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Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD). The extent to which the excess CVD risk is captured by risk factors in QRISK, a widely used CVD risk scoring tool, is not well studied., Methods: We created an incidence cohort of diagnosed COPD patients from the United Kingdom (UK) Clinical Practice Research Datalink GOLD database (January 1998-July 2018). The outcome was a composite of fatal or non-fatal CVD events. Sex-specific age-standardised incidence ratios (SIR) were compared with values for the UK primary-care population. The observed 10-year CVD risk was derived using the Kaplan-Meier estimator and was compared with predicted 10-year risk from the QRISK3 tool., Results: 13 208 patients (mean age 64.9 years, 45% women) were included. CVD incidence was 3.53 events per 100 person-years. The SIR of CVD was 1.71 (95% CI 1.61 to 1.75) in women and 1.62 (95%CI 1.54-1.64) in men. SIR was particularly high among patients younger than 65 years (women=2.13 (95% CI 1.94 to 2.19); men=1.86 (95% CI 1.74 to 1.90)). On average, the observed 10-year risk was 52% higher than QRISK predicted score (33.5% vs 22.1%). The difference was higher in patients younger than 65 years (observed risk 82% higher than predicted)., Conclusion: People living with COPD are at a significantly heightened risk of CVD over and beyond their predicted risk. This is particularly the case for younger people whose 10-year CVD risk can be >80% higher than predicted. Risk scoring tools must be validated and revised to provide accurate CVD predictions in patients with COPD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear., Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV 1 ) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52., Results: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV 1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab., Conclusions: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes., Methods: The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV 1 /forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [≥2%] or placebo if eosinophil count was low [<2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete., Findings: Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46-84] and mean percent predicted FEV 1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33-1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study., Interpretation: Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests SR reports personal salary support from the National Institute for Health and Care Research, an unrestricted research grant from AstraZeneca to his institution, and speaker fees and conference travel support from AstraZeneca, all outside of the submitted work. MB reports salary support and direct funding for the study from the National Institute for Health and Care Research through a named fellowship. Outside of the submitted work, MB reports research grant funding paid to her institution from AstraZeneca, Roche, the European Respiratory Society, and Asthma + Lung UK. Outside of the submitted work, she also reports consulting fees from AstraZeneca, Sanofi, GSK, and Areteia, paid to her and her institution. She has received conference travel support from Chiesi. She has a leadership and board roles at the British Thoracic Society, AlbusHealth, and ProAxsis. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral corticosteroids (OCS) are often prescribed for chronic obstructive pulmonary disease (COPD) exacerbations., Methods: This observational, individually matched historical cohort study used electronic medical records (1987-2019) from the UK Clinical Practice Research Datalink linked to English Hospital Episode Statistics (HES) to evaluate adverse outcomes in patients with COPD who used OCS (OCS cohort) and those not exposed to OCS (non-OCS cohort). Risk of 17 adverse outcomes was estimated using proportional hazard regression., Results: Of 323,722 patients, 106,775 (33.0%) had COPD-related OCS prescriptions. Of the 106,775 patients in the overall cohort, 58,955 had HES linkage and were eligible for inclusion in the OCS cohort. The individual matching process identified 53,299 pairs of patients to form the OCS and non-OCS cohorts. Median follow-up post-index was 6.9 years (OCS cohort) and 5.4 years (non-OCS cohort). Adjusted risk of multiple adverse outcomes was higher for the OCS cohort versus the non-OCS cohort, including osteoporosis with/without fractures (adjusted hazard ratio [aHR] 1.80; 95% confidence interval [CI] 1.70-1.92), type 2 diabetes mellitus (aHR 1.44; 95% CI 1.37-1.51), cardiovascular/cerebrovascular disease (aHR 1.26; 95% CI 1.21-1.30), and all-cause mortality (aHR 1.04; 95% CI 1.02-1.07). In the OCS cohort, risk of most adverse outcomes increased with increasing categorized cumulative OCS dose. For example, risk of cardiovascular/cerebrovascular disease was 34% higher in the 1.0-<2.5 g group versus the <0.5 g group (HR 1.34; 95% CI 1.26-1.42)., Conclusion: Any OCS use was associated with higher risk of adverse outcomes in patients with COPD, with risk generally increasing with greater cumulative OCS dose., Competing Interests: GT and CA are former employees of the Observational and Pragmatic Research Institute (OPRI), which was funded by AstraZeneca to conduct this study. VC, JZ, and DS are employees of OPRI, which was funded by AstraZeneca to conduct this study. BE, XX, and HM are employees of AstraZeneca and hold stock and/or stock options in the company. MB has received research grants to her institution from AstraZeneca; honoraria to her institution from AstraZeneca, Chiesi, and GlaxoSmithKline; and is an advisory board member for Albus Health and ProAxsis. AP has received scientific grants to his institution from Agenzia Italiana del Farmaco (AIFA), AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi; has received consulting fees from AstraZeneca, Avillion, Chiesi, ELPEN Pharmaceuticals, GlaxoSmithKline, Novartis, and Sanofi; has received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from AstraZeneca, Avillion, Chiesi, Edmond Pharma, ELPEN Pharmaceuticals, Moderna, GlaxoSmithKline, IQVIA, Menarini, Mundipharma, Novartis, Sanofi, and Zambon; and is an advisory board member for AstraZeneca, Avillion, Chiesi, ELPEN Pharmaceuticals, GlaxoSmithKline, IQVIA, MSD, Novartis, and Sanofi. DP is an employee of OPRI, which was funded by AstraZeneca to conduct this study; has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Thermo Fisher; has consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON, Fieldwork International, GlaxoSmithKline, Mundipharma, Mylan, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance, and WebMD Global LLC; has received grants and unrestricted funding for investigator-initiated studies (conducted through OPRI) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance, and UK National Health Service; has received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mundipharma, Mylan, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme; has received payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermo Fisher; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of OPRI (Singapore); has a 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation Programme and Health Technology Assessment; and has been an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2023 Tse et al.)

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

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.

