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Competing Interests: Conflict of interest statement All authors are current/past members of the GOLD Scientific Committee but declare that none has a conflict of interest in relation to this manuscript.

Rationale: Body mass index (BMI) is associated with chronic obstructive pulmonary disease (COPD) mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate the causal mechanisms and predict risk. Objectives: To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD. Methods: We developed a polygenic score (PGS) for BMI (PGS BMI ) and tested for associations of the PGS BMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene (Genetic Epidemiology of COPD), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMI diff ) and categorized participants into groups of discordantly low (BMI diff <20th percentile), concordant (BMI diff between the 20th and 80th percentiles), and discordantly high (BMI diff >80th percentile) BMI. We applied Cox models, examined potential nonlinear associations of the PGS BMI and BMI diff with mortality, and summarized results with meta-analysis. Measurements and Main Results: We observed significant nonlinear associations of measured BMI and BMI diff , but not PGS BMI , with all-cause mortality. In meta-analyses, a one-standard deviation increase in the PGS BMI was associated with an increased hazard for cardiovascular mortality (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.12-1.49), but not for respiratory or all-cause mortality. Compared with participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher risks for all-cause mortality (HR, 1.57; 95% CI, 1.41-1.74) and respiratory death (HR, 2.01; 95% CI, 1.61-2.51). Conclusions: In people with COPD, a higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with a discordantly low BMI have higher all-cause and respiratory mortality rates than those with a concordant BMI.

Introduction: Treatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/μL., Methods: The ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92μg/umeclidinium (UMEC) 55μg/vilanterol (VI) 22μg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia., Results: The first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026., Conclusions: The ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Exercise limitation and physical inactivity are separate, but related constructs. Both are commonly present in individuals with COPD, contribute to disease burden over and above the respiratory impairments, and are independently predictive of adverse outcomes. Because of this, clinicians should consider assessing these variables in their patients with COPD. Field tests of exercise performance such as the 6-min walk test and the incremental and endurance shuttle walk tests require limited additional resources, and results correlate with negative outcomes. Laboratory measures of exercise performance using a treadmill or cycle ergometer assess exercise capacity, provide prognostic information and have the advantage of explaining physiological mechanisms (and their interactions) underpinning exercise limitation. Limitations in exercise capacity ( i.e. "cannot do") and physical inactivity ( i.e. "do not do") are both associated with mortality; exercise limitation appears to be the more important driver of this outcome., Competing Interests: Conflict of interest: All authors have no perceived conflict of interest., (Copyright ©ERS 2024.)

Introduction: The Global Lung Function Initiative (GLI) has proposed new criteria for airflow limitation (AL) and recommends using these to interpret spirometry. The objective of this study was to explore the impact of the application of the AL GLI criteria in two well characterized GOLD-defined COPD cohorts., Methods: COPD patients from the BODE (n=360) and the COPD History Assessment In SpaiN (CHAIN) cohorts (n=722) were enrolled and followed. Age, gender, pack-years history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, history of exacerbations and survival were recorded. CT-detected comorbidities were registered in the BODE cohort. The proportion of subjects without AL by GLI criteria was determined in each cohort. The clinical, CT-detected comorbidity, and overall survival of these patients were evaluated., Results: In total, 18% of the BODE and 15% of the CHAIN cohort did not meet GLI AL criteria. In the BODE and CHAIN cohorts respectively, these patients had a high clinical burden (BODE≥3: 9% and 20%; mMRC≥2: 16% and 45%; exacerbations in the previous year: 31% and 9%; 6MWD<350m: 15% and 19%, respectively), and a similar prevalence of CT-diagnosed comorbidities compared with those with GLI AL. They also had a higher rate of long-term mortality - 33% and 22% respectively., Conclusions: An important proportion of patients from 2 GOLD-defined COPD cohorts did not meet GLI AL criteria at enrolment, although they had a significant burden of disease. Caution must be taken when applying the GLI AL criteria in clinical practice., (Copyright © 2023 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Competing Interests: SPB reports grants from the National Institutes of Health; research support from Nuvaira and Sanofi/Regeneron; consulting or advisory board fees from Sanofi/Regeneron, GSK, and Boehringer Ingelheim; honorarium from Integrity Continuing Education for continued medical education. AA declares grants from GSK, AstraZeneca, Chiesi, Sanofi, and Menarini; and consulting or advisory board fees from GSK, AstraZeneca, Chiesi, Menarini, Cipla, Zambon, Sanofi, and Regeneron. BRC reports consulting or advisory board fees or honoraria from GSK, AstraZeneca, Menarini, Sanofi, Axios, and Chiesi; and fees for participation in data safety monitoring boards from AstraZeneca, Sanofi, and Vertex. BEM serves as a contractor and consultant for the COPD Foundation. NP reports grants from the National Institutes of Health; and fees for participation on data safety monitoring boards for CSL Behring, GSK, and Pharmacosmos. NP reports grants from the National Institutes of Health, the American Lung Association, and the Department of Defense; royalties from Up To Date; serves on the Board of Directors of the COPD Foundation (unpaid); and consulting fees from AstraZeneca, Genentech, GSK, Novartis, Pulmonx, and Teva. All other authors declare no competing interests.

