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

Background: Disturbed sleep in patients with COPD impact quality of life and predict adverse outcomes., Research Question: To identify distinct phenotypic clusters of patients with COPD using objective sleep parameters and evaluate the associations between clusters and all-cause mortality to inform risk stratification., Study Design and Methods: A longitudinal observational cohort study using nationwide Veterans Health Administration data of patients with COPD investigated for sleep disorders. Sleep parameters were extracted from polysomnography physician interpretation using a validated natural language processing algorithm. We performed cluster analysis using an unsupervised machine learning algorithm (K-means) and examined the association between clusters and mortality using Cox regression analysis, adjusted for potential confounders, and visualized with Kaplan-Meier estimates., Results: Among 9992 patients with COPD and a clinically indicated baseline polysomnogram, we identified five distinct clusters based on age, comorbidity burden and sleep parameters. Overall mortality increased from 9.4 % to 42 % and short-term mortality (<5.3 years) ranged from 3.4 % to 24.3 % in Cluster 1 to 5. In Cluster 1 younger age, in 5 high comorbidity burden and in the other three clusters, total sleep time and sleep efficiency had significant associations with mortality., Interpretation: We identified five distinct clinical clusters and highlighted the significant association between total sleep time and sleep efficiency on mortality. The identified clusters highlight the importance of objective sleep parameters in determining mortality risk and phenotypic characterization in this population., Competing Interests: Declaration of competing interest None of the authors disclose any financial or personal relationship with other people or organizations that could inappropriately influence this work., (Published by Elsevier Ltd.)

Purpose: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS)., Methods: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio., Results: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports., Conclusion: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue., (© 2024. The Author(s).)

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White ( n  = 6,766) and AA ( n  = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Background: Respiratory complications often accompany influenza in patients with chronic obstructive pulmonary disease (COPD). In this retrospective study, we quantified the impact of antiviral therapy on exacerbations, healthcare resource utilization (HRU), and costs in patients with COPD across 5 influenza seasons., Methods: Using claims data from US MarketScan® databases, we identified patients with COPD who had an influenza diagnosis during the 2012-2016 influenza seasons. Patients who received a neuraminidase inhibitor within 48 h of diagnosis ( N  = 4134) were identified and propensity score-matched 1:1 to a comparator cohort of untreated patients. We determined COPD- and pneumonia-related HRU and costs during month 1, each subsequent quarter, and months 2-13., Results: Antiviral-treated patients had a significantly lower frequency of COPD-related outcomes than untreated patients during all periods (exacerbations: 10.4% vs 18.2% [month 1] and 17.7% vs 24.2% [months 2-13]; inpatient visit: 2.5% vs 7.9% [month 1] and 3.8% vs 6.7% [months 2-13]; P  < 0.0001, all comparisons). Treated patients also had significantly lower outpatient and emergency department (ED) visits beyond month 1. Pneumonia-related inpatient, ED, and outpatient visits were significantly lower in antiviral-treated patients than in untreated patients over all periods ( P  < 0.0001, all comparisons). In all HRU categories, COPD- and pneumonia-related costs were significantly lower in treated patients over all periods (month-1 ED visit costs were higher)., Conclusions: Antiviral treatment in patients with COPD and influenza is associated with significantly lower HRU and costs in the postinfection month and for an entire year following infection compared with untreated patients., Competing Interests: CW, TMT, SK, HM III, NW, and DM are current or past employees of Genentech/Roche, Inc. and hold Roche stock., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Based on current clinical guidelines, long-acting β2-agonists (LABA) are frequently prescribed before long-acting muscarinic antagonists (LAMA) as an add-on to inhaled corticosteroids (ICS) in uncontrolled asthma. However, there is insufficient real-world evidence that supports this therapeutic approach. Objective: The objective was to compare asthma exacerbations and healthcare resource utilization in patients with asthma using the LAMA tiotropium bromide (Tio) or a LABA as an add-on to ICS (ICS + Tio or ICS/LABA) in a real-world setting. Methods: This retrospective, observational study included patients aged ≥12 years with asthma diagnoses identified in a U.S. longitudinal claims database (October 2015 to August 2020). The ICS + Tio and ICS/LABA cohorts were 1:2 propensity score matched for baseline variables. Outcomes were compared in the postmatched cohorts, and the risk of exacerbation was evaluated by using Kaplan-Meier curves. Results: After propensity score matching, there were 633 and 1266 patients in the ICS + Tio and ICS/LABA cohorts, respectively. The proportion of patients who experienced a severe or a moderate-or-severe exacerbation during follow-up was similar between the ICS + Tio versus ICS/LABA cohorts (4% versus 3%, p = 0.472, and 50% versus 45%, p = 0.050, respectively). The mean time to first severe (ICS + Tio 43.8 days versus ICS/LABA 49.4 days, p = 0.758) and moderate-or-severe exacerbation (ICS + Tio 65.8 days versus ICS/LABA 58.9 days, p = 0.474) was not statistically different between cohorts. The treatments had no effect on the risk of severe exacerbation, although it was 36% lower in ICS + Tio users than in ICS/LABA users (hazard ratio 0.64 [95% confidence interval, 0.22-1.84]). All-cause and asthma-related average monthly healthcare resource utilization were comparable between the treatments for hospitalizations and emergency department visits but were significantly greater in the ICS + Tio cohort than in the ICS/LABA cohort for asthma-related outpatient visits (p < 0.0001). Conclusion: This study provides real-world evidence that ICS + Tio may be a valid alternative when ICS/LABA cannot be used as first-line treatment for asthma maintenance therapy.

Background: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV 1 /FVC < 0.7. African-Americans are less often diagnosed with COPD., Objective: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race., Design: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes., Setting: Multicenter, longitudinal US cohort study., Participants: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma., Measurements: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV 1  ≥ 80% predicted and FEV 1 /FVC ≥ 0.7)., Results: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV 1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV 1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse D L CO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW., Limitations: Lack of an alternative diagnostic metric for comparison., Conclusions: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV 1 leading to higher FEV 1 /FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: In 2008, a dedicated American Thoracic Society/European Respiratory Society task force published a paper on the possible use and limitations of clinical outcomes and biomarkers to evaluate the impact of pharmacological therapy in patients with chronic obstructive pulmonary disease. Since then, our scientific understanding of chronic obstructive pulmonary disease has increased considerably; there has been a progressive shift from a one-size-fits-all diagnostic and therapeutic approach to a personalized approach; and many new treatments currently in development will require new endpoints to evaluate their efficacy adequately. Objectives: The emergence of several new relevant outcome measures motivated the authors to review advances in the field and highlight the need to update the content of the original report. Methods: The authors separately created search strategies for the literature, primarily based on their opinions and assessments supported by carefully chosen references. No centralized examination of the literature or uniform criteria for including or excluding evidence were used. Measurements and Main Results: Endpoints, outcomes, and biomarkers have been revisited. The limitations of some of those reported in the American Thoracic Society/European Respiratory Society task force document have been highlighted. In addition, new tools that may be useful, especially in evaluating personalized therapy, have been described. Conclusions: Because the "label-free" treatable traits approach is becoming an important step toward precision medicine, future clinical trials should focus on highly prevalent treatable traits, and this will influence the choice of outcomes and markers to be considered. The use of the new tools, particularly combination endpoints, could help better identify the right patients to be treated with the new drugs.