Exacerbations in chronic obstructive pulmonary disease (COPD), which tend to occur in clusters and increase with disease severity, come with high societal and economic burdens. Prevention and delay of recurrent exacerbations is an unmet and significant therapeutic need for patients with COPD. GALATHEA (NCT02138916) and TERRANOVA (NCT02155660) were trials assessing efficacy of benralizumab in patients with frequent COPD exacerbations despite treatment. Although these studies found that benralizumab given as an add-on treatment did not significantly reduce annual rates of COPD exacerbations after 56 weeks of treatment, in the following exploratory post hoc analysis of the GALATHEA and TERRANOVA trials we identified a potential responder population in which treatment with benralizumab prevents recurrent COPD exacerbations during 30- and 90-day periods following an initial exacerbation, a vulnerable period for an exacerbation to occur. This responder population was characterized by high blood eosinophil counts and frequent previous exacerbations despite optimized triple therapy. These results highlight the importance of targeted therapies for high-risk populations and merit further research into the benefits of biologic therapies for COPD exacerbations., Competing Interests: DS has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona. GJC has received grants from NIH-NHLBI, PA-DOH, GSK, Boehringer Ingelheim, Novartis, AstraZeneca, Respironics, MedImmune, Novartis, Pearl, PneumRx, Pulmonx, Broncus, Spiration, Olympus, Fisher-Paykel Healthcare, Chiesi, Gilead, Pfizer, Corvus, Lilly, Regeneron, Genentech, and Roche and is a consultant for Almirall, AstraZeneca, Nuvaira, GSK, CSA Medical, PneumRx, BTG, Mereo, Broncus, Pulmonx, and EOLO. AA has received grants and private fees from AstraZeneca, Chiesi, GlaxoSmithKline, and Menarini and is a member of the GOLD Science Committee and Board of Directors. MB has received fees from AstraZeneca, Boehringer Ingelheim, Chiesi, and GlaxoSmithKline, and grants from AstraZeneca, Roche, and other support from Asthma & Lung UK, Albus Health and ProAxsis to the institution, outside the submitted work. JS, GLS, YS, MJ, UJM, and IP are or were employees of AstraZeneca at the time these analyses were conducted and may own stock/stock options in AstraZeneca. IL was a contractor for AstraZeneca at the time these analyses were conducted and affiliated with Cytel Inc. The authors report no other conflicts of interest in this work., (© 2023 Singh et al.)

Background: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation., Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV 1 ) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms)., Results: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV 1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups., Conclusions: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The ever-growing size, breadth, and availability of patient data allows for a wide variety of clinical features to serve as inputs for phenotype discovery using cluster analysis. Data of mixed types in particular are not straightforward to combine into a single feature vector, and techniques used to address this can be biased towards certain data types in ways that are not immediately obvious or intended. In this context, the process of constructing clinically meaningful patient representations from complex datasets has not been systematically evaluated., Aims: Our aim was to a) outline and b) implement an analytical framework to evaluate distinct methods of constructing patient representations from routine electronic health record data for the purpose of measuring patient similarity. We applied the analysis on a patient cohort diagnosed with chronic obstructive pulmonary disease., Methods: Using data from the CALIBER data resource, we extracted clinically relevant features for a cohort of patients diagnosed with chronic obstructive pulmonary disease. We used four different data processing pipelines to construct lower dimensional patient representations from which we calculated patient similarity scores. We described the resulting representations, ranked the influence of each individual feature on patient similarity and evaluated the effect of different pipelines on clustering outcomes. Experts evaluated the resulting representations by rating the clinical relevance of similar patient suggestions with regard to a reference patient., Results: Each of the four pipelines resulted in similarity scores primarily driven by a unique set of features. It was demonstrated that data transformations according to each pipeline prior to clustering can result in a variation of clustering results of over 40%. The most appropriate pipeline was selected on the basis of feature ranking and clinical expertise. There was moderate agreement between clinicians as measured by Cohen's kappa coefficient., Conclusions: Data transformation has downstream and unforeseen consequences in cluster analysis. Rather than viewing this process as a black box, we have shown ways to quantitatively and qualitatively evaluate and select the appropriate preprocessing pipeline., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mona Bafadhel has received grants from AstraZeneca, Roche (to institution). Has received honoraria from AstraZeneca, Chiesi, Cipla, GlaxoSmithKline, Sanofi (to institution) and is Scientific advisor to AlbusHealth® and ProAxsis®. The rest of authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright: © 2023 Pikoula et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count., Methods: Patients (40-80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (<100, ≥100, ≥100-<300, ≥300 cells/mm 3 ), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety., Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥100 cells/mm 3 . BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥100, ≥100-<300, and ≥300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George's Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the <100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups., Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥100 cells/mm³., Competing Interests: MB reports grants from AstraZeneca, and honoraria from AstraZeneca, Chiesi, and GlaxoSmithKline; and is on the scientific advisory board for Albus Health and ProAxsis. KFR reports grants and personal fees from AstraZeneca and Boehringer Ingelheim; and personal fees from Berlin Chemie, Chiesi Pharmaceuticals, GlaxoSmithKline, Novartis, Regeneron, Roche, and Sanofi, outside the submitted work. FJM reports grants, personal fees, and non-financial support from AstraZeneca during the conduct of the study; grants, personal fees, and non-financial support from AstraZeneca, Boehringer Ingelheim, Bioscale/Proterrix Bio, Chiesi, CSL Behring, Gala, GlaxoSmithKline, Metronic, Novartis, Polarean, Pulmatrix, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris, and Verona; grants and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi/Regeneron. He is also a COPD teleconsultant for Bayer. DS reports personal fees from AstraZeneca during the conduct of the study; and personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona, outside the submitted work. PDa, MJ, MA, and MP are employees of AstraZeneca and hold stock and/or stock options in the company. PDo is a former employee of AstraZeneca and previously held stock and/or stock options in the company. The authors report no other conflicts of interest in this work., (© 2022 Bafadhel et al.)

