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Introduction: In Japan, patients with chronic obstructive pulmonary disease (COPD) can be escalated to treatment with inhaled triple therapy. Two single-inhaler triple therapies combining an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β 2 -agonist (ICS/LAMA/LABA) are approved maintenance therapies for patients with COPD, and multiple-inhaler triple therapies (MITTs) are also available. There is limited evidence regarding real-life treatment patterns and characteristics of patients with COPD initiating triple therapies., Methods: This observational, retrospective cohort study identified patients with COPD in Japan from an administrative claims database (May 2018-December 2021). Demographics, clinical characteristics, and healthcare resource utilization (HCRU) were assessed in four cohorts initiating a triple therapy: budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) early adopters (initiated ≤ 12 months after market approval [September 1, 2019]), contemporary BGF users (initiated > 12 months after market approval), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) users, and any MITT users., Results: A total of 636 patients were BGF early adopters, 2558 were contemporary BGF users, 11,187 used FF/UMEC/VI, and 5931 used MITT. The percentage of patients with concomitant asthma in each cohort was 73.0%, BGF early adopter; 74.2%, contemporary BGF; 75.7%, FF/UMEC/VI; and 84.5%, MITT. During the 12-month baseline period, the frequency of patients with ≥ 1 moderate/severe exacerbation was 18.2%, BGF early adopter; 14.3%, contemporary BGF; 13.1%, FF/UMEC/VI; and 14.0%, MITT. ICS/LABA treatment during baseline was the most frequent pathway to triple therapy, ranging from 38.2% to 51.7% across cohorts. HCRU was relatively high across cohorts (range of hospital outpatient visits/patient during the 12-month baseline period, 11.0-14.1). Multimorbidity was observed in > 80% of patients in all cohorts; cardiovascular diseases were among the most common., Conclusion: Many patients initiating triple therapy for COPD had concomitant asthma and had previously received ICS/LABA maintenance therapy. Patients prescribed BGF in the initial post-launch period were more likely to have a previous exacerbation history versus other cohorts, indicating more severe disease., (© 2024. The Author(s).)

Background: Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiopulmonary and mortality risk, particularly following exacerbations. While single inhaler triple therapies (SITTs), such as budesonide/glycopyrrolate/formoterol fumarate (BGF), reduce cardiopulmonary risk versus dual bronchodilator therapy, there is limited evidence comparing outcomes with SITTs versus multiple inhaler triple therapies (MITTs)., Methods: SKOPOS-MAZI was a retrospective comparative effectiveness study in patients with COPD aged ≥40 years using US administrative claims data from Optum's de-identified Clinformatics® Data Mart Database. The primary and secondary endpoints were time to all-cause mortality and time to first severe cardiopulmonary event following initiation of BGF or MITT (identification period: October 1, 2020-June 30, 2023; index date: first prescription fill). Relative hazards of outcomes were assessed until a censoring event using Cox proportional hazards models, with inverse propensity treatment weighting accounting for between-group imbalances (standardized mean difference >0.1) in baseline characteristics., Results: In the primary cohort, risk (hazard ratio [95% confidence intervals]) of all-cause mortality and a first severe cardiopulmonary event were 18% (0.82 [0.75, 0.91]) and 12% (0.88 [0.83, 0.93]) lower in patients initiating BGF versus MITT; results were consistent across censoring definitions, landmark periods, and sensitivity cohorts., Conclusion: In this real-world comparative effectiveness study of patients with COPD initiating BGF or MITT, BGF was associated with lower all-cause mortality and severe cardiopulmonary event risk versus MITT after accounting for between-group differences in baseline sociodemographic and clinical characteristics, supporting the benefits of BGF over MITT and the need to consider proactive use of SITTs in COPD management., Competing Interests: Declaration of competing interest Michael Pollack, Eleni Rapsomaniki, Kirsty Rhodes, Jonathan Marshall, and Hana Müllerová are employees of AstraZeneca and may hold stock and/or stock options in the company. Antonio Anzueto is a consultant for AstraZeneca, GlaxoSmithKline, Viatrix, Sanofi/Regeneron, Novartis, and Boehringer-Ingelheim. Nathaniel Hawkins is a consultant and speaker and has received research grants from AstraZeneca. Claus Vogelmeier has conducted presentations at symposia and/or participation in scientific advisory boards for Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols, Insmed, MedUpdate, Menarini, Novartis, Nuvaira, Roche, and Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data., Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori)., Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV 1 : 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting β 2 -agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period., Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days., Competing Interests: Hana Müllerová, Stefan Franzén, Johann Castaneda, and Jonathan Marshall are employees of, and own stock in, AstraZeneca. Jeffrey Shi Kai Chan, Heath Heatley, Victoria Carter, John Townend, and Derek Skinner are employees of Observational and Pragmatic Research Institute. David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy and lecture fees from Medscape, Inside Practice paid to Observational and Pragmatic Research Institute; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Teva Pharmaceuticals; 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 Observational and Pragmatic Research Institute Pte Ltd (Singapore); 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 was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this work., (© 2024 Müllerová et al.)

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) represent a period of vulnerability. This study explored the association between time periods following an exacerbation and the risk of severe cardiovascular (CV) events or death in Germany., Methods: A longitudinal cohort study was conducted using routinely collected healthcare data. Individuals with COPD were identified between 2014 and 2018. Exposure was moderate or severe exacerbation of COPD. Periods at risk were the 1-7, 8-14, 15-30, 31-180 and 181-365 days following each exacerbation onset occurring after cohort entry. The main outcome of interest was the first hospitalisation for a CV event or all-cause death. Time-dependent Cox proportional hazards models estimated the HR for the association between subperiods versus periods outside exacerbations, and the risk of outcome., Results: Among 126 795 patients, 58 720 (46.3%) exacerbated at least once and 48 982 (38.6%) experienced at least one CV event or died during a median follow-up of 36 months. The rate of outcome was increased during 1-7 days following a severe exacerbation onset (HR 15.84, 95% CI 15.26 to 16.45), and remained elevated for up to a year (181-365 days HR 1.17, 95% CI 1.11 to 1.23). In the 1-7 days following a moderate exacerbation onset, the increased rate was HR 1.17, 95% CI 1.05 to 1.31)., Conclusion: The risk of a CV event or death increased in time periods following both moderate and severe exacerbations of COPD, emphasising the need to promptly manage the risk of CV events following the onset of an exacerbation, to prevent exacerbations of any severity, and more generally, to address the cardiopulmonary risk in patients with COPD., Competing Interests: Competing interests: CFV reports financial support was provided by AstraZeneca. CFV reports a relationship with Boehringer Ingelheim that includes: consulting or advisory and funding grants. CFV reports a relationship with CSL Behring that includes: consulting or advisory and funding grants. CFV reports a relationship with Chiesi Pharmaceuticals GMBH that includes: consulting or advisory and funding grants. CFV reports a relationship with GlaxoSmithKline that includes: consulting or advisory and funding grants. CFV reports a relationship with Grifols Deutschland GmbH Head Office that includes: consulting or advisory and funding grants. CFV reports a relationship with A Menarini Pharma GmbH that includes: consulting or advisory and funding grants. CFV reports a relationship with Novartis that includes: consulting or advisory and funding grants. CFV reports a relationship with Nuvaira Inc that includes: consulting or advisory and funding grants. CFV reports a relationship with MedUpdate that includes: consulting or advisory and funding grants. CFV reports a relationship with Aerogen Ltd that includes: consulting or advisory and funding grants. CFV reports a relationship with Sanofi-Aventis Deutschland GmbH that includes: consulting or advisory and funding grants. CFV reports a relationship with Roche that includes: consulting or advisory and funding grants. KR is an employee of AstraZeneca and owns shares and stock options of AstraZeneca. EG was working at the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are post-authorization safety studies (PASS) requested by health authorities. The studies and the resulting publications are not influenced by the pharmaceutical industry. EG has been consultant for AZ on this study and to Bayer, Nycomed, Takeda, Astellas, Novartis, and GSK unrelated to the subject of this study. MA is an employee of AstraZeneca and owns shares and stock options of AstraZeneca. MH is an employee of AstraZeneca. HM is an employee of AstraZeneca and owns shares and stock options of AstraZeneca. NK is an employee of WIG2 GmbH Scientific Institute for Health Economics and Health Service Research which received funding from AstraZeneca UK Limited for the conduct of the study. PT is an employee of WIG2 GmbH Scientific Institute for Health Economics and Health Service Research which received funding from AstraZeneca UK Limited for the conduct of the study. NK is an employee of ZEG - Berlin Center for Epidemiology and Health Research GmbH which received funding from AstraZeneca UK Limited for the conduct of the study. CN is an employee of AstraZeneca and owns shares and stock options of AstraZeneca., (© 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.)