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

Older adults have a higher prevalence of chronic obstructive pulmonary disease (COPD), which will likely increase substantially in the coming decades owing to aging populations and increased long-term exposure to risk factors for this disease. COPD in older adults is characterized by low-grade chronic systemic inflammation, known as inflamm-aging. It contributes substantially to age-associated pulmonary changes that are clinically expressed by reduced lung function, poor health status, and limitations in activities of daily living. In addition, inflamm-aging has been associated with the onset of many comorbidities commonly encountered in COPD. Furthermore, physiologic changes that are often seen with aging can influence the optimal treatment of older patients with COPD. Therefore, variables such as pharmacokinetics, pharmacodynamics, polypharmacy, comorbidities, adverse drug responses, drug interactions, method of administration, and social and economic issues that impact nutrition and adherence to therapy must be carefully evaluated when prescribing medication to these patients because each of them alone or together may affect the outcome of treatment. Current COPD medications focus mainly on alleviating COPD-related symptoms, so alternative treatment approaches that target the disease progression are being investigated. Considering the importance of inflamm-aging, new anti-inflammatory molecules are being evaluated, focusing on inhibiting the recruitment and activation of inflammatory cells, blocking mediators of inflammation thought to be important in the recruitment or activation of these inflammatory cells or released by these cells. Potential therapies that may slow the aging processes by acting on cellular senescence, blocking the processes that cause it (senostatics), eliminating senescent cells (senolytics), or targeting the ongoing oxidative stress seen with aging need to be evaluated., (© 2023. The Author(s).)

Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4 + and CD8 + T lymphocytes are key players in this process, although the extent of their participation varies according to the patient's endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD., Competing Interests: M.C. participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Abdi Ibrahim, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Edmond Pharma, GlaxoSmithKline, Glenmark, Lallemand, Mankind Pharma, Menarini Group, Mundipharma, Novartis, Pfizer, Sanofi, Teva, Verona Pharma, and Zambon and is or was a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon. N.A.H. received honoraria for serving as advisor or consultant for GSK, AstraZeneca, Sanofi, Regeneron, Boehringer Ingelheim, Verona, Amgen, Genentech, Novartis and Teva. His institution received research grant support of his behalf from GSK, Genentech, Sanofi, Teva, Novartis, and Astra Zeneca. C.P.P. has acted as a consultant to Eurodrug, Recipharm, Glycosynnovation and PrEP Biopharma. C.P.P. also holds equity in Verona Pharma. M.G.M. participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of ABC Farmaceutici, Almirall, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, and Novartis and was a consultant to Chiesi Farmaceutici and GlaxoSmithKline. Her department was funded by GlaxoSmithKline and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2023 Cazzola et al.)

Purpose: To examine the impact of initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in a single device on chronic obstructive pulmonary disease (COPD) exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related healthcare resource utilization (HCRU) and costs in patients with COPD., Methods: Retrospective database analysis of patients with COPD aged ≥40 years who initiated FF/UMEC/VI between September 1, 2017, and December 31, 2018 (index date: first pharmacy claim for FF/UMEC/VI), following evidence of multiple-inhaler triple therapy (MITT) (≥30 consecutive days) in the year prior to index. COPD exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related HCRU and costs were compared between the baseline period (12 months prior to and including index) and follow-up period (12 months following index)., Results: Data from 912 patients (mean [SD] age: 71.2 [8.1], 51.2% female) were included in the analyses. Among the overall cohort, mean count of total COPD exacerbations (moderate or severe) per patient was statistically significantly lower in the follow-up period compared to baseline (1.2 vs 1.4, p=0.001). The proportion of patients with ≥1 COPD exacerbation (moderate or severe) was also statistically significantly lower in the follow-up period compared to baseline (56.4% vs 62.4%, p=0.001). All-cause and COPD-related HCRU were similar during follow-up compared to baseline, although the proportion of patients with COPD-related ambulatory visits was lower during follow-up (p<0.001). COPD-related office visit costs, emergency room visit costs, and pharmacy costs were statistically significantly lower during follow-up compared to baseline (p<0.001; p=0.019; p<0.001, respectively)., Conclusion: In a real-world setting, patients on MITT who subsequently initiated FF/UMEC/VI in a single device had significant reductions in the rate of COPD exacerbations (moderate or severe). Switching to FF/UMEC/VI also resulted in improvements in some HCRU and cost outcomes. These data support the use of FF/UMEC/VI among patients at high risk of exacerbation to reduce future risk and improve outcomes., Competing Interests: The authors declare the following conflicts of interest during the last three years in relation to this manuscript: NAH reports research support from AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Novartis, and Sanofi; and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, and Teva. LGSB is an employee of Optum, which received research funds from GSK to conduct this study, although not for manuscript development. SHB was an employee of Optum at the time of study conduct. ASI is an employee of and holds stocks/shares in GSK. ASI is also an unpaid part-time professor at McMaster University, Hamilton, ON, Canada. MB was a permanent employee of, and held stock/shares in, GSK at the time of study conduct. He is now an employee of Gilead Sciences, Foster City, CA, USA. The authors report no other conflicts of interest in this work., (© 2023 Hanania et al.)

Introduction: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry., Methods: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD., Results: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated., Conclusions: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment., Competing Interests: Declaration of competing interest Alejandro Comellas has consulted for GSK and VIDA Diagnostics. Arianne K. Baldomero is supported by the NIHNational Center for Advancing Translational Sciences Grants KL2TR002492 and UL1TR002494. Jeffrey L. Curtis is supported by R01 HL144718, R01 HL144849, U01 HL137880, and I01 CX001969 and has consulted for AstraZeneca PLC, Novartis AG, and CSL Behring LLC. Richard Casaburi has received consultant fees or honoraria from Boehringer Ingelheim, Glaxo Smith Kline and Inogen. Victor Kim has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from American Board of Internal Medicine. Alejandro A. Diaz is supported by NIH grants R01-HL133137, R01-HL14986; has reported speaker fees from Boehringer Ingelheim, outside the submitted work. Edwin K. Silverman has received grant support from GlaxoSmithKline and Bayer. Surya P. Bhatt is supported by NIH Grants R01HL151421, R21EB027891, and UG3HL155806 and he has served on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. Spyridon Fortis has received grants from American Thoracic Society and Fisher &Paykel and served as a consultant for Genentech. The rest of the authors have no relevant conflicts to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chronic Obstructive Pulmonary Disease (COPD) is a common disease associated with significant morbidity and mortality that is both preventable and treatable. However, a major challenge in recognizing, preventing, and treating COPD is understanding its complexity. While COPD has historically been characterized as a disease defined by airflow limitation, we now understand it as a multi-component disease with many clinical phenotypes, systemic manifestations, and associated co-morbidities. Evidence is rapidly emerging in our understanding of the many factors that contribute to the pathogenesis of COPD and the identification of "early" or "pre-COPD" which should provide exciting opportunities for early treatment and disease modification. In addition to breakthroughs in our understanding of the origins of COPD, we are optimizing treatment strategies and delivery of care that are showing impressive benefits in patient-centered outcomes and healthcare utilization. This special issue of Respiratory Medicine, "COPD: Providing the Right Treatment for the Right Patient at the Right Time" is a summary of the proceedings of a conference held in Stresa, Italy in April 2022 that brought together international experts to discuss emerging evidence in COPD and Pulmonary Rehabilitation in honor of a distinguished friend and colleague, Claudio Ferdinando Donor (1948-2021). Claudio was a true pioneer in the field of pulmonary rehabilitation and the comprehensive care of individuals with COPD. He held numerous leadership roles in in the field, provide editorial stewardship of several respiratory journals, authored numerous papers, statement and guidelines in COPD and Pulmonary Rehabilitation, and provided mentorship to many in our field. Claudio's most impressive talent was his ability to organize spectacular conferences and symposia that highlighted cutting edge science and clinical medicine. It is in this spirit that this conference was conceived and planned. These proceedings are divided into 4 sections which highlight crucial areas in the field of COPD: (1) New concepts in COPD pathogenesis; (2) Enhancing outcomes in COPD; (3) Non-pharmacologic management of COPD; and (4) Optimizing delivery of care for COPD. These presentations summarize the newest evidence in the field and capture lively discussion on the exciting future of treating this prevalent and impactful disease. We thank each of the authors for their participation and applaud their efforts toward pushing the envelope in our understanding of COPD and optimizing care for these patients. We believe that this edition is a most fitting tribute to a dear colleague and friend and will prove useful to students, clinicians, and researchers as they continually strive to provide the right treatment for the right patient at the right time. It has been our pleasure and a distinct honor to serve as editors and oversee such wonderful scholarly work., Competing Interests: Declaration of competing interest To the best of my knowledge as editor and corresponding author for the above manuscript, neither I nor any of the coauthors or editor have any perceived conflict of interest with respect to the subject matter of this paper. This, by necessity, must be a preliminary statement, as I assume each author must at a later date submit a personal COI statement., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a spectrum of pulmonary diseases ranging from normal spirometry to severe COPD., Research Question: Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study?, Study Design and Methods: We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV 1 % predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk., Results: The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV 1 % predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio [HR], 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk., Interpretation: In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function., (Copyright © 2022 American College of Chest Physicians. All rights reserved.)