Competing Interests: SPC, APC, and DVN Jr declare no competing interests. REKR discloses consultancy or speaker fees paid to their institution from AstraZeneca, Chiesi, and GlaxoSmithKline, is a scientific advisor to GlaxoSmithKline, and discloses support for attending meetings from Boehringer Ingelheim. MB discloses grants paid to their institution from AstraZeneca, Roche, and Asthma & Lung UK, has received consultancy or speaker fees paid to their institution from AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi, and is a scientific advisor to ProAxsis and AlbusHealth.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused severe illness and mortality for millions worldwide. Despite the development, approval and rollout of vaccination programmes globally to prevent infection by SARS-CoV-2 and the development of coronavirus disease 2019 (COVID-19), treatments are still urgently needed to improve outcomes. Early in the pandemic it was observed that patients with pre-existing asthma or COPD were underrepresented among those with COVID-19. Evidence from clinical studies indicates that the inhaled corticosteroids (ICS) routinely taken for asthma and COPD could have had a protective role in preventing severe COVID-19 and, therefore, may be a promising treatment for COVID-19. This review summarises the evidence supporting the beneficial effects of ICS on outcomes in patients with COVID-19 and explores the potential protective mechanisms., Competing Interests: Conflict of interest: M. Bafadhel has unrestricted research grants from AstraZeneca and Roche, and has received honoraria to her institution for speaker's fees from AstraZeneca, Chiesi, Cipla and GlaxoSmithKline. She is a scientific adviser to Albus Health and ProAxsis. Conflict of interest: R. Faner has received research funding, advisory board fees and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline and Menarini. Conflict of interest: C. Taillé has received grants to her institution, advisory board fees and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis and Sanofi. Conflict of interest: R.E.K. Russell has received advisory board fees and lecture fees from AstraZeneca, Chiesi, Cipla and GlaxoSmithKline. Conflict of interest: T. Welte has received lecture fees from AstraZeneca, Basilea, Bayer, Berlin Chemie, Biotest, Boehringer Ingelheim, GlaxoSmithKline, MSD, Novartis, Pfizer, Roche and Sanofi-Aventis, and advisory board fees from AstraZeneca, Basilea, Bayer, Biotest, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer and Roche. Conflict of interest: P.J. Barnes has received research funding from AstraZeneca and Boehringer Ingelheim, and funding for consultancy, scientific advisory boards and talks from AstraZeneca, Boehringer Ingelheim, Covis, Epi-Endo, Novartis, Pieris and Teva. Conflict of interest: A. Agustí has unrestricted research grants from AstraZeneca and GlaxoSmithKline, and has received honoraria for speaker's fees from AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Orion Pharma and Zambon., (Copyright ©The authors 2022.)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment., Competing Interests: Declaration of interests SAC reports grant funding paid to her institution from the National Institutes of Health (NIH) and Merck; consulting fees paid from AstraZeneca, GlaxoSmithKline, and Glenmark Pharmaceuticals; payment and honoraria paid from AstraZeneca, Sanofi/Regeneron, Genentech, and Sunovion; and participation in advisory boards or Data and Safety Monitoring Boards (DSMBs) for AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron, and Glenmark Pharmaceuticals. BMS reports grants paid to their institution from NIH, Canadian Institutes of Health Research, Canadian Lung Association, Quebec Respiratory Health Research Network, and McGill University Health Centre Foundation, and leadership as director for the Centre for Outcomes and Research Evaluation of the McGill University Health Centre Research Institute. MB reports grants paid to their institution from AstraZeneca and Roche; consulting fees paid to their institution from AstraZeneca and GlaxoSmithKline; honoraria paid to their institution from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; and participation in advisory boards or DSMBs with fees paid to their institution from AstraZeneca and GlaxoSmithKline. NP reports research funding paid to their institution from NIH and CSL Behring, and participation in advisory boards for CSL Behring and Pharmacosmos., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Demographic and disease characteristics have been associated with the risk of chronic obstructive pulmonary disease (COPD) exacerbations. Using previously collected multinational clinical trial data, we developed models that use baseline risk factors to predict an individual's rate of moderate/severe exacerbations in the next year on various pharmacological treatments for COPD., Methods: Exacerbation data from 20,054 patients in the ETHOS, KRONOS, TELOS, SOPHOS, and PINNACLE-1, PINNACLE-2, and PINNACLE-4 studies were pooled. Machine learning was used to identify predictors of moderate/severe exacerbation rates. Important factors were selected for generalized linear modeling, further informed by backward variable selection. An independent test set was held back for validation., Results: Prior exacerbations, eosinophil count, forced expiratory volume in 1 s percent predicted, prior maintenance treatments, reliever medication use, sex, COPD Assessment Test score, smoking status, and region were significant predictors of exacerbation risk, with response to inhaled corticosteroids (ICSs) increasing with higher eosinophil counts, more prior exacerbations, or additional prior treatments. Model fit was similar in the training and test set. Prediction metrics were ~10% better in the full model than in a simplified model based only on eosinophil count, prior exacerbations, and ICS use., Conclusion: These models predicting rates of moderate/severe exacerbations can be applied to a broad range of patients with COPD in terms of airway obstruction, eosinophil counts, exacerbation history, symptoms, and treatment history. Understanding the relative and absolute risks related to these factors may be useful for clinicians in evaluating the benefit: risk ratio of various treatment decisions for individual patients.Clinical trials registered with www.clinicaltrials.gov (NCT02465567, NCT02497001, NCT02766608, NCT02727660, NCT01854645, NCT01854658, NCT02343458, NCT03262012, NCT02536508, and NCT01970878).