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV 1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV 1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease.

The observational retrospective cohort Study on HEalthcare Resource utiLization (HCRU) related to exacerbatiOns in patients with COPD (SHERLOCK; D5980R00014) evaluated exacerbation-related HCRU and costs using the U.K. National Health Service Greater Glasgow and Clyde Health Board data. Patients (≥40 years) with COPD were stratified by exacerbations one year before the index date: Group A (none), B (1 moderate), C (1 severe) and D (≥2 moderate and/or severe). All-cause and COPD-related HCRU and costs were assessed over 36 months. Adjusted rate ratios (RRs) or relative costs versus Group A were estimated using generalized linear models with appropriate distributions and link functions. The study included 22 462 patients (Group A, n  = 7788; B, n  = 5151; C, n  = 250 and D, n  = 9273). At 12 months, RRs (95% CI) versus Group A for all-cause and COPD-related HCRU, respectively, were highest in Groups C (1.28 [1.18, 1.39] and 1.18 [1.09, 1.29]) and D (1.26 [1.23, 1.28] and 1.29 [1.26, 1.31]). General practitioner and outpatient visits, and general ward stays/days accounted for the greatest COPD-related HCRU. All-cause and COPD-related relative costs (95% CI) versus Group A at 12 months, respectively, were 1.03 (0.94, 1.12) and 1.06 (0.99, 1.13) in Group B; 1.47 (1.07, 2.01) and 1.54 (1.20, 1.97) in Group C; 1.47 (1.36, 1.58) and 1.63 (1.54, 1.73) in Group D. Increased HCRU and costs in patients with exacerbation histories persisted at 36 months, demonstrating the sustained impact of exacerbations. The study suggests the importance of management and prevention of exacerbations through intervention optimization and budgeting by payers for exacerbation-related costs.

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.)

Objective: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. While two approved fixed-dose inhaled corticosteroid/long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) triple therapies reduce all-cause mortality (ACM) versus dual LAMA/LABA therapy in patients with COPD, head-to-head studies have not compared the effects of these therapies on ACM. We compared ACM in adults with moderate-to-very severe COPD receiving budesonide/glycopyrrolate/formoterol fumarate (BGF) in ETHOS versus fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in IMPACT using a matching-adjusted indirect comparison (MAIC)., Methods: A systematic literature review identified two studies (ETHOS [NCT02465567]; IMPACT [NCT02164513]) of ≥52 weeks reporting ACM as an efficacy endpoint in patients receiving triple therapy. As ETHOS and IMPACT lack a common comparator, an unanchored MAIC compared ACM between licensed doses of BGF (320/18/9.6 μg) from ETHOS and FF/UMEC/VI (100/62.5/25 μg) from IMPACT in patients with moderate-to-very severe COPD. Using on- and off-treatment data from the final retrieved datasets of the intention-to-treat populations, BGF data were adjusted according to aggregate FF/UMEC/VI data using 11 baseline covariates; a supplementary unadjusted indirect treatment comparison was also conducted. P -values for these post-hoc analyses are not adjusted for Type I error., Results: ACM over 52 weeks was statistically significantly reduced by 39% for BGF versus FF/UMEC/VI in the MAIC (hazard ratio [HR] [95% CI]: 0.61 [0.38, 0.95], p  = 0.030) and unadjusted analysis (HR [95% CI]: 0.61 [0.41, 0.92], p  = 0.019)., Conclusion: In this MAIC, which adjusted for population heterogeneity between ETHOS and IMPACT, ACM was significantly reduced with BGF versus FF/UMEC/VI in patients with moderate-to-very severe COPD.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are complex diseases, the definitions of which overlap., Objective: To investigate clustering of clinical/physiological features and readily available biomarkers in patients with physician-assigned diagnoses of asthma and/or COPD in the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329)., Methods: Two approaches were taken to variable selection using baseline data: approach A was data-driven, hypothesis-free and used the Pearson dissimilarity matrix; approach B used an unsupervised Random Forest guided by clinical input. Cluster analyses were conducted across 100 random resamples using partitioning around medoids, followed by consensus clustering., Results: Approach A included 3796 individuals (mean age, 59.5 years; 54% female); approach B included 2934 patients (mean age, 60.7 years; 53% female). Each identified 6 mathematically stable clusters, which had overlapping characteristics. Overall, 67% to 75% of patients with asthma were in 3 clusters, and approximately 90% of patients with COPD were in 3 clusters. Although traditional features such as allergies and current/ex-smoking (respectively) were higher in these clusters, there were differences between clusters and approaches in features such as sex, ethnicity, breathlessness, frequent productive cough, and blood cell counts. The strongest predictors of the approach A cluster membership were age, weight, childhood onset, prebronchodilator FEV 1 , duration of dust/fume exposure, and number of daily medications., Conclusions: Cluster analyses in patients from NOVELTY with asthma and/or COPD yielded identifiable clusters, with several discriminatory features that differed from conventional diagnostic characteristics. The overlap between clusters suggests that they do not reflect discrete underlying mechanisms and points to the need for identification of molecular endotypes and potential treatment targets across asthma and/or COPD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Little is known about how lower respiratory tract infections (LRTIs) before chronic obstructive pulmonary disease (COPD) are associated with future exacerbations and mortality. We investigated this association in patients with COPD in England., Methods: Clinical Practice Research Datalink Aurum, Hospital Episode Statistics and Office of National Statistics data were used. Start of follow-up was patient's first ever COPD diagnosis date and a 1-year baseline period prior to start of follow-up was used to find mild LRTIs (general practice (GP) events/no antibiotics), moderate LRTIs (GP events+antibiotics) and severe LRTIs (hospitalised). Patients were categorised as having: none, 1 mild only, 2+ mild only, 1 moderate, 2+ moderate and 1+ severe. Negative binomial regression modelled the association between baseline LRTIs and subsequent COPD exacerbations and Cox proportional hazard regression was used to investigate mortality., Results: In 215 234 patients with COPD, increasing frequency and severity of mild and moderate LRTIs were associated with increased rates of subsequent exacerbations compared with no recorded LRTIs (1 mild adjusted IRR 1.16, 95% CI 1.14 to 1.18, 2+ mild IRR 1.51, 95% CI 1.46 to 1.55, 1 moderate IRR 1.81, 95% CI 1.78 to 1.85, 2+ moderate IRR 2.55, 95% CI 2.48 to 2.63). Patients with 1+ severe LRTI (vs no baseline LRTIs) also showed an increased rate of future exacerbations (adjusted IRR 1.75, 95% CI, 1.70 to 1.80). This pattern of association was similar for risk of all-cause and COPD-related mortality; however, patients with 1+ severe LRTIs had the highest risk of all-cause and COPD mortality., Conclusion: Increasing frequency and severity of LRTIs prior to COPD diagnosis were associated with increasing rates of subsequent exacerbations, and increasing risk of all-cause and COPD-related mortality., Competing Interests: Competing interests: JKQ has received grants from The Health Foundation, MRC, GSK, Bayer, BI, AUK-BLF, Chiesi, and AZ, and personal fees for advisory board participation or speaking fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca and Bayer. HW has nothing to disclose. CL, AR, HM, TM and YX are employees of AstraZeneca and holds stock and/or options in the company. EDN is a former employee of AstraZeneca, but was employed by AstraZeneca at the time of the study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In this study, we compare management of patients with high-risk chronic obstructive pulmonary disease (COPD) in the United States to national and international guidelines and quality standards, including the COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST)., Methods: Patients were identified from the DARTNet Practice Performance Registry and categorized into three high-risk cohorts in each year from 2011 to 2019: newly diagnosed (≤12 months after diagnosis), already diagnosed, and patients with potential undiagnosed COPD. Patients were considered high-risk if they had a history of exacerbations or likely exacerbations (respiratory consult with prescribed medication). Descriptive statistics for 2019 are reported, along with annual trends., Findings: In 2019, 10% (n = 16,610/167,197) of patients met high-risk criteria. Evidence of spirometry for diagnosis was low; in 2019, 81% (n = 1228/1523) of patients newly diagnosed at high-risk had no record of spirometry/peak expiratory flow in the 12 months pre- or post-diagnosis and 43% (n = 651/1523) had no record of COPD symptom review. Among those newly and already diagnosed at high-risk, 52% (n = 4830/9350) had no evidence of COPD medication., Interpretation: Findings suggest inconsistent adherence to evidence-based guidelines, and opportunities to improve identification, documentation of services, assessment, therapeutic intervention, and follow-up of patients with COPD., Funding: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution., Competing Interests: Alan Kaplan is a member of the advisory board of, or speakers bureau for, AstraZeneca, Behring, Boehringer Ingelheim, Covis, Grifols, GlaxoSmithKline, Merck Frosst, Novo Nordisk, Novartis, Pfizer, Purdue, Sanofi, Teva, and Trudel. M. Bradley Drummond has received grant support from the NIH, Department of Defense, Boehringer-Ingelheim, Midmark and Teva; consultancy fees from Astra Zeneca, GlaxoSmithKline, Boehringer-Ingelheim, Chiesi, Verona, and Teva in the prior 18 months. Catherine Meldrum reports no conflict of interest. Douglas Mapel has received grant funding from Boehringer Ingelheim Pharmaceuticals, GlaxoSmithKline, Sunovion; and consultancy fees from Boehringer Ingelheim Pharmaceuticals, Mylan, Theravance Biopharma, and Novartis. Fernando Martinez has received personal fees and non-financial support from the American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, ConCert, Genentech, GSK, Inova Fairfax Health System, Miller Communications, National Society for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rico Respiratory Society, Chiesi, Sunovion, Theravance, Potomac, University of Alabama Birmingham, Physicians Education Resource, Canadian Respiratory Network, Teva and Dartmouth; non-financial support from ProterrixBio, Gilead, Nitto and Zambon; and personal fees from Columbia University, Integritas, MD magazine, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Patara/Respivant, PlatformIQ, American Thoracic Society, Rockpointe, Rare Disease Healthcare Communications and France Foundation; grant support from NIH; and is a member of steering committees for Afferent/Merck, Biogen, Veracyte, Prometic, Bayer, Bridge Biotherapeutics and ProMedior. Jill Ohar has participated in advisory boards for Sunovion Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Mylan, and Theravance and has received grant funding from Sunovion Pharmaceuticals Inc and Boehringer Ingelheim. MeiLan Han reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Amgen, UpToDate, Altesa Biopharma, Medscape, NACE, MDBriefcase, Integrity and Medwiz. 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. She has received stock options from Meissa Vaccines and Altesa Biopharma. Nicola Hanania served as an advisor or consultant for Astra Zeneca, GSK, Sanofi, Genentech, Teva, Verona, Amgen and his institution received research grant support from Astra Zeneca, GSK, Sanofi, Genentech and Teva. Wilson Pace is on the advisory board for Mylan; stock from Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi. Michael Pollack, Hana Muellerova, Norbert Feigler and Hitesh Gandhi are employees of AstraZeneca and hold stock and/or stock options in the company. AstraZeneca is a co-funder of the CONQUEST initiative. Konstantinos Kostikas has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, GILEAD, GSK, Menarini, Novartis, Sanofi, Specialty Therapeutics; (paid to the University of Ioannina); his department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir (paid to the University of Ioannina); KK is a member of the GOLD Assembly. Marije van Melle, Maja Kruszyk, Alex Federman, Juan Wisnivesky, Yasir Tarabichi, Dennis Williams reports no conflict of interest. Margee Kerr is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Victoria Carter is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Alexander Evans is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Ruth Murray is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Rachel Pullen is an employee of the Observational and Pragmatic Research Institute, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Amy Couper is an employee of the Observational and Pragmatic Research Institute, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. David Price has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrolment or completion of research from Novartis; 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 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline., (© 2023 The Author(s).)