In 2020, chronic obstructive pulmonary disease (COPD) was the fifth leading cause of death in the United States excluding COVID-19, and its mortality burden has been rising since the 1980s. Smoking cessation, long-term oxygen therapy, noninvasive ventilation, and lung volume reduction surgery have had a beneficial effect on mortality; however, until recently, the effects of pharmacologic therapies on all-cause mortality have been unclear. Inhaled pharmacologic treatments for patients with COPD include combinations of long-acting muscarinic receptor antagonists (LAMAs), long-acting-β 2 - agonists (LABAs), and inhaled corticosteroids (ICS). The recent IMPACT and ETHOS clinical trials reported mortality benefits with ICS/LAMA/LABA triple therapy compared with LAMA/LABA dual therapy. In IMPACT, fluticasone furoate/umeclidinium/vilanterol therapy significantly reduced the risk of on-/off-treatment all-cause mortality vs umeclidinium/vilanterol (hazard ratio, 0.72; 95% CI, 0.53 to 0.99; P=.042). The ETHOS trial found a reduction in the risk of on-/off-treatment all-cause mortality in patients treated with budesonide/glycopyrrolate/formoterol vs glycopyrrolate/formoterol (hazard ratio, 0.51 [0.33 to 0.80]; nominal P=.0035). Both trials included populations of patients with symptomatic COPD at high risk of future exacerbations, and a post hoc analysis of the final retrieved vital status data suggested that the observed mortality benefits are conferred by the ICS component. In conclusion, triple therapy reduces the risk of mortality in patients with symptomatic COPD characterized by moderate or severe airflow obstruction and a recent history of moderate or severe exacerbations. This benefit is likely to be driven by reductions in exacerbations. Future research efforts should focus on improving the long-term prognosis of patients living with COPD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo., Objective: To assess whether dupilumab improves clinical outcomes in QUEST patients with persistent airflow obstruction (PAO) defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio less than 0.7 at baseline., Methods: End points were annualized rate of severe exacerbations, pre and post-bronchodilator forced expiratory volume in 1 second over time, proportion achieving reversal of PAO, and quality of life. Efficacy was evaluated in patients with or without PAO at baseline in subpopulations with eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 25 ppb or eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb., Results: Of 1902 patients enrolled in QUEST, 1039 (55%) had PAO at baseline. Dupilumab vs placebo rapidly and significantly improved lung function in patients with PAO and elevated type 2 inflammatory biomarkers at baseline. Dupilumab improved probability of reversing airflow obstruction (hazard ratio vs placebo 1.616 [95% confidence interval, 1.272-2.052] and 1.813 [1.291-2.546]; both P < .001) and significantly reduced severe exacerbations by 69% (relative risk, 0.411; 95% confidence interval [0.327-0.516]; P < .0001) and by 75% (0.252 [0.178-0.356]; P < .0001) in patients with PAO with eosinophils ≥ 150 cells/µL or FeNO ≥ 25 ppb and eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb, respectively. Similar results were observed in patient subgroups without PAO., Conclusion: In patients with uncontrolled moderate-to-severe asthma, treatment with dupilumab facilitates reversal of PAO status and improves clinical outcomes., Trial Registration: ClinicalTrials.gov identifier: NCT02414854., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status., Methods: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed., Results: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers., Conclusions: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers., Clinical Trial Registration: GSK (CTT116855/NCT02164513)., Competing Interests: Declaration of competing interest DM and DAL are GSK employees and hold GSK stocks/shares. SB is a former GSK employee and holds GSK stocks/shares. GJC has received personal fees from Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, Chiesi, CSA Medical, Eolo, Gala Therapeutics, GSK, Helios Medical, HGE Technologies, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Nuvaira, Olympus, Philips, Pulmonx, Respironics, Respivant Sciences, The Implementation Group and Verona. DMGH has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer and Sanofi, and non-financial support from Boehringer Ingelheim and GSK. MKH reports personal fees from Medscape and Integrity, as well as consulting fees from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Altesa Biopharma and United Therapeutics. She has received royalties from UpToDate, WW Norton and Penguin Random House. She has received payment or honoraria for consultancy from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GSK, Medscape and Integrity. She has served roles on boards or scientific committees for COPD foundation, ALA, Emerson School and GOLD, and has been a volunteer spokesperson for ALA and deputy editor of the ATS journal. 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 holds stock options from Meissa Vaccines and Altesa Biopharma. NAH is the Editor-in-Chief for Respiratory Medicine and was an investigator on the IMPACT study. He reports receiving personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Sanofi Genzyme, Novartis, Regeneron, Genentech, Sunovion, and Mylan for serving as an advisor or consultant. He also received research support from GSK, Boehringer Ingelheim and AstraZeneca. DH has received personal fees from GSK, Boehringer Ingelheim, AstraZeneca, Mylan, Novartis, and Sunovion. Research support from GSK, Boehringer Ingelheim and Mylan. He is a National Board of Directors member for the American Lung Association. PL has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi and GSK. FJM has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, GSK, Novartis, Polarean, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and Verona; grant support from AstraZeneca, Chiesi, GSK and Sanofi/Regeneron; payment or honoraria from UpToDate for participation in COPD CME activities; and participated in an event adjudication committee for MedTronic. FJM states that AstraZeneca, Boehringer Ingelheim and GSK are partners of the SPIROMICS program and partners in the NHLBI CAPTURE validation study; Novartis, Sanofi/Regeneron, Sunovion and Teva are partners of the SPIROMICS program; Theravance/Viatris are partners in the NHLBI CAPTURE validation study. TMS has received research grants from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Compleware, Evidera (PPD), Forest Research Institute (now AstraZeneca), GSK, Novartis, Pearl Therapeutics, Proterix BioPharma, Oncocyte, Sanofi, Seer, Sunovion, Teva, Theravance BioPharma, Vapotherm, Verona Pharma, Restorbio and Westward, and personal fees from GSK, Sunovion, Theravance Biopharma and Vapotherm. DS has received consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GSK, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona. RAW has received personal fees from AstraZeneca, Boehringer Ingelheim, Contrafect, Roche-Genentech, Bristol Myers Squibb, Merck, Verona, Theravance, AbbVie, GSK, Chemerx, Kiniksa, Savara, Galderma, Kamada, Pulmonx, Kinevant, Vaxart, Polarean, Chiesi, 4D Pharma, Puretech, and grant support from AstraZeneca, Sanofi, Verona, Genentech, Boehringer Ingelheim and 4DX imaging. He has received payment for expert testimony from the United States Government and Genentech; and support for attending meetings and/or travel from AstraZeneca. Additionally, he has received editorial support from GSK, AstraZeneca, Boehringer Ingelheim and Merck Foundation; and has served on the Board of Directors/Medical and Scientific Advisory Committee for the COPD Foundation, and on a Scientific Advisory Board for the American Lung Association. RNvZS was an investigator on the IMPACT study and reports receiving personal fees from Aspen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, MSD, Pfizer, Sanofi, Novartis and Roche. NB was an investigator on the IMPACT study and reports receiving consulting fees and serving as a participant in advisory boards for Kamada, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi Genzyme and Novartis, as well as serving as a participant in advisory boards for Teva. He has also received lecture fees for Kamada, AstraZeneca, Boehringer Ingelheim, GSK and Sanofi Genzyme., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The best therapeutic approach to patients with asthma-chronic obstructive pulmonary disease overlap (ACO) is unknown. Current treatment recommendations rely on expert opinions, roundtable discussions, and strategy documents, because patients with ACO have been excluded from most clinical studies in asthma and COPD. Because of the underlying asthma initial therapy, early use of inhaled corticosteroids along with a long-acting bronchodilator is recommended. If maintenance inhaler therapy is not effective, advanced therapies based on phenotyping and identification of treatable traits may be considered., Competing Interests: Disclosure Dr N. Hanania reports receiving consulting fees from GSK, Astra Zeneca, Sadslnofi, Regeneron, Teva, Amgen, Roche/Genentech, Boehringer Ingelheim, and Novartis; his institution has received research support from Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca, Sanofi, Teva, Genentech. M. Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols, and Novartis; consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, pH Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi, and Grifols; and research grants from Grifols., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Asthma and chronic obstructive pulmonary disease (COPD) are common diseases that often overlap. The term asthma-COPD overlap (ACO) has been used to define this entity but there remain several speculations on its exact definition, impact, pathophysiology, and clinical features. Patients with ACO have greater morbidity than those with asthma or COPD alone, but the information on the best therapeutic approach to this group of patients is still limited. Current treatment recommendations rely on expert opinions, roundtable discussions, and strategy documents. It is prudent to examine existing knowledge about ACO and determine the path for future research., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Asthma and chronic obstructive pulmonary disease are considered unique diseases with distinct characteristics. Asthma-chronic obstructive pulmonary disease overlap is a disorder in which the clinical characteristics of asthma and chronic obstructive pulmonary disease coexist. Asthma-chronic obstructive pulmonary disease overlap is a heterogenous condition; patients can have varied clinical presentations. There are significant gender variations among different phenotypes overlap. Age of symptom onset is another important consideration. Severity of symptoms, spirometry findings, smoking history, and type of airway inflammation varies between the different phenotypes. Understanding disease pathophysiology and establishing phenotypic models will improve a precision approach., Competing Interests: Disclosure The authors declare no relevant disclosures pertinent to this article. No funding was received for the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Individuals with Chronic Obstructive Pulmonary Disease (COPD) often develop anxiety and depression, which worsen illness management and prognosis. Physical and psychological symptoms, contextual and illness-related factors display complex reciprocal interactions, which give rise to heterogeneous presentations. Examining the patterns of association between specific physical and psychological symptoms in patients with COPD may help to focus on the precision of the patient-centred care., Research Question: We used network analyses to examine the links between symptoms of COPD, depression and anxiety., Methods: Data from 1587 individuals with COPD from the COPDGene study were included. We estimated a Bayesian Gaussian Graphical Model to highlight the unique associations between symptoms of COPD (assessed with the COPD Assessment Test), depression and anxiety (assessed with the Hospital Anxiety and Depression Scale (HADS), while examining the role of sociodemographic characteristics, lung function tests, and health status., Results: Unique Variable Analysis reduced 14 HADS items to Tension/worry (chronic anxiety), Fear/panic (acute anxiety), Restlessness, Anhedonia, Sadness and Slowing. In network analyses, chest-tightness was related to acute anxiety, while cough and weakness were connected with core depressive symptoms (sadness and lack of pleasure). Chronic anxiety was linked with acute anxiety and depressive symptoms. Findings were confirmed accounting for the role of confounders, including lung function, sex, ethnicity and lifestyle factors. A simulation based on our model yielded distinct predictions about anxiety and depression in two participants with similar COPD severity, but different symptom profiles., Conclusion: Network analyses highlighted specific associations between symptoms of COPD, depression and anxiety. Accounting for symptom-level interactions may help to promote personalized treatment approaches., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: We examined the prevalence of comorbid depression and anxiety in patients with chronic obstructive pulmonary disease (COPD) and their response to eight-weeks of pulmonary rehabilitation (PR)., Methods: Seven hundred thirty four patients with clinically stable COPD completed an eight-week outpatient multidisciplinary PR, comprising 2-h (1-h exercise and 1-h education) per/week. Depression and anxiety, exercise capacity, quality of life (QOL), and dyspnea were measured pre- and post-PR by the incremental shuttle walk test (ISWT), St. George's Respiratory Questionnaire (SGRQ), and modified Medical Research Council (mMRC) scale, respectively. The Depression Anxiety Stress Scale (DASS-21) was completed and patients classified as having clinically significant comorbid anxiety and depression, anxiety alone, depression alone, or with neither., Results: The mean (SD) age of patients was 71 (8.8) years, and 51% were men. Prevalence of pre-PR comorbid depression and anxiety was 34%, anxiety alone 20%, depression alone 5% and neither 41%. The prevalence of stress was 59%. In patients with anxiety and depressive symptoms, total SGRQ score improved from 64.9 (13.8) pre-PR to 50.1 (17.2) post PR (p < 0.001), mMRC score improved from 3.4(1.0) pre-PR to 2.8 (1.1) post PR (p < 0.001), and ISWT distance walked increased from 188.6 (117.6) pre-PR to 248.6 (149.1) post PR, p < 0.001., Conclusion: One in three patients with COPD suffer from comorbid depression and anxiety with a high level of disease burden, reflected by symptoms of elevated dyspnea and impaired QOL. PR improves QOL and exercise capacity, and reduces dyspnea in patients with COPD and comorbid depression and anxiety., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with high rates of hospitalizations, costs, and morbidity. Therefore, hospitalists and the multidisciplinary team (hospital team) need to take a proactive approach to ensure patients are effectively managed from hospital admission to postdischarge. Comprehensive screening and diagnostic testing of patients at admission will enable an accurate diagnosis of COPD exacerbations, and severity, as well as other factors that may impact the length of hospital stay. Depending on the exacerbation severity and cause, pharmacotherapies may include short-acting bronchodilators, systemic corticosteroids, and antibiotics. Oxygen and/or ventilatory support may benefit patients with demonstrable hypoxemia. In preparation for discharge, the hospital team should ensure that patients receive the appropriate maintenance therapy, are counseled on their medications including inhalation devices, and proactively discuss smoking cessation and vaccinations. For follow-up, effective communication can be achieved by transferring discharge summaries to the primary care physician via an inpatient case manager. An inpatient case manager can support both the hospitalist and the patient in scheduling follow-up appointments, sending patient reminders, and confirming that a first outpatient visit has occurred. A PubMed search (prior to 26 January 2021) was conducted using terms such as: COPD, exacerbation, hospitalization. This narrative review focuses on the challenges the hospital team encounters in achieving optimal outcomes in the management of patients with COPD exacerbations. Additionally, we propose a novel simplified algorithm that may help the hospital team to be more proactive in the diagnosis and management of patients with COPD exacerbations.