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients' pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence., Competing Interests: Conflict of interest: R.A. Wise reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; grants and personal fees from AstraZeneca/Medimmune/Pearl (data monitoring committee, grants, consulting), grants and personal fees from Boehringer Ingelheim (steering committee, data monitoring committee, grants), personal fees from Contrafect (clinical end-point committee), grants and personal fees from AstraZeneca (research grant, consulting), grants and personal fees from GSK (research grant, consulting), personal fees from Sunovion (workshop, consulting), personal fees from Merck (data monitoring committee), personal fees from Verona (consultant), personal fees from Mylan/Theravance (consultant), personal fees from Propeller Health (consultant), grants and personal fees from GSK (scientific advisory board, clinical end-point committee, Data Monitoring Committee, research grant support), personal fees from Novartis (consultant), personal fees from ChimRix (data monitoring committee), personal fees from FSD Pharma (data monitoring committee), personal fees from AbbVie (data monitoring committee), personal fees from Bristol Myers Squibb (data monitoring committee), personal fees from Puretech (data monitoring committee), personal fees from Galderma (clinical end-point committee), personal fees from Chiesi (clinical end-point committee), outside the submitted work. Conflict of interest: M. Bafadhel reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; grants, personal fees and other from AstraZeneca (research grants, advisory board attendance, educational meeting attendance), personal fees and other from Chiesi (advisory board attendance, educational meeting attendance), personal fees and other from Boehringer Ingelheim (advisory board attendance, educational meeting attendance), personal fees and other from GlaxoSmithKline (advisory board attendance), personal fees and other from ProAxsis (scientific advisor), personal fees and other from AlbusHealth (scientific advisor), outside the submitted work. Conflict of interest: C. Crim reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; C. Crim is a former employee of GlaxoSmithKline and has shares/options held in GSK, outside the submitted work. Conflict of interest: G.J. Criner reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, Eolo, GlaxoSmithKline, HGE Technologies, Novartis, Nuvaira, Olympus, Pulmonx and Verona, outside the submitted work. Conflict of interest: N.C. Day reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; N.C. Day is an employee of GlaxoSmithKline and has shares/options held in GSK, outside the submitted work. Conflict of interest: D.M.G. Halpin reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; personal fees from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees from Pfizer, outside the submitted work. Conflict of interest: M.K. Han reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; outside the submitted work, M.K. Han also reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Inhgelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, United Therapeutics, Medscape and Integrity. She has received either in kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. Conflict of interest: P. Lange reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: D.A. Lipson reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; D.A. Lipson is an employee of GlaxoSmithKline and has shares/options held in GSK, outside the submitted work. Conflict of interest: F.J. Martinez reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; other from Afferent/Merck (IPF Steering Committee (academic productivity)), personal fees, non-financial support and other from AstraZeneca (COPD Advisory Boards (personal fees honoraria and non-personal travel support), study steering committee (non-personal travel support), DSMB (other – academic co-authorship)), other from Bayer (ILD Steering Committee (academic productivity)), personal fees, non-financial support and other from Boehringer Ingelheim (COPD Advisory Board (personal fees and non-personal travel support); ATS presentation (personal fees); progressive pulmonary fibrosis DSMB (no financial support but travel); ERS IPF study result presentation (personal fee and travel support; IPF study steering committee chair), non-financial support and other from Bioscale/ProterrixBio (COPD scientific advisory board (no direct financial compensation, support for NIH study)), other from Bridge Biotherapeutics (IPF consultation), personal fees and non-financial support from Canadian Respiratory Network (COPD CME presentation (honorarium and travel support)), personal fees and non-financial support from Chiesi (COPD CME presentation (personal fees honoraria and non-personal travel support); Advisory Board (personal fees honoraria and travel support)), personal fees from France Foundation (IPF CME presentation (honorarium)), personal fees and non-financial support from Genentech (COPD advisory board (personal fee and non-personal travel support) and asthma DSMB (no support); IPF advisory board (personal fees honorarium and non-personal travel support)), other from Gilead (IPF study steering committee (other – co-authorship)), personal fees and non-financial support from GlaxoSmithKline (COPD advisory boards (personal fees honoaria and non-personal travel support), study steering committee (non-personal travel support), DSMB (other – academic co-authorship)), personal fees and non-financial support from Inova Fairfax Health System (COPD CME presentation (personal support honorarium and non-personal travel support)), personal fees from MD Magazine (COPD CME programme (personal fee honorarium and non-personal travel support)), personal fees and non-financial support from Methodist Hospital Brooklyn (IPF and COPD CME programs (personal fee honoraria)), personal fees and non-financial support from Miller Communications (COPD and IPF CME programs (personal fees honoraria and non-personal travel support)), non-financial support from Nitto (IPF Study Teleconference and Steering Committee (non-personal travel support)), personal fees and non-financial support from Novartis (COPD advisory board and international meeting COPD disease presentations (personal fees honoraria and non-personal travel support)), personal fees from New York University (ILD CME programme (personal fee honoraria)), personal fees and other from Patara (venture capital expert advice for IPF study (personal fees honoraria); IPF steering committee), personal fees and non-financial support from Pearl Pharmaceuticals (COPD advisory boards (personal fee honoraria and non-personal travel support) and COPD steering committee (academic productivity)), personal fees and non-financial support from PeerView Communications (COPD and IPF CME programmes (personal fees honoraria and non-personal travel support)), personal fees, non-financial support and other from Physicians Education Resource (IPF advisory board (personal fee honorarium and travel support)), personal fees from Prime Communications (COPD CME programme (personal fee honorarium)), other from Roche (IPF Steering Committee (academic productivity)), other from ProMetic (IPF steering committee (academic productivity)), personal fees from Rare Disease Health Communications (IPF CME programme (personal fee honorarium)), personal fees from Rockpointe (COPD CME programme (personal fee honorarium)), other from Biogen (IPF study DSMB (no support) and IPF study steering committee (academic productivity)), personal fees and non-financial support from Sunovion (COPD advisory boards (personal fee honoraria and non-personal travel support)), personal fees and non-financial support from Teva (COPD advisory board (personal fee honorarium and travel support)), personal fees and non-financial support from University of Alabama Birmingham (IPF CME presentation (personal fee honoraria and non-personal travel support)), personal fees from UpToDate (COPD CME (personal fee honoraria)), other from Veracyte (IPF study steering committee (other co-authorship)), personal fees from WebMD/MedScape (COPD and IPF CME presentations (personal fee honoraria)), non-financial support from Zambon (IPF study meeting (non-personal travel support) and advisory board (personal fees honorarium)), personal fees and non-financial support from American College of Chest Physicians, personal fees and non-financial support from ConCert, personal fees and non-financial support from Continuing Education, personal fees and non-financial support from National Society for Continuing Education, personal fees and non-financial support from Potomac, personal fees and non-financial support from Puerto Rico Respiratory Society, personal fees and non-financial support from Theravance, non-financial support from Nitto, personal fees from Columbia University, personal fees from Integras, personal fees from Unity, personal fees from Western Connecticut Health Network, personal fees from Academic CME, personal fees from Platform IQ, personal fees from American Thoracic Society, grants from Promedior, outside the submitted work. Conflict of interest: D.J. Maselli reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; personal fees from AstraZeneca, personal fees from Sanofi/Regeneron, personal fees from Amgen, outside the submitted work. Conflict of interest: D. Midwinter reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; D. Midwinter is an employee of GlaxoSmithKline and has shares/options held in GSK, outside the submitted work. Conflict of interest: D. Singh reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; personal fees from GlaxoSmithKline, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, grants and personal fees from Glenmark, grants and personal fees from Menarini, grants and personal fees from Mundipharma, grants and personal fees from Novartis, personal fees from Peptinnovate, grants and personal fees from Pfizer, grants and personal fees from Pulmatrix, grants and personal fees from Theravance, grants and personal fees from Verona, outside the submitted work. Conflict of interest: M. Zysman reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees from CSL Behring, outside the submitted work. Conflict of interest: M.T. Dransfield reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; other from Boehringer Ingelheim (consulting and contracted clinical trials), personal fees and other from GlaxoSmithKline (consulting and contracted clinical trials), personal fees and other from AstraZeneca (consulting and contracted clinical trials), other from PneumRx/BTG (contracted clinical trials), other from Pulmonx (contracted clinical trials), personal fees from Teva (consulting), other from Gala (contracted clinical trials), other from Nuvaira (contracted clinical trials), outside the submitted work. Conflict of interest: R.E.K. Russell reports other and non-financial support from GlaxoSmithKline (funding the study and funding medical writing support by Anne Errichelli at Fishawack Indicia Ltd, UK), during the conduct of the study; grants and personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Cipla, personal fees from Chiesi, personal fees from Boehringer Ingelheim, personal fees from Albus Health (Advisor), non-financial support from National Institute for Health Research Oxford Biomedical Research Centre, outside the submitted work., (Copyright ©The authors 2021.)