Most patients with chronic obstructive pulmonary disease (COPD) have at least one additional, clinically relevant chronic disease. Those with the most severe airflow obstruction will die from respiratory failure, but most patients with COPD die from non-respiratory disorders, particularly cardiovascular diseases and cancer. As many chronic diseases have shared risk factors (eg, ageing, smoking, pollution, inactivity, and poverty), we argue that a shift from the current paradigm in which COPD is considered as a single disease with comorbidities, to one in which COPD is considered as part of a multimorbid state-with co-occurring diseases potentially sharing pathobiological mechanisms-is needed to advance disease prevention, diagnosis, and management. The term syndemics is used to describe the co-occurrence of diseases with shared mechanisms and risk factors, a novel concept that we propose helps to explain the clustering of certain morbidities in patients diagnosed with COPD. A syndemics approach to understanding COPD could have important clinical implications, in which the complex disease presentations in these patients are addressed through proactive diagnosis, assessment of severity, and integrated management of the COPD multimorbid state, with a patient-centred rather than a single-disease approach., Competing Interests: Declaration of interests LMF declares consulting fees from Chiesi Farmaceutici; payment or honoraria for lectures, presentations, manuscript writing, or educational events from Novartis, Chiesi Farmaceutici, Chiesi Italia, GSK, AstraZeneca, and Alfasigma; and participation on a data safety monitoring board (DSMB) for Novartis and Chiesi, all outside of the submitted work. LMF was formerly a member of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). BRC declares consultancy fees from GSK, AstraZeneca, Menarini, Sanofi Aventis, and Axios; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Menarini, Chiesi, and Regeneron; support for attending meetings or travel from GSK and Sanofi Aventis; and participation on a DSMB or advisory board for GSK, AstraZeneca, AZ Therapeutics, Sanofi Aventis, and Vertex, all outside of the submitted work. BRC is a member of GOLD. AA declares grants for research projects from GSK, AstraZeneca, and Menarini; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron, all outside of the submitted work. AA holds the Chair of the Board of Directors of GOLD. GJC is member of GOLD. MTD declares grants paid to his institution from the US Department of Defense, American Lung Association, and National Institutes of Health; royalties from UpToDate; consulting fees from AstraZeneca, GSK, Novartis, Pulmonx, and Teva; and an unpaid role on the Board of Directors of the COPD Foundation, all outside of the submitted work. MD declares consulting fees from Sanofi Regeneron, outside of the submitted work. JKK declares grants paid to her institution from the American Thoracic Society Fellowship in Health Equity, Research Assistance for Primary Parents Award, COMMUNITY Center Investigator Development Core, Weill Cornell Medicine Dean's Diversity and Healthcare Disparity Research Award, and the National Institutes of Health (T32 HL134629); medical writing support from Novartis; medication samples delivered to her institution by Boehringer Ingelheim and GSK; and a donor gift to her institution from the Donna Redel Research Fund, all outside of the submitted work. LL declares fees to her institution from AstraZeneca for expert consultation, Chiesi for a lecture, and IPSA vzw, for lectures, outside of the submitted work. MM declares honoraria for lectures on COPD from AstraZeneca and GSK, outside of the submitted work. MMdO is a member of GOLD. SSS declares payments to his institution from Cipla for lectures, presentations, speakers bureaus, manuscript writing, or educational events. SSS has an unpaid leadership or fiduciary role with the Indian Chest Society, outside of the submitted work, and is a member of GOLD. DS declares grants to her institution from Curetis and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi; and participation on a DSMB or advisory board for CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi, all outside of the submitted work. LEGWV declares research grants to his institution from The Family Kamprad Foundation (20190024), the Swedish government and country council (ALF grant ALFGBG-824371), The Swedish Heart and Lung Foundation (20200150), and Svensk Lungmedicinsk Förening; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Boehringer, Novartis, Chiesi, Resmed, and Pulmonx, all outside of the submitted work. CFV declares grants to his institution from the German Ministry of Education and Science, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Grifols, and Novartis; consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, and Nuvaira; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, Roche, and Sanofi, all outside the submitted work. CFV holds the Chair of the Science Committee of GOLD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, progressive inflammatory airway disease associated with a significant impact on patients' lives, including morbidity and mortality, and significant healthcare costs. Current pharmacologic strategies, including first- and second-line therapies such as long-acting β 2 -agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD. However, many patients remain symptomatic, with persistent symptoms and/or acute exacerbations and progressive lung function loss. Although neutrophilic inflammation is the most common type of inflammation in COPD, 20-40% of patients with COPD exhibit type 2 inflammation, with roles for CD4 + (cluster of differentiation 4) T-helper cell type 1 cells, type 2 innate lymphoid cells, eosinophils, and alternatively activated macrophages. On the basis of the current limitations of available therapies, a significant unmet need exists in COPD management, including the need for targeted therapies to address the underlying pathophysiology leading to disease progression, such as type 2 inflammation, as well as biomarkers to help select the patients who would most benefit from the new therapies. Significant progress is being made, with evolving understanding of the pathobiology of COPD leading to novel therapeutic targets including epithelial alarmins. In this review, we describe the current therapeutic landscape in COPD, discuss unmet treatment needs, review the current knowledge of type 2 inflammation and epithelial alarmins in COPD, explore potential biomarkers of type 2 inflammation in COPD, and finally provide a rationale for incorporating therapies targeting type 2 inflammation and epithelial alarmins in COPD. Video Abstract available online at www.atsjournals.org.