Introduction: To date, very little is known about the risk factors that contribute to premature discontinuation (dropout) from pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). We examined prevalence and predictors of premature discontinuation in patients who participated in an eight week PR program., Methods: We analyzed a prospectively maintained data-base of patients with COPD who attended a PR program from 2013 to 2019. We included patients 40 years or older with forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) ratio less than 0.7. Subjects were assigned completers or non-completers based on whether they completed the 8-week PR program. Quality of life was measured using the St-George's Respiratory Questionnaire (SGRQ), anxiety using the Anxiety Inventory for Respiratory disease (AIR), dyspnea using the modified Medical Research Council (mMRC) scale, and exercise capacity using the Incremental Shuttle Walk Test (ISWT)., Results: Nine hundred nighty three COPD patients (mean age = 70.82 years, FEV 1  = 59.21% predicted, 51% male) entered the PR program. Of these, 259 (26%) discontinued PR prematurely and 139 (53%) were male. Compared with completers, non-completers had elevated symptoms of dyspnea and anxiety, had reduced exercise tolerance, were younger, and had poorer quality of life at entry (all p < 0.05). On multivariate analysis, the following variables were independently associated with discontinuation from PR: younger age (p < 0.001), elevated symptoms of anxiety (p < 0.001), elevated symptoms of dyspnea (p < 0.01) and reduced exercise tolerance (p < 0.002)., Conclusion: Over a quarter of COPD patients discontinued the PR program prematurely. Discontinuation of PR was associated with younger age, elevated symptoms of dyspnea and anxiety, and reduced exercise capacity, but not with severity of airflow obstruction., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Influenza is a common cause of acute respiratory infection that leads to exacerbation of underlying chronic obstructive pulmonary disease (COPD). To elucidate the short- and long-term effects of influenza in patients with COPD, we examined health care resource utilization (HRU) and costs up to 13 months following influenza infection., Methods: We conducted a retrospective cohort study using U.S. insurance claims data from MarketScan. Patients with an influenza diagnosis during the 2012-2014 influenza seasons and continuous enrollment in a health plan from 12 months before to 13 months after the index influenza diagnosis were identified and propensity score-matched 1:5 to controls without evidence of influenza. COPD- and pneumonia-related outcomes were assessed over 13 months following influenza diagnosis., Results: COPD-associated outcomes after diagnosis were significantly worse in patients with influenza ( n  = 7,087) vs. controls ( n  = 35,435) during the first month (exacerbation: 16.1 vs. 3.4%; outpatient visits: 57.1 vs. 35.2%; emergency department (ED) visits: 10.5 vs. 1.8%; and inpatient visits: 5.6 vs. 0.7%) and months 2-13 (exacerbation: 25.1 vs. 21.1%; outpatient visits: 86.1 vs. 85.8%; ED visits: 20.0 vs. 15.7%; and inpatient visits: 6.5 vs. 5.3%). COPD- and pneumonia-associated costs for months 1 and 2-13 were higher in patients with influenza., Limitations: The study was subject to a residual imbalance between cohorts despite propensity score matching. The use of diagnostic codes to select patients and identify complications could introduce inaccuracies in estimating events., Conclusions: HRU and costs were higher in COPD patients with influenza during the first month and over the entire year following infection. This suggests influenza has an impact on respiratory health in patients with COPD that lasts beyond the acute infection.