Background: Therapeutic inertia, defined as failure to escalate or initiate adequate therapy when treatment goals are not met, contributes to poor management of COPD exacerbations., Methods: A multidisciplinary panel of five expert clinicians actively managing COPD and representative of UK practice developed action points to reduce exacerbation risk, based on evidence, clinical expertise, and experience. The action points are applicable despite changing circumstances (eg, virtual clinics). The panel agreed areas where further evidence is needed., Results: The four action points were (1) an experienced HCP, such as a GP or member of the multi-professional COPD team should review patients within one month of every exacerbation that requires oral steroids, antibiotics, or hospitalization to address modifiable risk factors, optimize non-pharmacological measures, and evaluate pharmacological therapy. (2) Presenting to hospital with an exacerbation defines an important window of opportunity to reduce the risk of further exacerbations. Follow-up by a GP, or member of the multi-professional specialist COPD team within one month of discharge with a full management review and appropriate escalation of pharmacological treatment is essential. (3) Healthcare professionals (HCPs) in all healthcare settings should be able to recognize COPD exacerbations, refer as appropriate and document the episode accurately in medical records across service boundaries. HCPs should support patients to recognize and report exacerbations. (4) HCPs should intervene proactively based on risk assessments, disease activity and any treatable traits at or as soon as possible after diagnosis and annually thereafter. Delivering these action points needs coordinated action with policymakers, funders, and service providers., Conclusion: These action points should be a fundamental part of clinical practice to determine if a change in management is necessary to reduce the risk of exacerbations. Policymakers should use these action points to develop systems and initiatives that reduce the risk of further exacerbations., Competing Interests: Claire Adams: Honoraria and speaker fees from AstraZeneca; Boehringer Ingelheim; Chiesi; Napp; GlaxoSmithKline; Mona Bafadhel: Research Grants from AstraZeneca. Educational Talks with AstraZeneca, Cipla and GlaxoSmithKline. Scientific Advisor to ProAxsis and Albus Health and is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Steve Holmes: Honoraria and speaker fees in the last 2 years from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Napp, Roche, Teva, Trudell, Viatris. John R Hurst: Support to attend meetings, and personal payment and payment to his employer (UCL) for educational and advisory work from pharmaceutical companies that make medicines to treat COPD including AstraZeneca, Chiesi and Boehringer Ingelheim. Dave Singh: Grants and personal fees from Aerogen, AstraZeneca, CSL Behring, Boehringer Ingelheim, Chiesi, Cipla, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona, and is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). The authors report no other conflicts of interest relevant to this work., (© 2021 Singh et al.)

Background: Patients with COPD experience acute worsenings, termed 'exacerbations'. While other terms to describe these events have been proposed there is no consensus on terminology which has led to multiple terms being used across the UK. Respiratory nurses are part of a multi-disciplinary team managing COPD patients, however, the nursing perspective on the term 'exacerbation' is unknown., Methods: An anonymised survey of 17 questions was sent to respiratory nurses through an email invitation link. The survey link was open for one month. The aim was to understand the nurse perspective on 'exacerbation'. Alternative terms used in the UK were compared versus the term 'exacerbation'., Results: Responses were received from 113 nurses. The majority (88%) were female. There was no consensus on preference or meaning for the term 'exacerbation' between nurses. Less than 5% of nurses thought that patients with COPD would understand the term 'exacerbation'. In ranked order, the nurses preferred the following terms: 'flare-up', 'lung attack', 'crisis', 'exacerbation' and 'chest infection'. The term 'crisis', although new, was considered to be the term that most resonated with clinical practice., Conclusion: Respiratory nurses in the UK report that the term 'exacerbation' is not fit for purpose for patients, and alternatives should be sought., (© 2021. The Author(s).)

Background: COPD and asthma exacerbations result in many emergency department admissions. Not all treatments are successful, often leading to hospital readmissions., Aims: We sought to develop predictive models for exacerbation treatment outcome in a cohort of exacerbating asthma and COPD patients presenting to the emergency department., Methods: Treatment failure was defined as the need for additional systemic corticosteroids (SCS) and/or antibiotics, hospital readmissison or death within 30 days of initial emergency department visit. We performed univariate analysis comparing characteristics of patients either given or not given SCS at exacerbation and of patients who succeeded versus failed treatment. Patient demographics, medications and exacerbation symptoms, physiology and biology were available. We developed multivariate random forest models to identify predictors of SCS prescription and for predicting treatment failure., Results: Data were available for 81 patients, 43 (53%) of whom failed treatment. 64 (79%) of patients were given SCS. A random forest model using presence of wheeze at exacerbation and blood eosinophil percentage predicted SCS prescription with area under receiver operating characteristic curve (AUC) 0.69. An 11 variable random forest model (which included medication, previous exacerbations, symptoms and quality of life scores) could predict treatment failure with AUC 0.81. A random forest model using just the two best predictors of treatment failure, namely, visual analogue scale for breathlessness and sputum purulence, predicted treatment failure with AUC 0.68., Conclusion: Prediction of exacerbation treatment outcome can be achieved via supervised machine learning combining different predictors at exacerbation. Validation of our predictive models in separate, larger patient cohorts is required., Competing Interests: Mona Bafadhel reports outside the submitted work research grant reports from AZ; honoraria from AZ, Chiesi, and GlaxoSmithKline; and is on the scientific advisory board for AlbusHealth® and ProAxsis®. Richard Russell has received honoraria from AZ, GSK, Boheringer Ingelheim, Chiesi, Cipla and is on the advisory board for AlbusHealth®, has received research funding from Circassia UK and his work is supported by the Oxford NIHR Biomedical Research Centre. The remaining authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Competing Interests: MB, CEB, TB, JKQ, HAR, ES, TMAW, and JRH were applicants on the original grant to the British Lung Foundation (BLF). MB, CEB, SH, JK, JKQ, ES, TMAW, and JRH have received support to attend meetings, personal payment or payment to their employers for education or advisory work, or academic grants from pharmaceutical companies that make medicines to treat COPD. TMAW is a Director and shareholder at Mymhealth. SU is a JLA PSP Advisor. JSA, JA, JL, and JM have no competing interests. We thank the BLF for funding this research, and all the participants who took part in our surveys and workshops.