Introduction: In patients with chronic obstructive pulmonary disease (COPD), the risk of certain cardiovascular (CV) events is increased by threefold to fivefold in the year following acute exacerbation of COPD (AECOPD), compared with a non-exacerbation period. While the effect of severe AECOPD is well established, the relationship of moderate exacerbation or prior exacerbation to elevated risk of CV events is less clear. We will conduct cohort studies in multiple countries to further characterise the association between AECOPD and CV events., Methods and Analysis: Retrospective longitudinal cohort studies will be conducted within routinely collected electronic healthcare records or claims databases. The study cohorts will include patients meeting inclusion criteria for COPD between 1 January 2014 and 31 December 2018. Moderate exacerbation is defined as an outpatient visit and/or medication dispensation/prescription for exacerbation; severe exacerbation is defined as hospitalisation for COPD. The primary outcomes of interest are the time to (1) first hospitalisation for a CV event (including acute coronary syndrome, heart failure, arrhythmias or cerebral ischaemia) since cohort entry or (2) death. Time-dependent Cox proportional hazards models will compare the hazard of a CV event between exposed periods following exacerbation (split into these periods: 1-7, 8-14, 15-30, 31-180 and 181-365 days) and the unexposed reference time period, adjusted on time-fixed and time-varying confounders., Ethics and Dissemination: Studies have been approved in Canada, Japan, the Netherlands, Spain and the UK, where an institutional review board is mandated. For each study, the results will be published in peer-reviewed journals., Competing Interests: Competing interests: CN, KR, JM, MO and HM are employees of AstraZeneca and own stock and/or stock options in the company. JKQ has received grants from MRC, HDR UK, GSK, Bayer, BI, asthma+lung, Chiesi and AstraZeneca; and personal fees for advisory board participation or speaking fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Chiesi, Teva, Insmed and Bayer. CFV gave presentations at symposia and/or served on scientific advisory boards sponsored by Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, Nuvaira and MedUpdate. SOS has received grants from Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline, consulting fees from GlaxoSmithKline, honoraria for educational events from AstraZeneca and Chiesi, and honoraria for participation on advisory board from Boehringer Ingelheim and Chiesi, all paid to his institution. NMH has acted as speaker for and received consulting fees from AstraZeneca, Novartis and Servier. EG has been chairwoman of a department at the Leibniz Institute that occasionally performed studies for pharmaceutical industries. The pharmaceutical companies included Byk-Gulden, Nycomed, Bayer, Celgene, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Aventis, Sanofi Pasteur MSD and STADA. EG has been a consultant to Bayer-Schering, Nycomed, GlaxoSmithKline, Schwabe, Teva, Novartis and AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) was modified to permit use in asthma and/or COPD. This tool is called the Chronic Airways Assessment Test (CAAT)., Methods: The psychometric properties of the CAAT were evaluated using baseline data from the NOVELTY study (NCT02760329) in patients with physician-assigned asthma, asthma + COPD or COPD. Analyses included exploratory/confirmatory factor analyses, differential item functioning and analysis of construct validity. Responses to the CAAT and CAT were compared in patients with asthma + COPD and those with COPD., Results: CAAT items were internally consistent (Cronbach's alpha: > 0.7) within each diagnostic group (n = 510). Models for structural and measurement invariance were strong. Tests of differential item functioning showed small differences between asthma and COPD in individual items, but these were not consistent in direction and had minimal overall impact on the total score. The CAAT and CAT were highly consistent when assessed in all NOVELTY patients who completed both (N = 277, Pearson's correlation coefficient: 0.90). Like the CAT itself, CAAT scores correlated moderately (0.4-0.7) to strongly (> 0.7) with other PRO measures and weakly (< 0.4) with spirometry measures., Conclusions: CAAT scores appear to reflect the same health impairment across asthma and COPD, making the CAAT an appropriate PRO instrument for patients with asthma and/or COPD. Its brevity makes it suitable for use in clinical studies and routine clinical practice., Trial Registration: NCT02760329., (© 2023. The Author(s).)

The NOVEL observational longiTudinal studY (NOVELTY; ClinicalTrials.gov identifier NCT02760329) is a global, prospective, observational study of ∼12 000 patients with a diagnosis of asthma and/or COPD. Here, we describe the design of the Advanced Diagnostic Profiling (ADPro) substudy of NOVELTY being conducted in a subset of ∼180 patients recruited from two primary care sites in York, UK. ADPro is employing a combination of novel functional imaging and physiological and metabolic modalities to explore structural and functional changes in the lungs, and their association with different phenotypes and endotypes. Patients participating in the ADPro substudy will attend two visits at the University of Sheffield, UK, 12±2 months apart, at which they will undergo imaging and physiological lung function testing. The primary end-points are the distributions of whole lung functional and morphological measurements assessed with xenon-129 magnetic resonance imaging, including ventilation, gas transfer and airway microstructural indices. Physiological assessments of pulmonary function include spirometry, bronchodilator reversibility, static lung volumes via body plethysmography, transfer factor of the lung for carbon monoxide, multiple-breath nitrogen washout and airway oscillometry. Fractional exhaled nitric oxide will be measured as a marker of type-2 airways inflammation. Regional and global assessment of lung function using these techniques will enable more precise phenotyping of patients with physician-assigned asthma and/or COPD. These techniques will be assessed for their sensitivity to markers of early disease progression., Competing Interests: Conflict of interest: H. Marshall, J. Wild and L. Smith are employees of the University of Sheffield, who received funding to conduct the study. H. Marshall has received support for attending meetings from AstraZeneca. T. Fihn-Wikander and H. Müllerová are employees of AstraZeneca. R. Hughes has received personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis outside of the submitted work, and is an employee of AstraZeneca. L. Hardaker has no conflicts to disclose., (Copyright ©The authors 2023.)

