim, Novartis and AstraZeneca, and grants from Johnson and Johnson, and Chiesi, outside the submitted work. Conflict of interest: C. Vogelmeier reports personal fees from Almirall, Cipla, Berlin-Chemie/Menarini, CSL Behring and Teva, grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma, Novartis and Takeda, grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Bayer Schering Pharma AG, MSD and Pfizer, outside the submitted work., (Copyright ©ERS 2019.)

The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations. We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676. There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48-0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment. Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk., Competing Interests: Conflict of interest: J. Vestbo reports that he was reimbursed for his work as chair of the SUMMIT Steering Committee by GlaxoSmithKline during the conduct of the study; and that he has received consultancy fees for the COPD Phase 2 and 3 programme and payment for lectures including service in a speaker bureau from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis and AstraZeneca, outside the submitted work. Conflict of interest: M. Dransfield reports consulting fees from GlaxoSmithKline during the conduct of the study; and grants from the Department of Defense and the NIH, personal fees for consulting and contract clinical trials from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, PneumRx/BTG and Boston Scientific, support for contract clinical trials from Novartis, Yungjin and Pulmonx, and consulting fees from Genentech and Quark Pharmaceuticals, outside the submitted work. Conflict of interest: J.A. Anderson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: R.D. Brook reports work on the SUMMIT Steering Committee for GSK during the conduct of the study. Conflict of interest: P.M.A. Calverley reports personal fees from Astra Zeneca Pharmaceuticals, GSK, Boehringer Ingelheim and Recipharm, outside the submitted work. Conflict of interest: B.R. Celli reports support for a research site from AstraZeneca, and consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Novartis, Chiesi and Menarini, all outside the submitted work. Conflict of interest: N.J. Cowans is an employee of Veramed Limited, a company that GSK paid to carry out the statistical analysis for this article. Conflict of interest: C. Crim reports is an employee of and holds restricted shares in GlaxoSmithKline. Conflict of interest: F. Martinez reports that GSK was the supporter of the parent study to the current study; and honoraria and nonfinancial travel support from the American College of Chest Physicians for COPD CME programmes in India, personal fees and nonfinancial travel support from AstraZeneca for COPD advisory boards, the study steering committee and an ALAT presentation, personal fees and nonfinancial support from Boehringer Ingelheim for a COPD advisory board, an ATS presentation, an IPF study steering committee, an IPF disease state presentation at ALAT and a progressive pulmonary fibrosis DSMB, nonfinancial support from ProterrixBio for a COPD scientific advisory board, honoraria from Columbia University for a COPD CME programme, honoraria and nonpersonal travel support from ConCert for a COPD advisory board, personal fees and nonpersonal travel support from Genentech for a COPD advisory board, personal fees and nonfinancial support from GlaxoSmithKline for COPD advisory boards, a study steering committee, a DSMB and an ERS presentation, honoraria from Haymarket Communications for a COPD CME presentation, honoraria and nonpersonal travel support from the Inova Fairfax Health System for a COPD CME presentation, honoraria from Integritas for a COPD CME presentation, honoraria and nonpersonal travel support from MD Magazine for a COPD CME programme, honoraria from Methodist Hospital Brooklyn for a COPD CME programme, honoraria and nonpersonal travel support from Miller Communications for COPD and IPF CME programmes, honoraria and nonpersonal travel support from the National Association for Continuing Education for COPD and IPF CME programmes, honoraria and nonpersonal travel support from Novartis for a COPD advisory board and international meeting COPD presentations, honoraria from New York University for a COPD CME programme, personal fees and nonfinancial support from Pearl Pharmaceuticals for COPD advisory boards and a COPD steering committee, honoraria and nonpersonal travel support from PeerView Communications for COPD and IPF CME programmes, honoraria and nonpersonal travel support from Prime Communications for COPD CME programmes, honoraria and nonpersonal travel support from the Puerto Rican Respiratory Society for a COPD and IPF CME programme, honoraria and nonpersonal travel support from Chiesi for a COPD CME presentation and an advisory board, honoraria and nonpersonal travel support from Sunovion for COPD advisory boards, honoraria and nonpersonal travel support from Theravance for a COPD advisory board, honoraria from Unity for COPD teleconferences, honoraria from UpToDate for COPD CME, honoraria from WebMD/MedScape for COPD CME presentations, honoraria from the Western Connecticut Health Network for COPD CME presentations, coauthorship from Afferent/Merck for an IPF study steering committee, honoraria from Academic CME for IPF CME programmes, coauthorship from Gilead for an IPF study steering committee, nonfinancial support from Nitto for an IPF study teleconference and steering committee, honoraria from Patara for venture capital expert advice for an IPF study, honoraria from PeerView for an IPF CME presentation, honoraria from PlatformIQ for an IPF CME programme, honoraria and nonpersonal travel support from Potomac for IPF CME presentations, nonfinancial support from Stromedix/Biogen for an IPF study DSMB and IPF study steering committee, honoraria and nonpersonal travel support from the University of Alabama Birmingham for and IPF CME presentation, coauthorship from Veracyte for an IPF study steering committee, nonpersonal travel support to attend an IPF study meeting and an honorarium for an advisory board from Zambon, an honorarium for acting as AJRCCM DE from the American Thoracic Society, grants from the NIH, an honorarium and travel support from the Physicians Education Resource for a COPD CME programme, an honorarium from Rockpointe for a COPD CME programme, nonfinancial support from Prometic for an IPF steering committee, grants from Rare Disease Health are Communications, and an honorarium and travel support from Teva for a COPD advisory board, outside the submitted work. Conflict of interest: D.E. Newby reports consultancy fees from GSK for serving on the trial steering committee during the conduct of the study, and grants and personal fees for other research and consultancy activities from GSK, outside the submitted work. Conflict of interest: J. Yates is an employee of and holds shares in GSK. Conflict of interest: P. Lange reports personal fees for membership of the data monitoring board from GSK during the conduct of the study; and consultancy and teaching fees from AstraZeneca, Boehringer Ingelheim, Chiesi and GSK, outside the submitted work.