Background: A pre-specified meta-analysis of individual patient data from the 52-week METREX and METREO trials, which investigated mepolizumab for chronic obstructive pulmonary disease (COPD) in patients with blood eosinophil counts ≥150 cells/µL (screening) or ≥300 cells/µL (prior year) and frequent exacerbations, enables more robust characterization of mepolizumab efficacy in COPD and exploration of the relationship between blood eosinophil count and treatment responses., Methods: In METREX (117106/NCT02105948) and METREO (117113/NCT02105961), randomized patients received mepolizumab or placebo added to existing inhaled corticosteroid (ICS)-based triple maintenance therapy. The annual rate of moderate/severe exacerbations (primary endpoint) was compared between subcutaneous (SC) mepolizumab 100 mg versus placebo (primary comparison of interest) and all doses (100 mg and 300 mg SC) versus placebo in patients with blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the prior year. Secondary/other endpoints included time to first moderate/severe exacerbation, exacerbations leading to emergency department visit/hospitalization and health-related quality of life (HRQoL). A predictive model of the relationship between screening blood eosinophil counts and exacerbation rates included data from all randomized patients., Results: In total, 1510 patients were randomized in METREX and METREO and 1136 patients were included in the pre-specified meta-analysis. From the meta-analysis, mepolizumab 100 mg SC significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82; 95% confidence interval: 0.71, 0.95; p=0.006) and delayed time to first moderate/severe exacerbation (hazard ratio: 0.80 [0.68, 0.94]; p=0.006). Mepolizumab 100 mg SC versus placebo numerically reduced exacerbations leading to ED visits/hospitalization and improved HRQoL. A modelling approach demonstrated increasing efficacy for moderate/severe exacerbations with increasing screening blood eosinophil count; this relationship was more pronounced for exacerbations requiring oral corticosteroids (post hoc). The all-doses comparison had similar results., Conclusion: Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD. Results suggest that blood eosinophil counts (≥150 cells/µL at screening or ≥300 cells/µL in the prior year) allow for identification of patients with COPD who experience exacerbations while treated with maximal ICS-based triple maintenance therapy who are likely to benefit from mepolizumab., Competing Interests: MB has received honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Novartis and has received independent/institutional grant support from Pfizer and AstraZeneca. KRC reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Grifols, Sanofi, Genentech, Kamada, Mereo Biopharma, Regeneron, Roche and Novartis; grants from Baxter, GSK, Vertex, and Amgen; and personal fees from Merck, Takeda. He also holds a Canadian Institute of Health Research-GSK research chair in Respiratory Health Care Delivery at the University Health Network. In the last 5 years, IDP received funding from the NIHR as a Senior Investigator; he has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Menarini, Novartis, Teva, Chiesi and GSK and payments for organizing educational events from AstraZeneca and Teva. He has received honoraria for attending advisory panels with Genentech, Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Sanofi, Circassia, Chiesi and Knopp. He has received sponsorships to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva and Chiesi. He has also received a grant from Chiesi to support a Phase II clinical trial in Oxford. In addition, IDP has a patent Leicester Cough Questionnaire with royalties paid. FCS received grants from the National Institutes of Health, Patient-Centered Outcomes Research Institute, the COPD Foundation, the US Department of Defense, Astellas, AstraZeneca, Boehringer Ingelheim, GSK, Phillips Respironics, PulmonX, PneumRx and Spiration; and personal fees from Circassia, Boehringer Ingelheim, GSK and PneumRx. ESB was an employee of GSK and holds GSK stock/shares during the conduct of the study, his current affiliation is Aeglea BioTherapeutics, Austin, Texas. SWY is an employee of GSK and hold GSK stock/shares. DBR was an employee of GSK and holds GSK stocks/shares during the conduct of the study, his current affiliation is DBR Consulting LLC, Raleigh NC. SSH was an employee of GSK and holds GSK stocks/shares during the conduct of the study. All authors received non-financial support from GSK in the form of editorial support. PP reports personal fees from GlaxoSmith Kline, during the conduct of the study; grants and/or personal fees from AstraZeneca, Chiesi, Novartis, and Sanofi, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Pavord et al.)

Rationale: Understanding the role of the airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches. Objectives: To understand the association of the airway microbiome with neutrophilic and eosinophilic COPD at stability and during exacerbations. Methods: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 patients with COPD recruited at four UK sites of the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic COPD), COPDMAP (Chronic Obstructive Pulmonary Disease Medical Research Council/Association of the British Pharmaceutical Industry), and AERIS (Acute Exacerbation and Respiratory Infections in COPD) cohorts. The microbiome was analyzed using COPDMAP and AERIS as a discovery data set and BEAT-COPD as a validation data set. Measurements and Main Results: The airway microbiome in neutrophilic COPD was heterogeneous, with two primary community types differentiated by the predominance of Haemophilus . The Haemophilus -predominant subgroup had elevated sputum IL-1β and TNFα (tumor necrosis factor α) and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to the greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic Haemophilus-predominant and eosinophilic states that were otherwise mutually exclusive. Time-series analysis on the microbiome showed that the temporal trajectories of Campylobacter and Granulicatella were indicative of intrapatient switches from neutrophilic to eosinophilic inflammation, in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns among neutrophilic Haemophilus -predominant, neutrophilic balanced microbiome, and eosinophilic subgroups. Conclusions: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are interchangeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.

Background: Chronic obstructive pulmonary disease (COPD) and asthma have heterogeneous inflammation with inhaled corticosteroids (ICS) as a mainstay of treatment. There is increased prevalence of non-typeable Haemophilus influenzae (NTHi) persistence in airways of patients with neutrophilic airway inflammation, potentially due to suppressed host defence after corticosteroid treatment. Antimicrobial peptides (AMPs) have antimicrobial activity against pathogens and immunomodulatory effects. We investigated whether AMPs associate with NTHi presence in COPD and asthma, and whether ICS alter this., Methods: Secretory leukocyte protease inhibitor (SLPI), osteopontin, elafin and beta defensin-1 were measured in sputum supernatants from healthy donors (n=9), asthmatics (n=21) and patients with COPD (n=14). Elafin and beta defensin-1 were measured in a primary human bronchial epithelial cells (HBECs) from healthy and COPD donors infected with NTHi and pre-treated with fluticasone propionate (FP) and budesonide (BUD). Internalised NTHi was quantified by qPCR., Results: Sputum SLPI was negatively correlated with FEV1 (p<0.001, r=-0.610), FEV1% predicted (p<0.001, r=-0.583) and FEV1/FVC (p=0.001, r=-0.528). Sputum beta defensin-1 was negatively associated with FEV1 (p<0.001***r=-0.594). SLPI and beta defensin-1 levels in sputum were higher in the healthy controls and COPD group compared to the asthma group (p=0.001 and p=0.014) and (p<0.001 and p=0.007, respectively). ICS use was associated with higher sputum osteopontin compared to those with no ICS use. NTHi infection of COPD HBECs produced higher levels of beta defensin-1 compared to healthy donors (mean (SD) release: 45.1pg/mL (7.3) vs 21.2pg/mL (7.3) respectively, p=0.014). Elafin release from HBECs from COPD donors did not change following NTHi infection; however, elafin from healthy donors was significantly reduced (%mean reduction: 23.7%, 95% confidence intervals (CI) of reduction: 5.3-38.4%, p<0.01)., Conclusion: Sputum SLPI and beta defensin-1 may be markers to identify those patients with declining lung function. ICS use was associated with higher sputum osteopontin compared to those with no ICS use., Competing Interests: The authors declare that they have no competing interests., (© 2021 Cane et al.)

Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting β 2 -agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes., Competing Interests: J. Bourbeau reports grants from CIHR and Canadian Respiratory Research Network (CRRN), Foundation of the McGill University Health Center, Aerocrine, AstraZeneca, Boehringer Ingelheim, Grifols, GSK, Novartis, and Trudell; personal conference and advisory board fees from Canadian Thoracic Society, CHEST, Astra Zeneca, Boehringer Ingelheim, Grifols, GSK, Novartis, and Trudell. M. Bafadhel reports grants from AstraZeneca; advisory board attendance for AstraZeneca, Chiesi, Boehringer Ingelheim, and GSK; attendance at educational meetings facilitated by AstraZeneca, Chiesi, and Boehringer Ingelheim; and scientific advisor for ProAxsis and AlbusHealth. C. Compton, P.W. Jones, N.C. Barnes, D.A. Lipson, V. Di Boscio, and G. Weiss are employees of GSK and hold stocks and shares in GSK. N. Martin was an employee of GSK at the time the study was conducted. D.M.G. Halpin has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, and Sanofi and non-financial support from Boehringer Ingelheim and Novartis. The authors report no other conflicts of interest in this work., (© 2021 Bourbeau et al.)