Background: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination., Main Body: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS., Conclusions: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD., (© 2023. The Author(s).)

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.)

In 2022, over 3 million people died of chronic obstructive pulmonary disease (COPD) and the global burden of the disease is expected to increase over the coming decades. Recommendations for the treatment and management of patients with COPD are published by the Global Initiative for Chronic Obstructive Lung Disease, and updated annually with scientific evidence-based recommendations. The 2023 updates, published in November 2022, contain key changes to recommendations for diagnosis and treatment of COPD that are anticipated to have a significant impact on clinical practice for patients with COPD. Updates to how COPD is defined and diagnosed, including the expansion of contributing factors beyond tobacco use, have the potential to lead to the diagnosis of more patients and to allow for the implementation of early interventions for patients during early stages of the disease. Simplification of the treatment algorithms, and placement of triple therapy within these algorithms, will support clinicians in providing appropriate, timely treatment for patients with COPD with a focus on reducing the risk of future exacerbations. Finally, recognition of mortality reduction as a treatment goal in COPD supports an increase in the use of triple therapy, the only pharmacological intervention that has been demonstrated to improve survival for patients with COPD. Although further guidance and clarification are needed in some areas, such as use of blood eosinophil counts in guiding treatment decisions and implementation of treatment protocols following hospitalizations, recent updates to the GOLD recommendations will support clinicians in addressing current gaps in patient care. Clinicians should utilize these recommendations to drive the early diagnosis of patients with COPD, the identification of exacerbations, and the selection of appropriate, timely treatments for patients., Competing Interests: Diana R Tamondong-Lachica has received consultancy fees from AstraZeneca. Neil Skolnik has received speaker/consultancy fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Genentech, GlaxoSmithKline, Idorsia, Merck, Novartis, Sanofi, Sanofi Pasteur, and Teva; and research funding from AstraZeneca, Bayer, GlaxoSmithKline, Novo Nordisk, and Sanofi. John R Hurst has received speaker/consultancy fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Takeda. Nathaniel Marchetti has received speaker/consultancy fees from AstraZeneca; grants from CSL Behring and NIH; and research funding from AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi. Adrian Paul J Rabe is an employee of AstraZeneca. Maria Montes de Oca has received speaker fees from AstraZeneca and GlaxoSmithKline. Bartolome R Celli has received speaker/consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gala Therapeutics, GlaxoSmithKline, Menarini, Novartis, Pulmonx, and Sanofi-Aventis; neither he, nor any member of his family, has shares or interest in any company; and he has not received or had any relationship with money from the tobacco industry. The authors report no other conflicts of interest in this work., (© 2023 Tamondong-Lachica et al.)

Patients with chronic obstructive pulmonary disease (COPD) may suffer from acute episodes of worsening dyspnea, often associated with increased cough, sputum, and/or sputum purulence. These exacerbations of COPD (ECOPDs) impact health status, accelerate lung function decline, and increase the risk of hospitalization. Importantly, close to 20% of patients are readmitted within 30 days after hospital discharge, with great cost to the person and society. Approximately 25% and 65% of patients hospitalized for an ECOPD die within 1 and 5 years, respectively. Patients with COPD are usually older and frequently have concomitant chronic diseases, including heart failure, coronary artery disease, arrhythmias, interstitial lung diseases, bronchiectasis, asthma, anxiety, and depression, and are also at increased risk of developing pneumonia, pulmonary embolism, and pneumothorax. All of these morbidities not only increase the risk of subsequent ECOPDs but can also mimic or aggravate them. Importantly, close to 70% of readmissions after an ECOPD hospitalization result from decompensation of other morbidities. These observations suggest that in patients with COPD with worsening dyspnea but without the other classic characteristics of ECOPD, a careful search for these morbidities can help detect them and allow appropriate treatment. For most morbidities, a thorough clinical evaluation supplemented by appropriate clinical investigations can guide the healthcare provider to make a precise diagnosis. This perspective integrates the currently dispersed information available and provides a practical approach to patients with COPD complaining of worsening respiratory symptoms, particularly dyspnea. A systematic approach should help improve outcomes and the personal and societal cost of ECOPDs.