COVID-19 has affected millions of patients, caregivers, and clinicians around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads via droplets and close contact from person to person, and there has been an increased concern regarding aerosol drug delivery due to the potential aerosolizing of viral particles. To date, little focus has been given to aerosol drug delivery to patients with COVID-19 treated at home to minimize their hospital utilization. Since most hospitals were stressed with multiple admissions and experienced restricted healthcare resources in the era of COVID-19 pandemic, treating patients with COPD at home became essential to minimize their hospital utilization. However, guidance on how to deliver aerosolized medications safely and effectively to this patient population treated at home is still lacking. In this paper, we provide some strategies and rationales for device and interface selection, delivery technique, and infection control for patients with COPD who are being treated at home in the era of COVID-19 and beyond., Competing Interests: Dr. Ari discloses her relationship with Aerogen Ltd, Boehringer Ingelheim, and Philips Healthcare. Dr. Hanania received honoraria for serving as a consultant or advisory boards for GlaxoSmithKline, Sanofi, Regeneron, Genentech, Novartis, Boehringer Ingelheim, Astra Zeneca, Teva, Amgen, and Mylan pharmaceuticals. His institution receives research grant support from GlaxoSmithKline, Sanofi, Genentech, Gossamer Bio, Boehringer Ingelheim, Novartis, and Astra Zeneca. The authors report no other conflicts of interest in this work., (© 2021 Ari et al.)

Rationale: Depression is a prevalent comorbidity of chronic obstructive pulmonary disease (COPD) that, along with COPD, has been associated with inflammation. An association between inflammation and depression in COPD has not been validated in a large COPD cohort., Methods: Individuals from the University of Pittsburgh SCCOR cohort and the COPDGene cohort with tobacco use history and airway obstruction (FEV 1 /FVC <0.7) were evaluated using the Beck Depression Inventory II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Participants completed symptom-related questionnaires and plasma IL-6 measurements. T -test, Fisher's Exact tests and logistic regression were used for statistical analysis., Results: The SCCOR cohort included 220 obstructed participants: 44% female and 21.4% with elevated depressive symptoms. GOLD staging distribution was predominantly stage I and II. The COPDGene cohort included 745 obstructed participants: 44% female and 13.0% with elevated depressive symptoms. GOLD distribution was predominantly stage II and III. In the SCCOR cohort, correlation between IL-6 and depressive symptoms trended toward significance (p= 0.08). Multivariable modeling adjusted for FEV 1 , age, gender and medical comorbidities showed a significant association (OR = 1.70, 95% CI = 1.08-2.69). IL-6 was significantly associated with elevated depressive symptoms in COPDGene in both univariate (p=0.001) and multivariable modeling (OR = 1.52, 95% CI =1.13-2.04)., Conclusion: Elevated plasma IL-6 levels are associated with depressive symptoms in individuals with COPD independent of airflow limitation and comorbid risk factors for depression. Our results suggest that systemic inflammation may play a significant and possibly bidirectional role in depression associated with COPD., Competing Interests: The authors have no conflicts of interest for this work to disclose., (© 2021 Strollo et al.)