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

The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100-300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD-the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response., Competing Interests: Competing interests: BD reports previous employment with, and stock/share ownership in, GlaxoSmithKline plc. MB reports grants from AZ, personal fees and non-financial support from AZ, Chiesi and GlaxoSmithKline plc, and other financial activities from AlbusHealth. ADS reports grants, personal fees and other financial activities from AstraZeneca, Bayer, GlaxoSmithKline plc, Gilead, Novartis, Pfizer, Teva and Chiesi., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-typeable Haemophilus influenzae (NTHi) is the most commonly found pathogen in the lower respiratory airways of patients with COPD. NTHi is predominantly regarded as an intracellular pathogen; however, like most pathogens, it can exist and co-exist in two broad forms: cell-associated (intracellularly or adhered to cells) or cell-dissociated (biofilm dispersed or planktonic). We sought to investigate if cell-dissociated NTHi can be detected from the sputum of COPD patients and assess this relationship to disease severity and airway inflammation., Methods: DNA was extracted from the sputum plug and cell-free supernatant to quantify absolute (cell-associated and cell-dissociated NTHi) and cell-dissociated NTHi, respectively, from 87 COPD subjects attending an observational longitudinal COPD exacerbation study. NTHi was quantified using TaqMan hydrolysis probes, targeting the OMP P6 gene using qPCR., Results: At stable state cell-dissociated NTHi was detected 56% of subjects with a median (IQR) of 9.95x10 2 gene copies (1.26x10 2 to 1.90x10 4 ). Cell-dissociated NTHi correlated with absolute NTHi levels (r=0.34, p<0.01) but not airway inflammation or spirometry at stable state. At exacerbation, cell-dissociated NTHi correlated with lung function (FEV 1 r=0.629, p=0.005; FEV 1 %predicted r=0.564, p=0.015; FVC r=0.476 p=0.046) and sputum neutrophilic inflammation (% neutrophils r=0.688, p=0.002; total neutrophils r=0.518, p=0.028)., Conclusion: In patients with COPD, NTHi can exist in both cell-associated and cell-dissociated forms. Cell-dissociated NTHi is associated with neutrophilic airway inflammation during exacerbations of COPD and may be a driving factor in worsening lung function during these episodes., Competing Interests: CEB was funded by a Wellcome Trust Senior Fellowship. MB was funded by a National Institute for Health Research (NIHR) Fellowship. MB has received travel support from AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline and consultancy honoraria outside the submitted work from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Pfizer. CEB has received grant support and consultancy honoraria outside the submitted work from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Medimmune, Novartis and Roche. IDP has received grant support and consultancy honoraria outside the submitted work from Aerocrine, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis. The authors report no conflicts of interest in this work., (© 2020 Thulborn et al.)

Background: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD)., Methods: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (mean±SD: age 69±8 years, haemoglobin 144.8±13.2 g/L, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3%±15.2%; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO 2 ) at rest after 1 week. The secondary endpoints included daily SpO 2 , overnight SpO 2 , exercise SpO 2 , 6 min walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures, and exacerbation frequency., Results: SpO 2 was unchanged 1 week after FCM administration (difference between groups 0.8%, 95% CI -0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6 min walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after 1 week (p=0.009). Modified MRC Dyspnoea Scale score was also significantly lower after FCM, and fewer participants reported scores ≥2 in the FCM group, compared with placebo (33.3% vs 66.7%, p=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs 8.3%, p<0.001)., Conclusions: FCM did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well tolerated and produced improvements in exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies., Trial Registration Number: ISRCTN09143837., Competing Interests: Competing interests: PAR reports grants from NIHR Oxford BRC during the conduct of the study and grants from Vifor Pharma, outside the submitted work. MB reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi and GSK, and other from ProAxsis and Albus Health, all outside the submitted work. MCF reports grants from the British Heart Foundation, during the conduct of the study. NPT reports grants from the NIHR, outside the submitted work. The other authors have no interests to declare., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum γP:F ratio., Methods: Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate-to-severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters., Results: Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n = 20), high γP:F ratio, increased H influenzae, low diversity measures and increased pro-inflammatory mediators when compared to the larger Haemophilus-low cluster (n = 121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the γP:F ratio consistently differentiated between clusters., Conclusion: Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The γP:F ratio was able to distinguish the Haemophilus-high versus Haemophilus-low subgroups, whether the Haemophilus-high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation., (© 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Clinically Important Deterioration (CID) is a novel composite measure to assess treatment effect in chronic obstructive pulmonary disease (COPD). We examined the performance and utility of CID in assessing the effect of inhaled corticosteroids (ICS) in COPD., Methods: This post-hoc analysis of four budesonide/formoterol (BUD/FORM) studies comprised 3576 symptomatic moderate-to-very-severe COPD patients with a history of exacerbation. Analysis of time to first CID event (exacerbation, deterioration in forced expiratory volume in 1 second [FEV 1 ] or worsening St George's Respiratory Questionnaire [SGRQ] score) was completed using Cox proportional hazards models., Results: The proportion of patients with ≥1 CID in the four studies ranged between 63 and 77% and 69-84% with BUD/FORM and FORM, respectively, with an average 25% reduced risk of CID with BUD/FORM. All components contributed to the CID event rate. Experiencing a CID during the first 3 months was associated with poorer outcomes (lung function, quality of life, symptoms and reliever use) and increased risk of later CID events. The effect of BUD/FORM versus FORM in reducing CID risk was positively associated with the blood eosinophil count., Conclusions: Our findings suggest that BUD/FORM offers protective effects for CID events compared with FORM alone, with the magnitude of the effect dependent on patients' eosinophil levels. CID may be an important tool for evaluation of treatment effect in a complex, multifaceted, and progressive disease like COPD, and a valuable tool to allow for shorter and smaller future outcome predictive trials in early drug development.

Background: Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups., Objective: To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers., Methods: Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study)., Results: ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r 2 =0.23; p<0.001). Prevalence of ARG positive signals in individuals was not related to COPD symptoms, lung function or their changes at exacerbation. In the COPD subgroups designated High γProteobacteria and High Firmicutes, ARG prevalence was not different at stable state but significantly declined from stable through exacerbation to recovery in the former (p=0.011) without changes in total bacterial abundance. The ARG patterns were similar in COPD versus health, COPD microbiome-subgroups and between sputum and bronchoscopic samples independent of antibiotic exposure in the last 12 months., Conclusions: ARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known., Methods: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed., Results: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo., Conclusions: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.)., (Copyright © 2019 Massachusetts Medical Society.)