Background: Chronic obstructive pulmonary disease (COPD) is a highly morbid and heterogenous disease. While COPD is defined by spirometry, many COPD characteristics are seen in cigarette smokers with normal spirometry. The extent to which COPD and COPD heterogeneity is captured in omics of lung tissue is not known., Methods: We clustered gene expression and methylation data in 78 lung tissue samples from former smokers with normal lung function or severe COPD. We applied two integrative omics clustering methods: (1) Similarity Network Fusion (SNF) and (2) Entropy-Based Consensus Clustering (ECC)., Results: SNF clusters were not significantly different by the percentage of COPD cases (48.8% vs. 68.6%, p = 0.13), though were different according to median forced expiratory volume in one second (FEV 1 ) % predicted (82 vs. 31, p = 0.017). In contrast, the ECC clusters showed stronger evidence of separation by COPD case status (48.2% vs. 81.8%, p = 0.013) and similar stratification by median FEV 1 % predicted (82 vs. 30.5, p = 0.0059). ECC clusters using both gene expression and methylation were identical to the ECC clustering solution generated using methylation data alone. Both methods selected clusters with differentially expressed transcripts enriched for interleukin signaling and immunoregulatory interactions between lymphoid and non-lymphoid cells., Conclusions: Unsupervised clustering analysis from integrated gene expression and methylation data in lung tissue resulted in clusters with modest concordance with COPD, though were enriched in pathways potentially contributing to COPD-related pathology and heterogeneity., (© 2023. The Author(s).)

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.

Rationale and Objective: Patients with chronic obstructive pulmonary disease (COPD), usually diagnosed after the 6th decade, frequently suffer from comorbidities. Whether COPD patients 50 years or younger (Young COPD) have similar comorbidities with the same frequency and mortality impact as aged-matched controls or older COPD patients is unknown., Methods: We compared comorbidity number, prevalence and type in 3 groups of individuals with ≥ 10 pack-years of smoking: A Young (≤ 50 years) COPD group (n = 160), an age-balanced control group without airflow obstruction (n = 125), and Old (> 50 years) COPD group (n = 1860). We also compared survival between the young COPD and control subjects. Using Cox proportional model, we determined the comorbidities associated with mortality risk and generated Comorbidomes for the "Young" and "Old" COPD groups., Results: The severity distribution by GOLD spirometric stages and BODE quartiles were similar between Young and Old COPD groups. After adjusting for age, sex, and pack-years, the prevalence of subjects with at least one comorbidity was 31% for controls, 77% for the Young, and 86% for older COPD patients. Compared to controls, "Young" COPDs' had a nine-fold increased mortality risk (p < 0.0001). "Comorbidomes" differed between Young and Old COPD groups, with tuberculosis, substance use, and bipolar disorders being distinct comorbidities associated with increased mortality risk in the Young COPD group., Conclusions: Young COPD patients carry a higher comorbidity prevalence and mortality risk compared to non-obstructed control subjects. Young COPD differed from older COPD patients by the behavioral-related comorbidities that increase their risk of premature death., (© 2022. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide; many recent advances have been made in many aspects of the disease. The aim of this article is to illustrate and discuss some of these advances in the management of different types of patients. Large-scale trials have confirmed that long-acting bronchodilator therapy, particularly using the combination of LABA/LAMA, remains the mainstay of COPD treatment, with special attention being paid to careful selection of inhaler devices. The initial choice of pharmacological therapy is based on the GOLD ABCD grouping of patients. It is very important to stress that there is a need to implement a management cycle because COPD is a chronic disease with varying clinical course and a high number of potential comorbidities that may affect morbidity and mortality. Therefore, regular reevaluation of the patient is mandatory. This allows identification of characteristics aimed at maximizing the benefits for a specific patient or a subset of patients. Within this context, the role of the blood eosinophil count as a marker of inhaled corticosteroids response to prevent future exacerbations in patients who, despite appropriate bronchodilator therapy, still suffer from them has been proven to be a useful simple biomarker in medication selection. These advances support the concept of precision medicine, with the goal that patients get the right medicine at the right time for the right reason. Finally, recent studies have shown that early life events may be of critical relevance for the development of COPD. With this as a background, concepts to identify individuals at risk and early identification of cases have become an important objective of current research with the hope of maximizing the effects of therapy and the possibility of impacting disease progression., Competing Interests: Bartolome R Celli reports having received compensation from Advisory Boards and consultation fees from Glaxo Smith Kline, Boehringer-Ingelheim, Astra Zeneca, Novartis, Pulmonx, CHIESI, Menarini and Bayer. He does not have shares or interest in any company, neither does any member of his family. He has not received or had any relationship with tobacco money. Dave Singh has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance and Verona Claus Vogelmeier gave presentations at symposia and/or served on scientific advisory boards sponsored by AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, OmniaMed and MedUpdate, reports personal fees from Aerogen, grants, personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSl Behring, GlaxoSmithKline, Grifols, Novartis. Alvar Agusti: Research project funds: AZ, GSK, Menarini. Lectures: AZ, Chiesi, GSK, Menarini. AB: AZ, Chiesi, GSK, MSD, Menarini. The authors report no other conflicts of interest in this work., (© 2022 Celli et al.)