Background: Little is known about the association between respiratory events prior to diagnosis of chronic obstructive pulmonary disease (COPD) and future clinical outcomes in Japan. We investigated the association between pre-COPD diagnosis respiratory events and the incidence of exacerbations in a cohort of newly diagnosed COPD patients in Japan., Patients and Methods: Data were retrieved from the JMDC claims database. Patients ≥40 years old with a first COPD diagnosis (≥1 hospitalization or ≥2 outpatient claims for COPD) between 2010 and 2016 were included. The incidence rate (IR) of exacerbations in patients with or without any respiratory event (including lower respiratory tract infection and respiratory failure) in the year preceding diagnosis was compared. A negative binomial model explored the association between pre-diagnosis respiratory event and IR ratio (IRR) of exacerbations., Results: A total of 20,212 patients newly diagnosed with COPD were identified: 61% male, mean age 55 years (SD 9); of these, 955 (4.7%) had experienced ≥1 respiratory event in the year preceding diagnosis. Median duration of follow-up was 3.3 years during which the IR of exacerbations was 0.31 per patient-year (95% confidence interval [CI] 0.29-0.33) in patients with respiratory event, and 0.11 (95% CI 0.10-0.13) in patients without. The IR for severe exacerbation was nearly 10 times greater in patients with respiratory event versus without. Experiencing respiratory event pre-diagnosis was independently associated with an increased IRR of future moderate-to-severe exacerbation (adjusted IRR, 2.7; 95% CI 2.3-3.1)., Conclusion: Patients experiencing respiratory events in the year preceding COPD diagnosis should be considered at-risk of worse clinical COPD outcomes., Competing Interests: BD, NM, CN, and HM are employees of AstraZeneca and hold stock and/or options in the company. RZ is a former employee of Evidera, which was contracted by AstraZeneca to conduct the study. SG, DL, and SH are employees of Evidera, which was contracted by AstraZeneca to conduct the study. SM has received lecture fees from AstraZeneca, GSK, Nippon Boehringer Ingelheim, Novartis Pharma, Teijin Pharma and grants from ROHTO Pharmaceutical Co., Ltd. The authors report no other conflicts of interest in this work., (© 2023 Ding et al.)

Objectives: During COVID-19 vaccination programmes, new safety signals have emerged for vaccines, including extremely rare cases of thrombosis with thrombocytopaenia syndrome (TTS). Background event rates before and during the pandemic are essential for contextualisation of such infrequent events. In the literature, most studies do not report an overall TTS event rate. Rather, background rates are mainly reported for subtypes of thrombotic/thromboembolic diagnoses included in the TTS clinical definition mostly by anatomical location, with reported rates for TTS subtypes varying widely. The objective of this study was to report prepandemic TTS background event rates in the general population., Methods: Prepandemic background TTS rates were generated via secondary data analysis using a cohort design in the IBM Truven MarketScan (now Merative MarketScan) US health insurance claims database, from 1 January 2019 to 31 December 2019. Two algorithms were applied: thrombocytopaenia occurring±7 days (algorithm 1) or occurring 1 day prior to ≤14 days after the thrombotic/thromboembolic event (algorithm 2)., Results: The study population derived from the MarketScan database analysis included approximately 9.8 million adults (aged ≥18 years; mean age 45 years, 52% females). Using this study population, prepandemic background TTS incidence was estimated as 9.8-11.1 per 100 000 person-years. Event rates were higher in males and increased with age. Similar patterns were observed with both algorithms., Conclusions: This study presents an estimate of aggregate prepandemic background TTS event rates including by type of thrombosis/thromboembolism and age group. The background event rates are dependent on the precision of capturing underlying TTS events in variable data sources, and the ability of electronic health records or insurance claims databases to reflect the TTS clinical definition. Differences between reported event rates demonstrate that estimating background event rates for rare, unprecedented safety events is methodologically challenging., Competing Interests: Competing interests: SdL has received grants through his University from AstraZeneca for research into COVID-19 vaccination (RAVEN) and adverse events of interest following COVID-19 vaccination (ATTEST). Although not directly related to this study, he is director of the Oxford Royal College of General Practitioners Research and Surveillance Centre. RH has no conflicts to report. HM, JM, SK, MA, MN, and HGdS are employees of, and may or may not hold stock in, AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objective: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy based on treatable traits (TTs) has been proposed, the prevalence and relationship of TTs to the diagnostic label and disease severity established by the attending physician in a real-world setting are unknown. We assessed how the presence/absence of specific TTs relate to the diagnosis and severity of 'asthma', 'COPD' or 'asthma + COPD'., Methods: The authors selected 30 frequently occurring TTs from the NOVELTY study cohort (NOVEL observational longiTudinal studY; NCT02760329), a large (n = 11,226), global study that systematically collects data in a real-world setting, both in primary care clinics and specialized centres, for patients with 'asthma' (n = 5932, 52.8%), 'COPD' (n = 3898, 34.7%) or both ('asthma + COPD'; n = 1396, 12.4%)., Results: The results indicate that (1) the prevalence of the 30 TTs evaluated varied widely, with a mean ± SD of 4.6 ± 2.6, 5.4 ± 2.6 and 6.4 ± 2.8 TTs/patient in those with 'asthma', 'COPD' and 'asthma + COPD', respectively (p < 0.0001); (2) there were no large global geographical variations, but the prevalence of TTs was different in primary versus specialized clinics; (3) several TTs were specific to the diagnosis and severity of disease, but many were not; and (4) both the presence and absence of TTs formed a pattern that is recognized by clinicians to establish a diagnosis and grade its severity., Conclusion: These results provide the largest and most granular characterization of TTs in patients with airway diseases in a real-world setting to date., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma., Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits., Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission., Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU., Competing Interests: Declaration of competing interest SMG, RH, HM, ER, TH: Employees of AstraZeneca (AZ). CJ: Honoraria from AZ, Boehringer Ingelheim (BI), Chiesi, GlaxoSmithKline (GSK), Novartis and Teva for lectures. MS: Honoraria from AZ for participations in the NOVELTY study. RB: Grants from AZ and Genentech; personal fees from Avillion, AZ, Cipla and Theravance; leadership role in the Asthma and Respiratory Foundation of New Zealand. JMF: Grants from AZ, GSK and Sanofi-Regeneron; personal fees from AZ, GSK, Teva and Sanofi-Regeneron; honoraria from AZ, Teva, GSK and Sanofi-Regeneron for presenting at symposia. JMO: Consulting fees from ALK; honoraria from ALK, GSK and Mundipharma for independent medical educational presentations; independent research funding from AZ, Eversens and Sanofi-Genzyme; leadership role in FUNDACION SEAIC and the JIACI editorial board. HKR: Participation in advisory boards for AZ, Chiesi, GSK, Novartis and Sanofi-Genzyme; honoraria from AZ, BI, Chiesi, GSK, Sanofi-Genzyme and Teva for independent medical educational presentations; independent research funding from AZ, GSK and Novartis; consulting fees from Novartis; leadership role in the Global Institute for Asthma and the National Asthma Council. BC: Advisor for, and on the speakers’ bureau for AZ, BI, Genentech, GSK, Novartis, Regeneron and Sanofi-Genzyme., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Persistent cough with sputum production is an important clinical trait in chronic obstructive pulmonary disease (COPD). We defined "frequent productive cough" based on 2 questions from the St George's Respiratory Questionnaire (SGRQ) and sought to determine its occurrence and associated outcomes in patients with physician-assigned asthma and/or COPD from the NOVELTY study., Methods: Frequent productive cough was defined as cough and sputum production most or several days/week for the past 3 months (scoring ≥3 for both SGRQ questions). Relationships with baseline disease characteristics and exacerbations over 12 months' follow-up were examined using logistic regression., Results: Baseline SGRQ data were available for 7125 patients, of whom 31.3% had frequent productive cough. It was more common in asthma+COPD (38.8%) and COPD (38.1%) than asthma (25.0%), increasing with physician-assessed severity, and in current versus former and never smokers. Patient-reported symptomatic worsening was more common in patients with versus without frequent productive cough. Reduced post-bronchodilator FEV 1 (odds ratio [OR] per 10% decrement 1.14 [95% confidence interval 1.11-1.16]) and history of pollutant exposure at home/work (OR 1.50 [1.33-1.69]) were associated with frequent productive cough in all diagnoses. Patients with baseline frequent productive cough were more likely to have ≥1 exacerbation over the subsequent 12 months (OR 1.71 [1.52-1.93]), including exacerbations requiring hospital admission and those treated with oral corticosteroids., Conclusions: Frequent productive cough represents an important indicator of adverse clinical outcomes across asthma and/or COPD. Research into the underlying pathologic mechanisms is required to support targeted therapy development., Clinicaltrials: GOV: NCT02760329., Competing Interests: Declaration of competing interest R.H., E.R., C.K., E.L.T., and H.M. are employees of AstraZeneca; C.J. has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Orion; B.J.M. has received CME personal fees from American College of Chest Physicians, Eastern Pulmonary Society, Integritas Communications, Medscape, National Jewish Health, Novartis, Mt Sinai, Projects in Knowledge, WebMD, and Wolters Kluwer Health; medical advisory board fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Phillips, Third Pole, and Verona; personal fees for data safety and monitoring board from Quintiles and Spiration; grants from American Lung Association, AstraZeneca, GlaxoSmithKline; personal fees from AstraZeneca, GlaxoSmithKline, Optimum Patient Care Global Limited, Spiration, and Third Pole; funding from the NHLBI for the COPDGene study; P-R.B. has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Pfizer, Vertex Pharmaceuticals, and Zambon; grants from Boehringer Ingelheim, GlaxoSmithKline and Vertex Pharmaceuticals; H.K.R. has participated in advisory boards for AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, and Sanofi-Genzyme; and has received honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Sanofi, and Teva Pharmaceuticals for independent medical educational presentations; and independent research funding from AstraZeneca, GlaxoSmithKline and Novartis., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Studies have shown that chronic obstructive pulmonary disease (COPD) exacerbation events are related to future events; however, previous literature typically reports frequent vs infrequent exacerbations per patient-year and no studies have investigated increasing number of severe exacerbations in relation to COPD outcomes., Objective: To investigate the association between baseline frequency and severity of exacerbations and subsequent mortality and exacerbation risk in a COPD cohort., Methods: Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics data were used to identify patients registered at general practices in the UK, who had a diagnosis of COPD, were over the age of 40 years, were smokers or ex-smokers and had data recorded from 2004 onwards. Frequency and severity of exacerbations in the baseline year were identified as moderate exacerbations (general practice events) and severe exacerbations (hospitalised events). Patients were categorised as having: none, 1 moderate only, 2 moderate only, 3+ moderate only, 1 severe (and any moderate), 2 severe (and any moderate), and 3+ severe (and any moderate exacerbations). Poisson regression was used to investigate the association between baseline exacerbation frequency/severity and exacerbation events and mortality over follow-up., Results: Overall, 340,515 COPD patients were included. Patients had higher rates of future exacerbations with increasing frequency and severity of baseline exacerbations compared to no baseline exacerbations. Adjusted incidence rate ratios (IRR) for patients with 1, 2, and 3+ moderate exacerbations compared to 0 exacerbations were 1.70 (95% CI 1.66-1.74), 2.31 (95% CI 2.24-2.37), and 3.52 (95% CI 3.43-3.62), respectively. Patients with increased frequency of baseline exacerbations were more likely to die from all-cause, COPD-related, and cardiovascular-related mortality in a graduated fashion., Conclusion: Increasing number and severity of exacerbations were associated with increasing risk of subsequent exacerbations, all-cause mortality and COPD-related mortality. Even a single moderate event increases the risk of future events, illustrating that every exacerbation counts., Competing Interests: JKQ has received grants from The Health Foundation, MRC, GSK, Bayer, BI, AUK-BLF, Chiesi, and AZ, and personal fees for advisory board participation or speaking fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca and Bayer. HW has nothing to disclose. AR, HM, TM, and YX are employees of AstraZeneca and holds stock and/or options in the company. PV and EdN are both former employees of AstraZeneca, but were employed by AstraZeneca at the time of the study. The authors report no other conflicts of interest in this work., (© 2022 Whittaker et al.)