In the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. 140 years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ECOPD) are important events. They are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ECOPD are common and are increasing in prevalence. Exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within 30 days. The healthcare costs are immense. Yet despite this, the tools available to diagnose and treat ECOPD are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over 25 years ago.An ECOPD is 'an acute worsening of respiratory symptoms that results in additional therapy'. This symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. There is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (POC). Corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over 30 years. This is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. So why has progress been so slow in ECOPD? This review examines the history of diagnosing and treating ECOPD. It suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all COPD is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment., Competing Interests: Competing interests: No, there are no competing interests for any author., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Chronic obstructive pulmonary disease (COPD) is predominantly associated with neutrophilic inflammation. Active neutrophil elastase (NE) is a serine proteinase, secreted by neutrophils, in response to inflammation and pathogen invasion. We sought to investigate if NE could be used as a biomarker for bacterial infection in patients with COPD., Methods: NE was quantified using ProteaseTag® Active NE Immunoassay (ProAxsis, Belfast) from the sputum of COPD subjects at stable state, exacerbation and 2 weeks post treatment visit., Results: NE was measured in 90 samples from 30 COPD subjects (18 males) with a mean (range) age of 65 (45-81) years and mean (SD) FEV 1 of 47% (18). The geometric mean (95%CI) of NE at stable state was 2454 ng/mL (1460 to 4125 ng/mL). There was a significant increase in NE levels at an exacerbation (p = 0.003), and NE levels were higher in a bacterial-associated exacerbation (NE log difference 3.873, 95% CI of log difference 1.396 to 10.740, p = 0.011). NE was an accurate predictor of a bacteria-associated exacerbation (area (95%CI) under the receiver operator characteristic curve 0.812 (0.657 to 0.968)., Conclusion: NE is elevated during exacerbations of COPD. NE may be a viable biomarker for distinguishing a bacterial exacerbation in patients with COPD., Trial Registration: Leicestershire, Northamptonshire and Rutland ethics committee (reference number: 07/H0406/157).

Introduction: Maintenance treatment with macrolides are useful in preventing COPD exacerbations. We investigated which characteristics of COPD patients with frequent exacerbations predicted the best response to maintenance treatment with azithromycin., Methods: This study was part of the COLUMBUS trial, a prospective randomized, double-blind, placebo-controlled study in 92 COPD patients with frequent exacerbations. During the 1-year treatment period, follow-up data were collected for spirometry, mMRC scores, sputum cultures and blood inflammatory markers., Results: In the azithromycin group a significant lower number of exacerbations per patient was observed in patients with the following characteristics: baseline blood eosinophil count ≥2.0% (x̄ = 1.26), compared to an eosinophil count < 2.0% (x̄ = 2.50; p = 0.02), GOLD stage 1-2 (x̄ = 1.06), versus GOLD stage 4 (x̄ = 2.62; p = 0.02) and GOLD group C (x̄ = 0.45) compared to group D (x̄ = 2.18; p < 0.01). Moreover, the number of hospitalizations was significantly lower in patients, with a blood eosinophil count ≥2.0% (x̄ = 0.26) compared to an eosinophil count < 2.0% (x̄ = 0.90; p = 0.01) and in GOLD stages 1-2 (x̄ = 1.06) compared to stage 4 (x̄ = 2.62; p = 0.04)., Conclusion: In conclusion, azithromycin maintenance treatment appears to be effective in COPD patients with frequent exacerbations, who are either classified in GOLD stage 1-2 or GOLD C and those with a blood eosinophil count of ≥2.0%., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: There has been an increase in interest in the peripheral blood eosinophil count as a biomarker in COPD. Few studies have examined the eosinophil count in patients attending the emergency department (ED) with acute exacerbations of COPD (AECOPD). We investigated the relationship between the blood eosinophil and other variables collected routinely at ED presentation and outcomes. Methods: Retrospective case note review of patients attending the ED with an AECOPD over 18 months. Demographic, clinical and pharmacological data were analyzed at the time of presentation, and clinical outcomes relating to hospital admission, length of hospital stay and mortality were investigated. Results: There were 743 AECOPD index events in 537 patients. Over half (57%) of all attendees were admitted to hospital. They were older, reported an increased number of exacerbations and higher levels of total leukocytes and neutrophils. Length of stay was shorter in patients with a blood eosinophil count ≥2% compared to <2% (median (IQR) 3 days (1-7) vs 4 days (2-8) respectively, p <0.05). Length of stay correlated with peripheral blood neutrophils ( r =0.12, p =0.021), peripheral blood absolute and relative eosinophils ( r =-0.12, p =0.024 and r =-0.11, p =0.035, respectively) and CRP ( r =0.16, p =0.027). Non-eosinophilic AECOPD were associated with an increased risk of mortality during an exacerbation ( χ 2 5.9, OR 3.08, 95% CI 1.19-7.96, p =0.015). Conclusion: In exacerbations of COPD presenting to ED, a higher blood eosinophil count is associated with a shorter length of stay and reduced mortality., Competing Interests: ID Pavord reports grants, personal fees, and in the last 5 years has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca (AZ), Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi and GSK and payments for organizing educational events from AZ and Teva. He has received honoraria for attending advisory panels with Genentech, Regeneron, AZ, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Sanofi, Circassia, Chiesi and Knopp. He has also received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AZ, Teva and Chiesi. In addition, he has received a grant from Chiesi to support a phase 2 clinical trial in Oxford, outside the submitted work. The authors report no other conflicts of interest in this work.

Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous., Objective: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations., Methods: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters., Results: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes., Conclusions: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease (COPD) who will experience fewer exacerbations when taking inhaled corticosteroids (ICS). Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response. We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD., Methods: We analysed data from three AstraZeneca randomised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts. Patients with any history of asthma were excluded. Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design. The trials are registered with ClinicalTrials.gov, NCT00206167, NCT00206154, and NCT00419744., Findings: 4528 patients were studied. A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone. At eosinophil counts of 0·10 × 10 9 cells per L or more, a significant treatment effect was recorded for exacerbation reduction with budesonide-formoterol compared with formoterol alone (rate ratio 0·75, 95% CI 0·57-0·99; p interaction =0·015). Interactions were observed between eosinophil count and the treatment effects of budesonide-formoterol over formoterol on St George's Respiratory Questionnaire (p interaction =0·0043) and pre-bronchodilator FEV 1 (linear effect p<0·0001, p interaction =0·067). Only eosinophil count and smoking history were independent predictors of response to budesonide-formoterol in reducing exacerbations (eosinophil count, p interaction =0·013; smoking history, p interaction =0·015)., Interpretation: In patients with COPD treated with formoterol, blood eosinophil count predicts exacerbation risk and the clinical response to ICS., Funding: AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)