Chronic obstructive pulmonary disease (COPD) and lung cancer are common global causes of morbidity and mortality. Because both diseases share several predisposing risks, the 2 diseases may occur concurrently in susceptible individuals. The diagnosis of COPD has important implications for the diagnostic approach and treatment options if lesions concerning for lung cancer are identified during screening. Importantly, the presence of COPD has significant implications on prognosis and management of patients with lung cancer. In this monograph, we review the mechanistic linkage between lung cancer and COPD, the impact of lung cancer screening on patients at risk, and the implications of the presence of COPD on the approach to the diagnosis and treatment of lung cancer. This manuscript succinctly reviews the epidemiology and common pathogenetic factors for the concurrence of COPD and lung cancer. Importantly for the clinician, it summarizes the indications, benefits, and complications of lung cancer screening in patients with COPD, and the assessment of risk factors for patients with COPD undergoing consideration of various treatment options for lung cancer., (JCOPDF © 2022.)

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

Background and Objective: The availability of chest computed tomography (CT) imaging can help diagnose comorbidities associated with chronic obstructive pulmonary disease (COPD). Their systematic identification and relationship with all-cause mortality have not been explored. Furthermore, whether their CT-detected prevalence differs from clinical diagnosis is unknown., Methods: The prevalence of 10 CT-assessed comorbidities was retrospectively determined at baseline in 379 patients (71% men) with mild to severe COPD attending pulmonary clinics. Anthropometrics, smoking history, dyspnoea, lung function, exercise capacity, BODE (BMI, Obstruction, Dyspnoea and Exercise capacity) index and exacerbations rate were recorded. The prevalence of CT-determined comorbidities was compared with that recorded clinically. Over a median of 78 months of observation, the independent association with all-cause mortality was analysed. A 'CT-comorbidome' graphically expressed the strength of their association with mortality risk., Results: Coronary artery calcification, emphysema and bronchiectasis were the most prevalent comorbidities (79.8%, 62.7% and 33.9%, respectively). All were underdiagnosed before CT. Coronary artery calcium (hazard ratio [HR] 2.09; 95% CI 1.03-4.26, p = 0.042), bronchiectasis (HR 2.12; 95% CI 1.05-4.26, p = 0.036) and low psoas muscle density (HR 2.61; 95% CI 1.23-5.57, p = 0.010) were independently associated with all-cause mortality and helped define the 'CT-comorbidome'., Conclusion: This study of COPD patients shows that systematic detection of 10 CT-diagnosed comorbidities, most of which were not detected clinically, provides information of potential use to patients and clinicians caring for them., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1 ) young adults with COPD and 2 ) those with pre-COPD at any age.