Background and Aims: Exacerbations of chronic obstructive pulmonary disease (COPD) drive disease progression and can lead to an accelerated decline in lung function and a burden on healthcare systems. The retrospective, observational cohort Study on HEalthcare Resource utiLization related to exacerbatiOns in patients with COPD (SHERLOCK; D5980R00014) evaluated the associations between exacerbation history and rates of subsequent COPD exacerbations in primary care patients from the National Health Service in Greater Glasgow and Clyde, United Kingdom., Methods: Patients were stratified into four groups according to exacerbation history in the year before the index date: Group A (no exacerbations), Group B (1 moderate exacerbation only), Group C (1 severe exacerbation only), and Group D (⩾2 moderate or severe exacerbations). The frequencies of moderate and/or severe exacerbations were recorded over 36 months of follow-up and compared with reference Group A, using generalized linear models., Results: Over 36 months of follow-up, the adjusted rate ratios (RRs, 95% confidence interval) of moderate or severe exacerbations relative to Group A were 1.60 (1.53, 1.67), 1.75 (1.50, 2.04), 1.61 (1.54, 1.68), and 3.61 (3.48, 3.74) for Groups B, C, B + C, and D, respectively. Compared with Group A, patients in Group C exhibited an increased rate of moderate (RR, 1.58 (1.35, 1.85)) and severe exacerbations (RR, 3.13 (2.20, 4.46))., Conclusion: SHERLOCK highlights that even one moderate exacerbation increases the risk for subsequent exacerbations compared with having no recent prior exacerbations. Reviewing recent exacerbation history to ascertain future exacerbation risk and inform COPD management may reduce hospitalizations and improve patient outcomes.

Background: The majority of patients with chronic obstructive pulmonary disease (COPD) suffer from comorbid cardiovascular (CV) disease. Accumulating evidence suggests a temporal association between COPD exacerbations and acute CV events, possibly due to lung hyperinflation, increased hypoxemia and systemic inflammation. The aims of the study were to estimate the risk of (1) acute CV events [acute myocardial infarction (AMI), CV-related death] or stroke in the months following a COPD exacerbation and (2) COPD exacerbation in the months following an acute CV event., Methods: A systematic literature review of observational studies published since 2000 was conducted by searching literature databases (Medline and Embase). Studies were eligible if conducted in adults with COPD, exposed to either COPD exacerbation or acute CV events, with outcomes of acute CV events or COPD exacerbation reported. Studies were appraised for relevance, bias and quality. Meta-analyses, using random-effect models, were performed for each outcome of interest, thus providing a pooled relative risk (RR) and its 95% confidence interval., Results: Eight studies were identified, of which seven were used for the meta-analyses examining the risk of CV events 1-3 months after an exacerbation compared with none. For stroke (six studies), RR was 1.68 (95% CI = 1.19-2.38). For AMI (six studies), RR was 2.43 (95% CI = 1.40-4.20). No studies exploring risk of exacerbation following an acute CV event were identified., Conclusion: This meta-analysis identified a markedly increased risk of stroke or AMI within a relatively short period of time following a COPD exacerbation. Although the underlying mechanisms are not fully elucidated, patients with COPD should be monitored for risk of CV outcomes after exacerbations. In addition, preventing exacerbations may decrease the risk of subsequent acute CV events., Registration: The study protocol was published via PROSPERO: International Prospective Register of Systematic Reviews (#CRD42020211055).