Introduction: Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI)., Methods: Efficacy and safety according to age groups (<65 and ≥65 years) were assessed using data from five clinical trials in patients ≥40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 µg; one 24-week trial with umeclidinium (UMEC) 62.5 µg; and two 12-week trials with UMEC 62.5 µg + FF/VI 100/25 µg. The primary endpoint was trough forced expiratory volume in 1 second (FEV 1 ) obtained 23 and 24 hours after dosing on the last day of the study., Results: A total of 2876 patients <65 years of age and 2148 patients ≥65 years of age were enrolled across all studies of whom 1333 and 1111 patients, respectively, received treatment at the doses presented. Statistically significant and clinically meaningful treatment differences in improvement from baseline in mean trough FEV 1 were reported for active comparators versus placebo at study end for both <65 and ≥65 years subgroups (FF/VI vs placebo: 143 mL and 111 mL; UMEC vs placebo: 110 mL and 123 mL; UMEC + FF/VI vs placebo + FF/VI: 136 mL and 105 mL; p<0.001 for all comparisons). The incidence of adverse events reported for active treatments was similar between age groups., Conclusion: These data provide evidence to support the use of FF/VI, UMEC, or UMEC + FF/VI, all delivered via the ELLIPTA DPI, to treat older (≥65 years) and younger (<65 years) patients with COPD., Competing Interests: NAH has received personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Sanofi Genzyme, Novartis, Regeneron, Genentech, Teva, Amgen, Sunovion, and Mylan for serving as an advisor or consultant. He also received grants research support from Gossamer Bio, GSK, Boehringer Ingelheim, and AstraZeneca. TS, SL, CC, HP and IHB are employees of GSK and hold stock and shares in GSK. SC and DMM were employees of GSK at the time of the study and hold stock and shares in GSK. SC is currently an employee of Dermavant since April 2020. LT is a contingent worker on assignment at GSK. ELLIPTA is owned by/licensed to the GSK group of companies., (© 2021 Hanania et al.)

Background: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited., Methods: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 µg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV 1 ) and health-related quality of life determined by St George's Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [-]) were examined following 12 weeks of GLY 25 µg twice-daily (BID) or placebo treatment., Results: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (-) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV 1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p<0.0001), in the A/D (+) and A/D (-) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was -3.16 (p>0.05) and -3.34 (p<0.001), for the A/D (+) and A/D (-) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (-) group in both treatment arms., Conclusion: GLY 25 µg BID resulted in numerical improvements in FEV 1 , SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments., Competing Interests: NAH received honoraria for serving as a consultant or advisory boards for GlaxoSmithKline, Sanofi, Regeneron, Genentech, Novartis, Boehringer Ingelheim, Astra Zeneca, Teva, Amgen, and Mylan Pharmaceuticals. His institution receives research grant support from GlaxoSmithKline, Sanofi, Genentech, Gossamer Bio, Boehringer Ingelheim, Novartis, and AstraZeneca. AMY received an honorarium for consultation fees from AstraZeneca. AOG was an employee of Sunovion Pharmaceuticals Inc. at the time of the study and is currently an employee of Alexion Pharmaceuticals. MT, TG, SSh, and SSa are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work., (© 2021 Hanania et al.)

Background: Pulmonary rehabilitation (PR) improves exercise capacity in patients with COPD in the short term., Research Question: In patients with COPD, does 8 weeks of PR confer long-term benefits on symptoms of dyspnea, anxiety, and depression, and on quality of life, 2 years after completion?, Study Design and Methods: One hundred and sixty-five patients with COPD completed an 8-week, community-based, comprehensive PR program, comprising 2-h sessions twice weekly. Sessions included aerobic exercise and an educational program. Patients were encouraged to perform daily walking exercise up to 30 min at home. We evaluated a number of outcome measures at baseline, 8 weeks, and 2 years, including the following: dyspnea measured with the modified Medical Research Council (mMRC) questionnaire, quality of life assessed with the St. George's Respiratory Questionnaire (SGRQ), and anxiety measured with the Anxiety Inventory for Respiratory Disease (AIR) and the Depression Anxiety Stress Scale (DASS). In addition, we measured exercise capacity, using the Incremental Shuttle Walk Test (ISWT), at baseline and 8 weeks., Results: Mean age (SD) was 72 (8.6) years; 55% were men. At 8 weeks, improvements in mMRC, SGRQ, ISWT, DASS, and AIR were all statistically significant (P < .001). During the 2-year follow-up, changes observed at 8 weeks were maintained for anxiety symptoms, and for symptoms, impact, and total SGRQ scores. In multivariate analysis, initial elevated levels of dyspnea, depression, anxiety, and decreased exercise capacity predicted greater quality of life improvement at 2 years (all P < .001)., Interpretation: Over a 2-year period, an effective 8-week PR program provides sustained improvement in anxiety and quality of life. Short-term improvements in dyspnea, depression, and stress symptoms at 8 weeks were not maintained at 2 years., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler triple-therapy fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) reduced moderate/severe exacerbation rates vs FF/VI and UMEC/VI in patients with symptomatic COPD and a history of exacerbations, with a similar safety profile., Research Question: Are trial outcomes with single-inhaler triple-therapy FF/UMEC/VI vs FF/VI and UMEC/VI affected by age in patients with symptomatic COPD and a history of exacerbations?, Study Design and Methods: IMPACT was a phase III, double-blind, 52-week trial. Patients ≥ 40 years of age with symptomatic COPD and ≥ 1 moderate/severe exacerbation in the previous year were randomly assigned 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. End points assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough FEV 1 , proportion of St. George's Respiratory Questionnaire (SGRQ) responders (≥ 4 units decrease from baseline in SGRQ total score), and safety., Results: The intention-to-treat population comprised 10,355 patients; 4,724 (46%), 4,225 (41%), and 1,406 (14%) were ≤ 64, 65 to 74, and ≥ 75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates vs FF/VI (% reduction [95% CI]: ≤ 64 years, 8% [-1 to 16]; P = .070; 65-74 years, 22% [14-29]; P < .001; ≥ 75 years, 18% [3-31]; P = .021) and vs UMEC/VI (≤ 64 years, 16% [7-25]; P = .002; 65-74 years, 33% [25-41]; P < .001; ≥ 75 years, 24% [6-38]; P = .012), with greatest rate reduction seen in the 65 to 74 and ≥ 75 years subgroups. Post hoc analyses of CFB in trough FEV 1 and proportion of SGRQ responders at week 52 were significantly greater with FF/UMEC/VI than with FF/VI or UMEC/VI in all subgroups. No new safety signals were identified., Interpretation: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status vs FF/VI and UMEC/VI irrespective of age for most end points, with a similar safety profile., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02164513; URL: www.clinicaltrials.govCTT116855., (Copyright © 2020. Published by Elsevier Inc.)