This document summarizes the work of the COPD Technical Expert Panel working group. For patients with COPD, the most pressing current coverage barriers identified were onerous diagnostic requirements focused on oxygenation (rather than ventilation) and difficulty obtaining bilevel devices with backup rate capabilities. Because of these difficulties, many patients with COPD were instead sometimes prescribed home mechanical ventilators. Critical evidence supports changes to current policies, including randomized controlled trial evidence suggesting a mortality benefit from bilevel positive airway pressure with backup rate and updated clinical practice guidelines from the American Thoracic Society as well as the European Respiratory Society. To achieve optimal access to noninvasive ventilation for patients with COPD, we make the following key recommendations: (1) removal of the need for overnight oximetry testing; (2) the ability to initiate therapy using bilevel devices with backup rate capability; and (3) increased duration of time to meet adherence criteria (ie, a second 90-day trial period) in those patients actively engaged in their care. Clear guidelines based on medical necessity are also included for patients who require initiation of or switch to a home mechanical ventilator. Adoption of these proposed recommendations would result in the right device, for the right type of patient with COPD, at the right time. Finally, we emphasize the need for adequate clinical support during initiation and maintenance of home noninvasive ventilation in such patients., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy., Methods: In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40-75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24-52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV 1 from baseline to weeks 16-24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov (NCT03546907)., Findings: Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32-1·97) in the placebo group and 1·30 (1·05-1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61-1·07], p=0·13), and least squares mean prebronchodilator FEV 1 change from baseline to weeks 16-24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01-0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39-0·85], p=0·0061) and FEV 1 improvement (least squares mean difference 0·09 L [0·02-0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74-1·61], p=0·65) or FEV 1 (least squares mean difference 0·02 [-0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%])., Interpretation: The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD., Funding: Sanofi and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests KFR reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Roche, and Sanofi, and federal funding of the German Ministry for Research and Technology for the German Center for Lung Research. BRC reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Pulmonx, Regeneron, and Sanofi. MEW reports personal fees from Boehringer Ingelheim, Cohero Health, Equillium, Gala Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pulmatrix, Regeneron Pharmaceuticals, resTORbio, and Sentien Biotechnologies; and grants and personal fees from AstraZeneca, Sanofi, and Teva. JEH, AB, MAF, MKR, MCN, NA, DMW, and GDY report employment by and are shareholders of Regeneron Pharmaceuticals. RMA, XL, MMB, HS, and HG report employment by and might hold stock or stock options in Sanofi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (Dlco) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low Dlco has not been explored., Research Question: Could a Dlco threshold help define an increased risk of death and a different clinical presentation in these patients?, Study Design and Methods: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 ± 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for Dlco was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality., Results: A Dlco cutoff value of <60% predicted was associated with all-cause mortality (Dlco ≥ 60%: 9% vs Dlco < 60%: 23%, P = .01). At a same FEV 1 % predicted and Charlson score, patients with Dlco < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a Dlco < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a Dlco < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Poor muscle quality in COPD patients relates to exercise intolerance and mortality. Muscle quality can be estimated on computed tomography (CT) by estimating psoas density (PsD). We tested the hypothesis that PsD is lower in COPD patients than in controls and relates to all-cause mortality., Methods: At baseline, PsD was measured using axial low-dose chest CT images in 220 COPD patients, 80% men, who were 65±8 years old with mild to severe airflow limitation and in a control group of 58 subjects matched by age, sex, body mass index (BMI) and body surface area (BSA). COPD patients were prospectively followed for 76.5 (48-119) months. Anthropometrics, smoking history, BMI, dyspnoea, lung function, exercise capacity, BODE index and exacerbations history were recorded. Cox proportional risk analysis determined the factors more strongly associated with long-term mortality., Results: PsD was lower in COPD patients than in controls (40.5 vs 42.5, p=0.045). During the follow-up, 54 (24.5%) deaths occurred in the COPD group. PsD as well as age, sex, pack-year history, FEV 1 %, 6MWD, mMRC, BODE index, were independently associated with mortality. Multivariate analysis showed that age (HR 1.06; 95% CI 1.02-1.12, p=0.006) and CT-assessed PsD (HR 0.97; 95%CI 0.94-0.99, p=0.023) were the variables independently associated with all-cause mortality., Conclusions: In COPD patients with mild to severe airflow limitation, chest CT-assessed psoas muscle density was lower than in matched controls and independently associated with long-term mortality. Muscle quality using the easy to evaluate psoas muscle density from chest CT may provide clinicians with important prognostic information in COPD., (Copyright © 2021 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression., Research Question: What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression?, Study Design and Methods: We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time., Results: The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV 1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039)., Interpretation: Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function., Trial Registry: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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.)

In chronic obstructive pulmonary disease (COPD), exacerbations (ECOPD), characterized by an acute deterioration in respiratory symptoms, are fundamental events impacting negatively upon disease progression, comorbidities, wellbeing and mortality. ECOPD also represent the largest component of the socioeconomic burden of COPD. ECOPDs are currently defined as acute worsening of respiratory symptoms that require additional therapy. Definitions that require worsening of dyspnoea and sputum volume/purulence assume that acute infections, especially respiratory viral infections, and/or exposure to pollutants are the main cause of ECOPD. But other factors may contribute to ECOPD, such as the exacerbation of other respiratory diseases and non-respiratory diseases (e.g., heart failure, thromboembolism). The complexity of worsening dyspnoea has suggested a need to improve the definition of ECOPD using objective measurements such as blood counts and C-reactive protein to improve accuracy of diagnosis and a personalized approach to management. There are three time points when we can intervene to improve outcomes: acutely, to attenuate the length and severity of an established exacerbation; in the aftermath, to prevent early recurrence and readmission, which are common, and in the long-term, establishing preventative measures that reduce the risk of future events. Acute management includes interventions such as corticosteroids or antibiotics and measures to support the respiratory system, including non-invasive ventilation (NIV). Current therapies are broad and better understanding of clinical phenotypes and biomarkers may help to establish a more tailored approach, for example in relation to antibiotic prescription. Other unmet needs include effective treatment for viruses, which commonly cause exacerbations. Preventing early recurrence and readmission to hospital is important and the benefits of interventions such as antibiotics or anti-inflammatories in this period are not established. Domiciliary NIV in those patients who are persistently hypercapnic following discharge and pulmonary rehabilitation can have a positive impact. For long-term prevention, inhaled therapy is key. Dual bronchodilators reduce exacerbation frequency but in patients with continuing exacerbations, triple therapy should be considered, especially if blood eosinophils are elevated. Other options include phosphodiesterase inhibitors and macrolide antibiotics. ECOPD are a key component of the assessment of COPD severity and future outcomes (quality of life, hospitalisations, health care resource utilization, mortality) and are a central component in pharmacological management decisions. Targeted therapies directed towards specific pathways of inflammation are being explored in exacerbation prevention, and this is a promising avenue for future research., (© 2021 Asian Pacific Society of Respirology.)