Background: Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort., Methods: Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis., Results: Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses., Conclusion: This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications., Competing Interests: Conflict of interest: H.K. Reddel reports grants, personal fees and non-financial support from AstraZeneca, during the conduct of the study; grants and personal fees for data monitoring committee work, advisory board work and providing independent medical education from AstraZeneca and GlaxoSmithKline, personal fees for data monitoring committee work from Merck, personal fees for data monitoring committee work, advisory board work and grant for registry from Novartis, personal fees for providing independent medical education from Teva, personal fees for advisory board work and providing independent medical education from Boehringer Ingelheim, and personal fees for advisory board work from Sanofi Genzyme and Chiesi, outside the submitted work; and is Chair of the GINA Scientific Committee and a member of the GINA Board. Conflict of interest: J. Vestbo reports personal fees for steering committee work from AstraZeneca, during the conduct of the study; and personal fees for consultancy and lectures from GlaxoSmithKline, Chiesi Pharmaceuticals, Novartis and AstraZeneca, and grants and personal fees for consultancy and lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Agusti reports personal fees for scientific committee work from AstraZeneca, during the conduct of the study; and grants and personal fees for lectures and advisory board work from GlaxoSmithKline and Menarini, and personal fees for lectures and advisory board work from Chiesi, outside the submitted work. Conflict of interest: G.P. Anderson reports personal fees for consultancy and share options from Pieris Pharmaceuticals, ENA Therapeutics and ENA Respiratory, personal fees for scientific committee work from AstraZeneca, and personal fees for lectures from GlaxoSmithKline, AstraZeneca, Menarini and Novartis, outside the submitted work; and has US Patent 7,455,836 licensed to MorphoSys, sublicensed to GlaxoSmithKline. Conflict of interest: A.T. Bansal has nothing to disclose. Conflict of interest: R. Beasley reports personal fees for steering committee work from AstraZeneca, during the conduct of the study; and grants and personal fees from AstraZeneca and GlaxoSmithKline, personal fees from Avillion and Theravance, and grants from Genentech, outside the submitted work. Conflict of interest: E.H. Bel reports grants and personal fees from AstraZeneca, GlaxoSmithKline, Novartis and Teva, and personal fees from Sanofi/Regeneron, Sterna and Chiesi, outside the submitted work. Conflict of interest: C. Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, outside the submitted work. Conflict of interest: B. Make reports grants, non-financial support and other (advisory board and presentations) from AstraZeneca, grants, non-financial support and other from GlaxoSmithKline, non-financial support for data monitoring committee work from Spiration, grants, non-financial support and other (advisory board) from Sunovion, other (CME activity) from Mt. Sinai, Web MD, National Jewish Health, Novartis, American College of Chest Physicians, Projects in Knowledge, Hybrid Communications, Medscape, Ultimate Medical Academy, Eastern Pulmonary Society, Catamount Medical, Eastern VA Medical Center, Academy Continued Health Care Learning and Wolters Kluwer Health, grants from Pearl Research and NHLBI, other (advisory board) from Verona, Boehringer Ingelheim, Theravance and Science 24/7, non-financial support and other (advisory board) from Circassia and Phillips, personal fees and non-financial support for consultancy from Third Pole, non-financial support and other (data monitoring committee) from Shire, and personal fees for data monitoring committee work from Takeda, outside the submitted work. Conflict of interest: I.D. Pavord reports personal fees for lectures, advisory board work, meeting attendance and organising educational events from AstraZeneca, personal fees for lectures, advisory board work and meeting attendance from Boehringer Ingelheim and GlaxoSmithKline, personal fees for lectures from Aerocrine and Chiesi, personal fees for lectures and advisory board work from Almirall and Novartis, personal fees for advisory board work from Genentech, Regeneron, Sanofi, Circassia and Knopp, personal fees for lectures, meeting attendance and organising educational events from Teva, and grants from NIHR, outside the submitted work. Conflict of interest: D. Price reports study funding from AstraZeneca, during the conduct of the study; personal fees for advisory board work and consultancy from Amgen, grants and personal fees for advisory board work, lectures, consultancy and travel/accommodation/meeting expenses from AstraZeneca and Boehringer Ingelheim, grants and personal fees for advisory board work, lectures and consultancy from Chiesi, Mylan and Teva, grants and personal fees for advisory board work from Circassia, personal fees for lectures from Cipla and Kyorin, personal fees for consultancy and lectures from GlaxoSmithKline, grants and personal fees for advisory board work, lectures, consultancy, travel/accommodation/meeting expenses and educational activities from Mundipharma and Novartis, grants and personal fees for consultancy from Pfizer and Theravance, grants and personal fees for advisory board work and lectures from Regeneron Pharmaceuticals and Sanofi Genzyme, grants from Respiratory Effectiveness Group and UK National Health Service, personal fees for advisory board work and travel/accommodation/meeting expenses from ThermoFisher, non-financial support for grant committee reviewing from Efficacy and Evaluation Mechanism Programme and Health Technology Assessment, outside the submitted work; has stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; and is part owner of the social enterprise Optimum Patient Care Ltd (Australia and UK) and of the Observational and Pragmatic Research Institute Pte Ltd (Singapore). Conflict of interest: E. Rapsomaniki is an employee of AstraZeneca (UK). Conflict of interest: N. Karlsson is an employee of AstraZeneca. Conflict of interest: D.K. Finch was an employee of AstraZeneca at the time of authorship. Conflict of interest: J. Nuevo is an employee of AstraZeneca. Conflict of interest: A. de Giorgio-Miller has nothing to disclose. Conflict of interest: M. Alacqua has nothing to disclose. Conflict of interest: R. Hughes reports personal fees from GlaxoSmithKline, Novartis, Boehringer Ingelheim and AstraZeneca, outside the submitted work; and is an employee of AstraZeneca. Conflict of interest: H. Müllerová is an employee of AstraZeneca. Conflict of interest: M. Gerhardsson de Verdier is an employee of AstraZeneca., (Copyright ©The authors 2021.)

Objectives: Severe asthma (SA) can be uncontrolled despite guideline-directed treatment. We described SA characteristics and identified factors associated with uncontrolled disease and frequent exacerbations., Methods: Post hoc analysis of the observational IDEAL study (201722/NCT02293265) included patients with SA aged ≥12 years receiving high-dose inhaled corticosteroids plus additional controller(s) for ≥12 months. Uncontrolled SA was defined by Asthma Control Questionnaire (ACQ)-5 scores ≥1.5 or ≥1 exacerbations (prior year), and further stratified by exacerbation frequency (no/infrequent [0-1] vs frequent [≥2]; prior year); associated factors were determined using multivariate logistic regression., Results: Of 670 patients with SA, 540 (81%) were uncontrolled (ACQ-5 scores ≥1.5: 80%; ≥1 exacerbations [prior year]: 71%). Uncontrolled patients had lower lung function and worse health-related quality of life (HRQoL) than controlled patients; 197/540 (37%) experienced frequent exacerbations (prior year). Worse St George's Respiratory Questionnaire (SGRQ) total score, comorbid sinusitis, or eczema were significantly associated with uncontrolled SA; younger age, never smoker status, exacerbation requiring hospitalization (previous year), worse SGRQ symptom score, comorbid nasal polyps, COPD, or osteoporosis were significantly associated with uncontrolled SA with frequent exacerbations., Conclusions: In IDEAL, one-fifth of patients with SA were controlled, based on symptoms. Uncontrolled, exacerbating SA was associated with specific comorbidities, frequent exacerbations, a lower lung function, and compromised HRQoL, although inference from this analysis is limited by the selective cross-sectional nature of the cohort. Nonetheless, these data highlight the need for more effective precision treatments in this population.

Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy., Competing Interests: Conflict of interest: T. Welte reports personal fees, fees for lectures and consultancy fees from AstraZeneca, Basilea, Biotest, Bayer, Boehringer, GlaxoSmithKline, Janssens, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Sanofi Aventis, outside the submitted work. Conflict of interest: L.J. Ambrose reports other funding from AstraZeneca, during the conduct of the study. Conflict of interest: G.C. Sibbring reports other funding from AstraZeneca, during the conduct of the study. Conflict of interest: S. Sheikh was an employee and shareholder of AstraZeneca at the time of manuscript preparation. Conflict of interest: H. Müllerová is an employee and shareholder of AstraZeneca. Conflict of interest: I. Sabir is an employee and shareholder of AstraZeneca., (Copyright ©The authors 2021.)