Introduction : We evaluated risk factors and demographic characteristics of associated with mild cognitive impairment (MCI) in patients with COPD. Methods : 220 individuals with COPD enrolled in a cohort study designed to evaluate anxiety conducted at 16 clinical centers. Cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA), a cutoff score of <26 defined as MCI. Data were collected including spirometry, 6-minute walk test, symptom burden by COPD Assessment Test and dyspnea by Modified Medical Research Council, anxiety measured by Anxiety Inventory of Respiratory Disease, Generalized Anxiety Disorder-7 and Hospital Anxiety Depression Scale, depression by Patient Health Questionnaire-9 and health status by Patient Reported Outcomes Measurement Information System and sleep quality by the Pittsburg Sleep Quality Index. Results : The median age was 65 years and 54% of participants were male. 119(54%) of participants had MCI as classified by MoCA. In multivariable logistic regression, higher odds ratios (OR) (95% confidence interval) for MCI (MoCA) <26 were associated with increased years of age, 1.06 (1.02 -1-09, p<0.003); African-American race, 3.68(1.67-8.11, p<0.001); persistent phlegm, 2 (1.12-3.57, p<0.01) and sleep disturbance, 1.04(1.01-1.08, p<0.01). Conclusions : COPD patients commonly screen positive for MCI. Characteristics associated with MCI included age, African-American race, sleep disturbance and persistent phlegm.

Background: A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective., Methods: Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD., Results: For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 μg/5 μg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 μg/2.5 μg) soft mist inhaler had the highest PrCP (42.3%)., Conclusions: Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A variety of maintenance inhaler therapies are available to treat asthma and COPD. Patient-centric treatment choices require understanding patient preferences for the alternative therapies., Methods: A self-completed web-based discrete choice experiment was conducted to elicit patient preferences for inhaler device and medication attributes. Selection of attributes was informed by patient focus groups and literature review., Results: The discrete choice experiment was completed by 810 patients with asthma and 1147 patients with COPD. Patients with asthma most valued decreasing the onset of action from 30 to 5 min, followed by reducing yearly exacerbations from 3 to 1. Patients with COPD most and equally valued decreasing the onset of action from 30 to 5 min and reducing yearly exacerbations from 3 to 1. Both patients with asthma and patients with COPD were willing to accept an additional exacerbation in exchange for a 15 min decrease in onset of action and a longer onset of action in exchange for a lower risk of adverse effects from inhaled corticosteroids. Patients with asthma and COPD valued once-daily over twice-daily dosing, pressurised inhalers over dry powder inhalers and non-capsule priming over single-use capsules, although these attributes were not valued as highly as faster onset of action or reduced exacerbations., Conclusions: The most important maintenance inhaler attributes for patients with asthma and COPD were fast onset of symptom relief and a lower rate of exacerbations. Concerns about safety of inhaled corticosteroids and device convenience also affected patient preferences but were less important., Competing Interests: Competing interests: IG is an employee of AstraZeneca, the study sponsor. TT, NH and SH are employees of Evidera, which was contracted by AstraZeneca to complete work related to this study. NAH has received honoraria for serving as an advisor/consultant and research funds (to his institution) from AstraZeneca. FJM reports personal fees from Adept, Afferent, Amgen, AstraZeneca, Axon, Axon Communication, Boehringer Ingelheim, Clarion, ConCert, Forest, Genentech, GlaxoSmithKline, Ikaria/Bellerophon, Informa, Janssen, Kadmon, Lucid, Methodist Hospital, Novartis, Nycomed/Takeda, Pearl Therapeutics, Pfizer, Prime, Roche, Sunovion, Theravance, Unity Biotechnology, Veracyte and WebMD; royalty fees from Informa and has spoken on behalf of AstraZeneca and Nycomed/Takeda., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Rationale: In October 2012, the initial phase of the Hospital Readmission Reduction Program imposed financial penalties on hospitals with higher-than-expected risk-adjusted 30-day readmission rates for Medicare beneficiaries with congestive heart failure, myocardial infarction, and pneumonia. We hypothesized that these penalties may also be associated with decreased readmissions for chronic obstructive pulmonary disease (COPD) in the general population before COPD became a target condition (October 2014). Objectives: To determine if implementation of the initial financial penalties for other conditions was associated with a decrease in hospital readmissions for COPD. Methods : We used population-level data to examine patients readmitted for any reason or for COPD within 30 days after an initial hospitalization for COPD. The data source was seven states in the State Inpatient Database. The preimplementation period included calendar years 2006 to 2012. The postimplementation period included 2013 to 2015. Using interrupted time series, the level change was examined, which reflected the difference between the expected and actual readmission rates in 2013. The difference in slopes between the pre- and postimplementation periods was also examined. Results: We identified 805,764 hospitalizations for COPD from 904 hospitals. Overall, 26% of patients had primary insurance other than Medicare. After the intervention, patients had lower rates of all-cause 30-day readmissions (level change, -0.93%; 95% confidence interval [CI], -1.44% to -0.43%; P  = 0.004), which was driven by fewer early readmissions (0-7 d). The postimplementation slope became positive; the difference in slopes was 0.39% (95% CI, 0.28% to 0.50%; P  < 0.001). Patients also had lower rates of COPD-related readmissions (level decrease, -0.52%; 95% CI, -0.93% to -0.12%; P  = 0.02), which was due to decreases in both early and late (8-30 d) readmissions. The postimplementation slope was negative; the difference in slopes was -0.21% (95% CI, -0.35% to -0.07%; P  = 0.009). Conclusions: In patients with COPD and any insurance status, there was an association between the initial phase of the Hospital Readmission Reduction Program and a decrease in both all-cause and COPD-related readmissions even before COPD became a target diagnosis. The large amount of money at risk to hospitals likely resulted in broad behavioral change. Future research is needed to test which levers can effectively reduce readmission rates for COPD.

Purpose of Review: To provide an update on the implementation of precision medicine, based on treatable traits and mechanisms, in the daily clinical management of chronic airways diseases., Recent Findings: Recent insights into the complex and heterogeneous nature of chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma identified several clinical and inflammatory phenotypes. This shifted the management focus of these diseases away from the prototypic disease labels and paved the way for developing novel targeted therapies.The concept of precision medicine aims to link the right patient to the right treatment, while minimizing the risk of adverse effects. Several treatable features ('treatable traits') have now been identified for these chronic airway diseases, including pulmonary, extra-pulmonary, and psychological/lifestyle/environmental traits. As the next step, innovative detection techniques should clarify underlying mechanisms and molecular pathways of these treatable traits and novel reliable point-of-care (composite) biomarkers to help predict responders to targeted therapies must be developed., Summary: Precision medicine links the right patient to the right treatment. Identification of treatable traits in asthma and COPD will help optimize the treatment approach in these heterogeneous diseases. Furthermore, in-depth identification of underlying molecular pathways and reliable biomarkers in chronic airways diseases to guide targeted treatment in individual patients is in progress.

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap., (Copyright © 2019. Published by Elsevier Inc.)