Rationale: Poor muscle quality in COPD patients relates to exercise intolerance and mortality. Muscle quality can be estimated on computed tomography (CT) by estimating psoas density (PsD). We tested the hypothesis that PsD is lower in COPD patients than in controls and relates to all-cause mortality., Methods: At baseline, PsD was measured using axial low-dose chest CT images in 220 COPD patients, 80% men, who were 65±8 years old with mild to severe airflow limitation and in a control group of 58 subjects matched by age, sex, body mass index (BMI) and body surface area (BSA). COPD patients were prospectively followed for 76.5 (48-119) months. Anthropometrics, smoking history, BMI, dyspnoea, lung function, exercise capacity, BODE index and exacerbations history were recorded. Cox proportional risk analysis determined the factors more strongly associated with long-term mortality., Results: PsD was lower in COPD patients than in controls (40.5 vs 42.5, p=0.045). During the follow-up, 54 (24.5%) deaths occurred in the COPD group. PsD as well as age, sex, pack-year history, FEV 1 %, 6MWD, mMRC, BODE index, were independently associated with mortality. Multivariate analysis showed that age (HR 1.06; 95% CI 1.02-1.12, p=0.006) and CT-assessed PsD (HR 0.97; 95%CI 0.94-0.99, p=0.023) were the variables independently associated with all-cause mortality., Conclusions: In COPD patients with mild to severe airflow limitation, chest CT-assessed psoas muscle density was lower than in matched controls and independently associated with long-term mortality. Muscle quality using the easy to evaluate psoas muscle density from chest CT may provide clinicians with important prognostic information in COPD., (Copyright © 2021 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Rationale: Whether pharmacological therapy alters decline in FEV 1 in chronic obstructive pulmonary disease remains controversial. Because pharmacotherapy improves health status, exacerbation rate, and symptoms, it may be unethical to complete placebo-controlled long-term studies aimed at modifying FEV 1 decline. Objectives: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV 1 decline. Methods: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation. Measurements and Main Results: There were 33,051 patients in the analysis (active component, n  = 21,941; placebo, n  = 11,110 in nine studies). The active treatment arms demonstrated a 5.0 ml/yr reduction (95% confidence interval, 0.8-9.1 ml/yr; P  < 0.001) in the rate of FEV 1 decline compared with the placebo arms. The relative FEV 1 differences between active and placebo arms were within the range of differences reported for health status and for the exacerbation rate in the same studies. Conclusions: In chronic obstructive pulmonary disease, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

Background: Lung Cancer (LC) screening with low dose chest computed tomography (LDCT) in smokers reduces LC mortality. Patients with Obstructive Lung Disease (OLD) are at high risk for LC. The potential effect of LC screening in this population is unknown., Objective: To determine if screening with LDCT reduces LC mortality in smokers with spirometrically defined OLD., Methods: The National Lung Screening Trial-American College of Radiology Imaging Network (NLST-ACRIN) study included 13,831 subjects (55-74 years of age with ≥30 pack-year history of smoking) that had a baseline spirometry. Randomly assigned to LDCT or Chest X-ray, all had 3 annual rounds of screening. LC mortality was compared between the LDCT and chest X-ray arms during the 1st year and at 6 years of follow up. Landmark analysis explored LC mortality differences between arms after the first year., Results: From the 4584 subjects with OLD (FEV1/FVC <0.7), 152 (3.3%) died from LC. Multivariable analysis showed that screening trended to decrease LC mortality at 6 years (HR, 95%CI: 0.75, 0.55-1.04, p=0.09). During the 1st year no differences were found between arms (p=0.65). However, after this year, LDCT significantly decreased LC mortality (HR, 95%CI: 0.63, 0.44-0.91, p=0.01). The number needed to screen to avoid one LC death in these subjects was 108 while in those without OLD was 218., Conclusions: LC screening with LDCT in smokers with spirometrically diagnosed OLD, showed a trend to reduce lung cancer mortality but a study with a larger number of patients and with a more robust design would be needed to confirm these findings., (Copyright © 2020 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