Background: The Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported diagnosis-agnostic tool designed to assess the frequency of respiratory symptoms and their impact on activity, without specifying a particular diagnosis. Our objective was to examine its validity in patients with asthma and/or chronic obstructive pulmonary disease (COPD)., Methods: Baseline data were randomly sampled from patients who completed the RSQ in the NOVELTY study (ClinicalTrials.gov: NCT02760329). The total sample (n=1530) comprised three randomly selected samples (n=510 each) from each physician-assigned diagnostic group (asthma, asthma+COPD and COPD). The internal consistency and structural validity of the RSQ were evaluated using exploratory and confirmatory factor analyses; psychometric performance was observed using Classical Test Theory and Item Response Theory analyses., Results: For the total sample, the mean±sd RSQ score was 5.6±4.3 (range 0-16). Irrespective of diagnosis, the internal consistency of items was uniformly adequate (Cronbach's α=0.76-0.80). All items had high factor loadings and structural characteristics of the measure were invariant across groups. Using the total sample, RSQ items informatively covered the θ score range of -2.0 to 2.8, with discrimination coefficients for individual items being high to very high (1.7-2.6). Strong convergent correlations were observed between the RSQ and the St George's Respiratory Questionnaire (0.77, p<0.001)., Conclusions: The RSQ is a valid, brief, patient-reported tool for assessing respiratory symptoms in patients across the whole spectrum of asthma and/or COPD, rather than using different questionnaires for each diagnosis. It can be used for monitoring respiratory symptoms in clinical practice, clinical trials and real-world studies., Competing Interests: Conflict of interest: N. Karlsson is an employee of AstraZeneca. Conflict of interest: M.J. Atkinson reports payment as an independent consultant to Evidera for activities contracted by AstraZeneca associated with the psychometric evaluation of the Respiratory Symptoms Questionnaire; he has provided analytic direction and unbiased interpretation of the RSQ findings. Conflict of interest: H. Müllerová is an employee of AstraZeneca. Conflict of interest: M. Alacqua is an employee of AstraZeneca. Conflict of interest: C. Keen is an employee of AstraZeneca. Conflict of interest: R. Hughes is an employee of AstraZeneca. Conflict of interest: C. Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva Pharmaceuticals, outside the submitted work. Conflict of interest: B. Make reports grants (with funds provided to, and controlled by, National Jewish Health) from AstraZeneca, GlaxoSmithKline, National Heart, Lung, and Blood Institute, Pearl Research and Sunovion; personal fees from Takeda and Third Pole; nonfinancial support from AstraZeneca, Circassia, GlaxoSmithKline, Phillips, Shire, Spiration, Sunovion and Third Pole; and other support from Academy Continued Health Care Learning, American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Catamount Medical, Circassia, Eastern Pulmonary Society, Eastern VA Medical Center, GlaxoSmithKline, Hybrid Communications, Medscape, Mount Sinai Medical Center, National Jewish Health, Novartis, Phillips, Projects in Knowledge, Science 24/7, Shire, Sunovion, Theravance, Ultimate Medical Academy, Verona, WebMD and Wolters Kluwer Health, all outside the submitted work. Conflict of interest: D. Price received funding for the conduct of this study from AstraZeneca and discloses board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mundipharma, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals and Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Mylan, Novartis, Pfizer, Teva Pharmaceuticals and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mundipharma, Mylan, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance and the UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mundipharma, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis and Thermofisher; funding for patient enrolment or completion of research from Novartis; 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 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Conflict of interest: H.K. Reddel reports that this study is funded by AstraZeneca. She received reimbursement from AstraZeneca for time spent working on the study but not for manuscript preparation. She also reports advisory boards for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Sanofi-Genzyme; data and safety monitoring boards for AstraZeneca, GlaxoSmithKline, Merck and Novartis; honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Teva Pharmaceuticals for independent medical educational presentations; and independent research funding from AstraZeneca, GlaxoSmithKline and Novartis, all outside the submitted work., (Copyright ©ERS 2021.)

Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions., Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status., Results: In a population of 1431 participants (57% male; mean FEV 1 % predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status., Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings., Competing Interests: MS-M, BM, ALL, MT, and TK are employees and shareholders of GlaxoSmithKline plc. HM, CEB and RT-S are former employees and shareholders of GlaxoSmithKline plc. HM is a current employee of AstraZeneca. CEB has also provided contracting for Eli Lilly, outside of the submitted work. RT-S also reports receipt of consulting fees from ImmunoMet outside of the submitted work. FJM reports a grant from NHLBI during the conduct of the study; serving on steering committees for GlaxoSmithKline plc., Afferent/Merck, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Nitto, Patara/Respivant, Pearl Pharmaceuticals, ProMedior/Roche, ProMetic, Stromedix/Biogen and Veracyte; being a member of advisory boards for GlaxoSmithKline plc., AstraZeneca, Boehringer Ingelheim, Bioscale/Proterrix Bio, Chiesi, Gala, Genentech, Novartis, Pearl Pharmaceuticals, Physicians Education Resource, CSL Behring, Sunovion, Teva and Zambon; consulting for BristolMyersSquibb, Bridge Biotherapeutics and two XR; has received continuing medical education presentation support from the Canadian Respiratory Network, Chiesi, CME outfitters, Dartmouth University, France Foundation, Inova Fairfax, MD Magazine, Methodist Hospital, Miller Communications, National Association for Continuing Education/Haymarket, New York University, PeerView, Prime Education, Rare Diseases Healthcare Communication, Rockpointe, University of Alabama Birmingham, UpToDate, Vindico, WebMD/MedScape, Zambon; also DSMB for Boehringer Ingelheim and GlaxoSmithKline plc. MH reports a grant from NHLBI during the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc., Merck and Mylan; research support from Novartis and Sunovion outside of the submitted work. MD reports grants from NIH during the conduct of the study and from NIH, American Lung Association, Department of Veterans Affairs, and Department of Defense outside of the submitted work. He reports personal fees from Boehringer Ingelheim, GlaxoSmithKline plc., PneumRx/BTG, AstraZeneca, Quark Pharmaceuticals, and Mereo; has contracted clinical trials for Boehringer Ingelheim, GlaxoSmithKline plc., Novartis, AstraZeneca, Yungjin, PneumRx/BTG, Pulmonx, Boston Scientific, Gala and Nuveira; and has received non-financial support from Pulmonx, outside the submitted work. NNH reports research grants from AstraZeneca, Boehringer Ingelheim, COPD Foundation, GlaxoSmithKline plc., NIH; advisory board fees for AstraZeneca, GlaxoSmithKline plc., Mylan. CBC reports grants from NIH/NHLBI and the NIH Foundation during the conduct of the study; personal fees from MGC Diagnostics, NUVEIRA and PulmonX; and has acted as a global medical expert for GlaxoSmithKline plc., outside of the submitted work. VK has received personal fees from Gala Therapeutics, AstraZeneca, Boehringer Ingelheim, and the American Board of Internal Medicine over the last 3 years, outside of the submitted work. APC reports a grant from NIH and receipt of consulting fees from GlaxoSmithKline plc., and non-financial support from VIDA outside of the submitted work. RP III reports research grants from COPD Foundation and NHLBI, and from the Department of Veterans Affairs outside of the submitted work. MBD reports a grant from NIH-NHLBI during the conduct of the study and receipt of consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc., Mylan Theravance, and Parion, outside of the submitted work. REK, PW, VEO and WA have no conflicts of interest to report. The authors report no other conflicts of interest in this work., (© 2020 Stott-Miller et al.)

Purpose: To characterize and estimate the proportion of patients with chronic obstructive pulmonary disease (COPD) who continue to exacerbate while receiving triple therapy and further describe these patients according to blood eosinophil counts., Methods: This was an analysis of the 2017 Adelphi Real-World Respiratory Disease Specific Programme (DSP) survey of patients with COPD from France, Germany, Italy, Spain, and the United Kingdom (UK). Demographics were assessed on the date of completion of the physician/patient questionnaire; clinical characteristics were captured for the previous 12 months. The proportion of patients receiving triple therapy, who had experienced ≥2 moderate or ≥1 severe acute exacerbations of COPD (AECOPD) in the 12 months prior to index, and had blood eosinophil counts ≥150 cells/µL (T-AECOPD-EOS150) or ≥300 cells/µL (T-AECOPD-EOS300), were calculated., Results: In total, 2876 patients were included of which 762 had an eosinophil value. A higher proportion of patients in the ≥300 cells/μL eosinophil group (55.9%) compared with 150-<300 cells/μL (48.7%) and <150 cells/μL (47.1%) groups experienced ≥2 moderate and/or ≥1 severe AECOPD in the year prior to index. The ≥300 cells/μL eosinophil group had the lowest reported level of health-related quality of life (HRQoL). More severe disease in terms of comorbidities, lung function, healthcare resource use, and HRQoL was seen in patients with ≥2 moderate or ≥1 severe AECOPD in the year prior to index while receiving triple therapy, compared with patients who did not meet these criteria. In total, 10.6% and 6.2% of the COPD population, respectively, met the criteria for the T-AECOPD-EOS150 and T-AECOPD-EOS300 cohorts., Conclusion: This analysis demonstrates that there is a subpopulation of patients with COPD who continue to experience exacerbations despite receiving triple therapy; approximately three-quarters of these had eosinophils ≥150 cells/μL and one-third had eosinophils ≥300 cells/μL; these patients may benefit from eosinophil-targeted therapies., Competing Interests: VB is an employee at GSK and holds stocks/shares. KP and HM are former employees of GSK and hold stocks/shares. KP is currently employed at Janssen, High Wycombe, UK. HM is currently employed by AstraZeneca, Cambridge, UK. MS and JS are full-time employees at Adelphi Real World, which received funding from GSK to perform this analysis. Employees of Adelphi Real World were not paid for manuscript development. The authors report no other conflicts of interest in this work., (© 2019 Benson et al.)