We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort.Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV 1 )), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates.Participants with more baseline emphysema had lower FEV 1 , BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV 1 , BMI and FFMI decline and more exacerbations, hospitalisations and mortality.COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·μL -1 ) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV 1 ) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV 1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·μL -1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·μL -1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·μL -1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses.Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative International Assessment (3CIA) initiative.Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated that the variables relevant for patient grouping differed markedly between patients with isolated respiratory disease (FEV 1 , dyspnoea grade) and those with multi-morbidity (dyspnoea grade, age, FEV 1 and body mass index). Application of this algorithm to the 3CIA cohorts confirmed that it identified subgroups of patients with different clinical characteristics, mortality rates (median, from 4% to 27%) and age at death (median, from 68 to 76 years).A simple algorithm, integrating respiratory characteristics and comorbidities, allowed the identification of clinically relevant COPD phenotypes., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed., (Copyright ©2017 the American Thoracic Society. Published with permission from the American Thoracic Society. Design and branding are copyright ©ERS 2017.)

Patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies., (Copyright ©ERS 2016.)

Multimorbidity frequently affects the ageing population and their co-existence may not occur at random. Understanding their interactions and that with clinical variables could be important for disease screening and management.In a cohort of 1969 chronic obstructive pulmonary disease (COPD) patients and 316 non-COPD controls, we applied a network-based analysis to explore the associations between multiple comorbidities. Clinical characteristics (age, degree of obstruction, walking, dyspnoea, body mass index) and 79 comorbidities were identified and their interrelationships quantified. Using network visualisation software, we represented each clinical variable and comorbidity as a node with linkages representing statistically significant associations.The resulting COPD comorbidity network had 428, 357 or 265 linkages depending on the statistical threshold used (p≤0.01, p≤0.001 or p≤0.0001). There were more nodes and links in COPD compared with controls after adjusting for age, sex and number of subjects. In COPD, a subset of nodes had a larger number of linkages representing hubs. Four sub-networks or modules were identified using an inter-linkage affinity algorithm and their display provided meaningful interactions not discernible by univariate analysis.COPD patients are affected by larger number of multiple interlinked morbidities which clustering pattern may suggest common pathobiological processes or be utilised for screening and/or therapeutic interventions., (Copyright ©ERS 2015.)

Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD., (Copyright ©ERS 2015.)

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes., (Copyright ©ATS/ERS 2015.)

Guidelines recommend defining chronic obstructive pulmonary disease (COPD) by airflow obstruction and other factors, but no studies have evaluated the ability of existing multicomponent indices to predict mortality up to 10 years. We conducted a patient-based pooled analysis. Survival analysis and C statistics were used to determine the best COPD index/indices according to several construct variables and by varying time-points. Individual data of 3633 patients from 11 COPD cohorts were collected, totalling the experience of 15 878 person-years. Overall, there were 1245 death events within our cohorts, with a Kaplan-Meier survival of 0.963 at 6 months, which was reduced to 0.432 at 10 years. In all patients, ADO (age, dyspnoea and forced expiratory volume in 1 s), BODE (body mass index, airflow obstruction, dyspnoea and exercise capacity) and e-BODE (BODE plus exacerbations) were the best indices to predict 6-month mortality. The ADO index was the best to predict 12-month (C statistic 0.702), 5-year (C statistic 0.695) and 10-year mortality (C statistic 0.698), and was significantly better than BODE (all p<0.05). The best indices to predict death by C statistics when adjusting by age were e-BODE, BODEx (substitution of exacerbations for exercise capacity) and BODE. No index predicts short-term survival of COPD well. All BODE modifications scored better than ADO after age adjustment. The ADO and BODE indices are overall the most valid multicomponent indices to predict time to death in all COPD patients.

Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases and comorbidities that can markedly influence patients' health status and prognosis. This is particularly true for cardiovascular disease (CVD). However, there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases. The "Study to Understand Mortality and Morbidity in COPD" (SUMMIT) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD. SUMMIT is a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial of 16 000 patients with moderate COPD randomly assigned to once daily treatment with fluticasone furoate/vilanterol (100/25 μg), fluticasone furoate (100 μg), vilanterol (25 μg) or matched placebo; mortality is the primary end-point. The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo. Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point. This article describes the design of the SUMMIT study.