The COVID-19 pandemic has profoundly affected health care delivery worldwide. A small yet significant number of patients with respiratory failure will require prolonged mechanical ventilation while recovering from the viral-induced injury. The majority of reports thus far have focused on the epidemiology, clinical factors, and acute care of these patients, with less attention given to the recovery phase and care of those patients requiring extended time on mechanical ventilation. In this paper, we review the procedures and methods to safely care for patients with COVID-19 who require tracheostomy, gastrostomy, weaning from mechanical ventilation, and final decannulation. The guiding principles consist of modifications in the methods of airway care to safely prevent iatrogenesis and to promote safety in patients severely affected by COVID-19, including mitigation of aerosol generation to minimize risk for health care workers., Competing Interests: Dr Pritchett has disclosed relationships with Medtronic, BodyVision, Intuitive Surgical, Philips, Biodesix, AstraZeneca, Johnson & Johnson, United Therapeutics, Actelion, Inivata, Pfizer, Ambu, and Boston Scientific. Dr Folch has disclosed relationships with Medtronic, Cook Medical, Boston Scientific, and Intuitive Surgical. The other authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

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.)

Chronic obstructive pulmonary disease (COPD) is a complex disease manifested primarily as airflow limitation that is partially reversible as confirmed by spirometry. COPD patients frequently develop systemic manifestations, such as skeletal muscle wasting and cachexia. COPD patients often develop other comorbid diseases, such as ischemic heart disease, heart failure, osteoporosis, anemia, lung cancer, and depression. Comorbidities complicate management of COPD and need to be evaluated because detection and treatment have important consequences. Novel approaches aimed at integrating the multiple morbidities seen in COPD and other chronic diseases will provide new avenues of research and allow developing more comprehensive and effective therapeutic approaches., Competing Interests: Disclosure The authors have no relevant financial interest related to the material in the article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Bronchodilators administered through inhalation devices are the mainstay treatment for patients with obstructive lung diseases. Patients do not view devices as interchangeable. This systematic review and meta-analysis examined device feature preferences among patients with obstructive lung diseases treated with handheld inhalers., Study Appraisal and Synthesis Methods: PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were searched to identify publications between 2010 and 2019 that met the following criteria:A manual search extended the study period from 2001 to 2019. Random-effects models were used to generate pooled mean effect sizes and 95% confidence intervals (CIs) for preferred device features. Heterogeneity was measured by the I statistic., Results: Nineteen studies (n = 11,256) were included in this meta-analysis. Average age ranged from 50.4 to 74.3 years. The majority of patients were male (57%) and had chronic obstructive pulmonary disease (92%).Patients preferred the following device features: CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS:: Adults with obstructive lung diseases preferred small inhaler devices that were portable, durable, perceived as easy to use, and fast in medication administration. Healthcare providers should give due consideration to the patient's device feature preferences when developing a treatment plan that prescribes an inhalation device.

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) differ in predictive value., Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV 1 %predicted, FVC %predicted, FEV 1 /FVC). The four highest quintiles (Q2-Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score., Results: Compared to Q1 (<53.5% FEV 1 predicted), increasing FEV 1 quintiles (Q2 53.5-457.5% predicted, Q3 57.5-461.6% predicted, Q4 61.6-465.8% predicted, and Q5 ≥65.8%) were all associated with significantly decreased all-cause mortality (20% (4-34%), 28% (13-40%), 23% (7-36%), and 30% (15-42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4-35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV 1 nor FVC was associated with cardiovascular risk. Increased FEV 1 and FEV 1 /FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8-52%) risk increase)., Conclusion: Our results suggest that FEV 1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks., Competing Interests: AB reports fees from AstraZeneca, Chiesi, and Sandoz. PL reports grants from AstraZeneca and GlaxoSmithKline and fees from Boehringer Ingelheim, AstraZeneca, Novartis, and GlaxoSmithKline. JAA, CC, and JCY are employees of and hold stock in GlaxoSmithKline plc. PMAC reports fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca. BRC reports fees from GlaxoSmithKline. NJC and IJD are employed by Veramed Ltd, a Contract Research Organization undertaking contracted statistical analyses of studies funded by GlaxoSmithKline plc. FJM reports grants, personal fees, non-financial support from AstraZeneca, personal fees, non-financial support from Boehringer Ingelheim, non-financial support from Proterrix Bio, personal fees from CME Outfitters, personal fees from Gala, Asthma DSMB from Genentech/Roche, grants, personal fees, non-financial support from GlaxoSmithKline, personal fees from INOVA Fairfox, personal fees from Miller Communications, personal fees from National Association for Continuing Education, personal fees from Novartis, personal fees from Pearl, personal fees from PeerView, personal fees from Physicians Education Resource, personal fees from Prime Education, personal fees from Sunovion, personal fees from Teva, personal fees, non-financial support from UpToDate, personal fees from WebMD/Medscape, during the conduct of the study; personal fees from Gentech, and is involved with COPD CME for UpToDate. DEN reports fees from GlaxoSmithKline. JV reports fees from GSK, AstraZeneca, Boehringer-Ingelheim, Chiesi, and Novartis. The authors report no other conflicts of interest in this work., (© 2020 Bikov et al.)