Background: There are currently limited real-world data on the clinical burden of illness in patients with COPD who continue to exacerbate despite receiving triple therapy. The aim of this study was to compare the burden of COPD in patients with and without a phenotype characterized by a high blood eosinophil count and high risk of exacerbations while receiving triple therapy. Methods: This retrospective cohort study (GSK ID: 207323/PRJ2647) used UK Clinical Practice Research Datalink records linked with Hospital Episode Statistics. Eligible patients had a COPD medical diagnosis code recorded between January 1, 2004 and December 31, 2014, and a blood eosinophil count recorded on/after that date. Patients were followed from index date (first qualifying blood eosinophil count) until December 31, 2015. The study phenotype was defined as ≥2 moderate/≥1 severe acute exacerbation of COPD (AECOPD) in the year prior to the index date, current use of multiple-inhaler triple therapy (MITT), and blood eosinophil count ≥150 cells/µL on the index date. Outcomes measured during follow-up included moderate/severe AECOPDs, severe AECOPDs, all-cause mortality, primary care (GP) clinical consultations, and non-AECOPD-related unscheduled hospitalizations. Results: Of 46,814 patients eligible for inclusion, 2512 (5.4%) met the definition of the study phenotype. Adjusted rate ratios (95% CI) of moderate/severe AECOPDs and all-cause mortality in patients with the study phenotype versus those without were 2.32 (2.22, 2.43) and 1.26 (1.16, 1.37), respectively. For GP visits and non-AECOPD-related unscheduled hospitalizations, adjusted rate ratios (95% CI), in patients with the study phenotype versus those without, were 1.09 (1.05, 1.12) and 1.31 (1.18, 1.46), respectively. Conclusion: Patients with COPD and raised blood eosinophil counts who continue to exacerbate despite MITT represent a distinct subgroup who experience substantial clinical burden and account for high healthcare expenditure. There is a need for more effective management and therapeutic options for these patients., Competing Interests: All authors are employees of and hold stocks/shares in GSK. Dr Hana Müllerová reports non-financial support from GSK during the conduct of the study, was an employee of GSK, and owns shares and stock options of GSK. Dr Wilhelmine Meeraus reports non-financial support from GSK during the conduct of the study, is an employee of GSK. Dr Dmitry Galkin reports not-financial support from GSK during the conduct of the study, is an employee of GSK, owns GSK stock and shares and is a GSK employee. Dr Frank Albers reports non-financial support from GSK during the conduct of the study and is an emplyee of GSK. Dr Sarah Landis reports non-financial support from GSK during the conduct of the study.

Purpose: Current understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited. This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use., Methods: This was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395). The population of interest comprised patients with COPD ≥40 years of age with ≥2 moderate or ≥1 severe exacerbations (prior year) while on inhaled maintenance therapy, with ≥1 blood EOS count. Data were analyzed during the year prior to index date (last COPD encounter between January 1, 2011 and December 31, 2016). Four subgroups were analyzed based on a combination of EOS counts (<150 and ≥150 cells/μL) and MITT use (receiving or not receiving). Among these groups, clinical characteristics, exacerbations, and HCRU were described. A sensitivity analysis that further stratified EOS into four categories (<150, ≥150-<300, ≥300-<500, and ≥500 cells/μL) was also performed., Results: The COPD population of interest comprised 34,268 patients. Subgroups with EOS ≥150 cells/μL vs <150 cells/μL had more comorbidities and experienced significantly higher mean numbers of moderate exacerbations (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 1.93 vs 1.82, P <0.0001; receiving MITT 2.26 vs 2.16, P =0.0062) and COPD-related emergency visits (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 3.0 vs 2.5, P <0.001; receiving MITT 3.4 vs 3.1, P =0.0011). Increasing EOS category was associated with higher HCRU., Conclusion: Blood EOS ≥150/μL cells were associated with increased HCRU and higher exacerbation rates compared with EOS <150 cells/μL, irrespective of MITT use. COPD phenotyping using blood EOS could help identify candidates for additional therapies that target eosinophilic inflammatory pathways., Competing Interests: Disclosure HM, BH, EPS, and GM are all GSK employees and own stock in GSK. All authors report no other conflicts of interest in this work.

Background: Distinct asthma phenotypes have previously been suggested, including benign asthma, atopic asthma and obese non-eosinophilic asthma. This study aims to establish if these phenotypes can be identified using data recorded in primary care clinical records and reports on patient characteristics and exacerbation frequency., Methods: A population-based cohort study identified 193,999 asthma patients in UK primary care from 2007 to 2017. We used linked primary and secondary care data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics. Patients were classified into predefined phenotypes or included in an asthma "not otherwise specified" (NOS) group. We used negative binomial regression to calculate the exacerbation rates and adjusted rate ratios. Rate ratios were further stratified by asthma treatment step., Results: In our cohort, 3.9% of patients were categorized as benign asthma, 28.6% atopic asthma and 4.8% obese non-eosinophilic asthma. About 62.7% of patients were asthma NOS, including asthma NOS without treatment (10.4%), only on short-acting beta agonist (6.1%) and on maintenance treatment (46.2%). Crude severe exacerbation rates per 1,000 person-years were lowest for benign asthma (106.8 [95% CI: 101.2-112.3]) and highest for obese non-eosinophilic asthma (469.0 [451.7-486.2]). Incidence rate ratios for all phenotype groups decreased when stratified by treatment step but remained raised compared to benign asthma., Conclusion: Established phenotypes can be identified in a general asthma population, although many patients did not fit into the specific phenotypes which we studied. Phenotyping patients and knowledge of asthma treatment step could help anticipate clinical course and therefore could aid clinical management but is only possible in a minority of primary care patients based on current phenotypes and electronic health records (EHRs)., Competing Interests: Disclosure FN is funded by a GlaxoSmithKline (GSK) scholarship during his PhD program. IJD is funded by an unrestricted grant from, has consulted for, and holds stock in GSK. HM is an employee of GSK R&D and owns shares of GSK. JKQ’s research group has received funding from The Health Foundation, Medical Research Council, Wellcome Trust, British Lung Foundation, GSK, Insmed, AstraZeneca (AZ), Bayer and Boehringer Ingelheim (BI) for other projects, none of which relate to this work. JKQ has received funds from AZ, GSK, Chiesi, Teva and BI for Advisory board participation or travel. The authors report no other conflicts of interest in this work.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are important adverse events in the natural history of chronic obstructive pulmonary disease (COPD)., Objectives: To investigate the natural history of AECOPDs over 10 years of follow-up., Methods: We identified 99,574 patients with COPD from January 1, 2004, to March 31, 2015, from the UK Clinical Practice Research Datalink. We defined moderate AECOPDs as those managed outside hospital and severe as those requiring hospitalization. During the baseline period (first year of follow-up), patients were grouped according to the number and severity of AECOPDs and then followed for a maximum of 10 years (mean, 4.9 yr). We investigated the effect of baseline AECOPD number and severity on risk of further events and death., Measurements and Main Results: Around one-quarter of the patients with COPD did not exacerbate during follow-up. Compared with no AECOPDs in the baseline period, AECOPD number predicted the future long-term rate of AECOPDs in a graduated fashion, ranging from hazard ratio (HR) of 1.71 (1.66-1.77) for one event to HR of 3.41 (3.27-3.56) for five or more events. Two or more moderate AECOPDs were also associated with an increased risk of death in a graduated fashion, ranging from HR of 1.10 (1.03-1.18) for two moderate AECOPDs to HR of 1.57 (1.45-1.70) for five or more moderate AECOPDs, compared with those with no AECOPDs at baseline. Severe AECOPDs were associated with an even higher risk of death (HR, 1.79; 1.65-1.94)., Conclusions: A large proportion of patients with COPD do not exacerbate over a maximum 10 years of follow-up. AECOPD frequency in a single year predicts long-term AECOPD rate. Increasing frequency and severity of AECOPDs is associated with risk of death and highlights the importance of preventing AECOPDs.