Background: We examined the validity and responsiveness of the Depression Anxiety and Stress Scales-21 (DASS-21) in patients with COPD following an 8-week pulmonary rehabilitation program (PRP)., Methods: Five hundred and fifty-seven patients with clinically stable COPD completed an 8-week outpatient multidisciplinary PRP, comprising 2 h (1 h of exercise and 1 h of education) per week. Anxiety, exercise capacity, quality of life, and dyspnea were measured pre- and post-PRP, utilizing the Anxiety Inventory for Respiratory Disease, Incremental Shuttle Walk Test, St. George's Respiratory Questionnaire, and modified Medical Research Council dyspnea scale, respectively. In addition, we administered the DASS-21 to assess both the validity and responsiveness of this tool compared with other, well-established metrics., Results: The mean (SD) age of participants was 71.6 (9.4) years, and 49% were women. The DASS-21 reflected responsiveness to pulmonary rehabilitation. Among participants with a high depression score (> 9), the depression subscale score fell from 18.62 pre-PRP to 13.12 post-PRP (P < .001). Similarly, among participants with a high anxiety score (> 7), the anxiety subscale fell from 14.60 pre-PRP to 10.99 post-PRP (P < .001). Likewise, among participants with a high stress score (> 14), the stress subscale score fell from 23.51 pre-PRP to 16.34 post-PRP (P < .001). Among these subsamples, the effect size was medium at 0.49 for depression and 0.54 for anxiety, and large at 0.81 for stress. The change in DASS-21 subset (depression, anxiety, and stress) correlated with the change in total SGRQ score, at P < .001., Conclusions: The DASS-21 has acceptable validity and is a responsive scale for use in PRP in patients with COPD., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Dyspnea is a distressing, debilitating, and near-ubiquitous symptom affecting patients with COPD. In addition to the functional consequences of dyspnea, which include activity limitation and reduced exercise tolerance, it is important to consider its psychological impact on patients with COPD, such as onset of depression or anxiety. Moreover, the anticipation of dyspnea itself can have a significant effect on patients' emotions and behavior, with patients frequently self-limiting physical activity to avoid what has become the hallmark symptom of COPD. Dyspnea is, therefore, a key target for COPD treatments. Pharmacologic treatments can optimize respiratory mechanics, provide symptom relief, and reduce patients' increased inspiratory neural drive to breathe. However, it is important to acknowledge the value of non-pharmacologic interventions, such as pulmonary rehabilitation and patient self-management education, which have proven to be invaluable tools for targeting the affective components of dyspnea. Furthermore, it is important to encourage maintenance of physical activity to optimize long-term patient outcomes. Here, we review the physiological and psychological consequences of activity-related dyspnea in COPD, assess the efficacy of modern management strategies in improving this common respiratory symptom, and discuss key unmet clinical and research needs that warrant further immediate attention., Competing Interests: NAH has received honoraria for serving on an advisory board or as a consultant for Genentech Inc., Roche, Sunovion Pharmaceuticals Inc., Novartis AG, AstraZeneca plc, and GlaxoSmithKline plc. His institution has received research grants on his behalf from Genentech, GlaxoSmithKline plc, Boehringer Ingelheim GmbH, Mylan., Sunovion Pharmaceuticals Inc., and AstraZeneca plc. DEO serves as a consultant to AstraZeneca plc, Boehringer Ingelheim GmbH, GlaxoSmithKline plc, and Novartis AG, and serves on the advisory boards of AstraZeneca plc, and Boehringer Ingelheim GmbH. His institution has received grant support from Boehringer Ingelheim GmbH and Novartis AG. DEO co-edited a book titled Dyspnea: Mechanisms, Measurement, and Management, 3rd edition, published by CRC Press, Taylor and Francis Group, and may receive royalties from sales of this book. The authors report no other conflicts of interest in this work.

Many patients with chronic obstructive pulmonary disease (COPD) continue to experience exacerbations despite receiving standard-of-care treatments. Novel approaches to COPD treatment focus on understanding and targeting molecular mechanisms of airway inflammation, airway obstruction, remodeling and lung destruction. Several identified phenotypes and endotypes of COPD will pave the future path for a more personalized approach to therapy. Although well known to be associated with neutrophilic inflammation, COPD may also be driven by eosinophilic inflammation both at stable states and during exacerbation. Targeting eosinophilic inflammation has been successful in managing severe eosinophilic asthma and may hold promise in certain phenotypes of COPD. The most promising biologic treatments at an advanced stage of development are agents blocking interleukin (IL)-5 or its receptor. This review examines our current understanding of the eosinophilic inflammation in COPD and the rationale for IL-5 targeting agents., Competing Interests: DKN has no conflicts of interest to disclose in this work. NAH received honoraria for serving as consultant or on advisory boards for GSK, Astra Zeneca, Sanofi/Regeneron, Novartis, Boehringer Ingelheim, Sunovion, Mylan and Gossamer Bio. His institutions have received research grant support on his behalf from Astra Zeneca, GSK, Boehringer Ingelheim.

Objectives: To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms., Methods: Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms., Key Results: Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02)., Conclusions: Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics., Primary Funding Source: National Institutes of Health and The COPD Foundation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Over the last few years, there has been a renewed interest in patients with characteristics of both asthma and COPD. Although the precise definition of asthma-COPD overlap (ACO) is still controversial, patients with overlapping features are frequently encountered in clinical practice, and may indeed have worse clinical outcomes and increased health-care utilization than those with asthma or COPD. Therefore, there is a critical need to set a framework for the therapeutic approach of such patients. There are key distinctions in the therapy between asthma and COPD, particularly regarding the initial choice of therapy. However, there is considerable overlap in the use of existing medications for both diseases. Furthermore, novel therapies approved for asthma, such as monoclonal antibodies, may have a role in patients with COPD and ACO. The use of biomarkers, such as peripheral blood eosinophils, exhaled nitric oxide, and serum IgE, may help in selecting appropriate therapies for ACO. In this review, we provide an overview of available treatments for both asthma and COPD and explore their potential role in the treatment of patients with ACO., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Formoterol fumarate inhalation solution (FFIS; Perforomist ® ) is a long-acting β 2 -agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients., Methods: This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry., Results: The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ≥1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrating that FFIS was noninferior to placebo. No respiratory deaths were observed in the FFIS group. Adverse events were similar for FFIS vs placebo (patients with ≥1 treatment-emergent adverse events: 374 [69.1%] vs 369 [69.6%], respectively). Compared with placebo, FFIS demonstrated statistically greater improvements from baseline in trough FEV 1 , FVC, percent predicted FEV 1 , and patient-reported outcomes (Transition Dyspnea Index)., Conclusions: Nebulized FFIS was noninferior to placebo with respect to safety in patients with moderate-to-severe COPD. Additionally, fewer treatment withdrawals and larger lung function improvements were observed with FFIS compared with placebo when added to other maintenance COPD therapies., Competing Interests: Disclosure NAH received fees as a consultant or serving on advisory board from Roche/Genentech, Novartis, Boehringer Ingelheim, Mylan, and AstraZeneca and grant support from GlaxoSmith-Kline, Mylan, Boehringer Ingelheim, and Roche/Genentech. SS received research support from AstraZeneca and Mylan; he was on advisory committees, a consultant, and/or a speaker for Aradigm, AstraZeneca, Bayer Schering Pharma, Boehringer Ingelheim, Cempra, CSL, Behring, GlaxoSmithKline, Merck, Invacare, Pulmonx, Sunovion, and Theravance Biopharma. AK is an employee of Mylan Inc., USA. JKW, JS, and DN are employees of Mylan Pharma UK Ltd. The authors report no other conflicts of interest in this work.