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Introduction: Accurate evaluation of exacerbation frequency is an essential part of COPD assessment. But relying on just the prior-year exacerbation history may not capture the full picture of risk given the inherent year-to-year fluctuations in exacerbation rates. This study aimed to evaluate the predictive performance of models incorporating the 3-year exacerbation history based on electronic medical record., Materials and Methods: This retrospective cohort study included 86,501 COPD hospitalized patients in Beijing from 2008 to 2014. The annual frequency of COPD exacerbation hospitalizations over a 3-year period after the index hospitalization was calculated, with patients segmented into seven distinct exacerbation trajectory groups. Logistic regression was used to evaluate the predictive capability of the 3-year exacerbation history for exacerbation readmission in the fourth year. Predictors included age, sex, comorbidities, and exacerbation hospitalization in previous 1-3 years. Model performance was evaluated using area under the receiver operating characteristic curve (AUC)., Results: Of the studied patients, 56.5% were men, and the mean age (SD) was 73.8 (10.3) years. The overall readmission rate for COPD exacerbation was 0.31 per person-year, with only 3.8% of patients persistently readmitted over three consecutive years. The 3-year trajectory of exacerbation frequency was associated with exacerbation risk in the fourth year. Compared to just the prior year, the inclusion of a 3-year exacerbation hospitalization history notably improved prediction accuracy, with AUC elevating from 0.731 (0.724-0.739) to 0.786 (0.779-0.792)., Conclusion: These results unveil the fluctuating nature of COPD exacerbation hospitalization frequency across years and demonstrate that integrating a more comprehensive 3-year exacerbation history significantly refines the prediction model for future risk, thus providing a more nuanced and actionable insight for clinical care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2023 guidelines proposed important changes to the stratification of disease severity using the "ABCD" assessment tool. The highest risk groups "C" and "D" were combined into a single category "E" based on exacerbation history, no longer considering symptomology., Purpose: We quantify the differential disease progression of individuals initially stratified by the GOLD 2022 "ABCD" scheme to evaluate these proposed changes., Patients and Methods: We utilise data collected from 1529 users of the myCOPD mobile app, a widely used and clinically validated app supporting people living with COPD in the UK. For patients in each GOLD group, we quantify symptoms using COPD Assessment Tests (CAT) and rate of exacerbation over a 12-month period post classification., Results: CAT scores for users initially classified into GOLD C and GOLD D remain significantly different after 12 months (Kolmogorov-Smirnov statistic = 0.59, P = 8.2 × 10 -23 ). Users initially classified into GOLD C demonstrate a significantly lower exacerbation rate over the 12 months post classification than those initially in GOLD D (Kolmogorov-Smirnov statistic = 0.26; P = 3.1 × 10 -2 ; all exacerbations). Further, those initially classified as GOLD B have higher CAT scores and exacerbation rates than GOLD C in the following 12 months., Conclusion: CAT scores remain important for stratifying disease progression both in-terms of symptomology and future exacerbation risk. Based on this evidence, the merger of GOLD C and GOLD D should be reconsidered., Competing Interests: Thomas MA Wilkinson (TMAW) reports a relationship with my mHealth Limited that includes: employment. Adam Kirk reports a relationship with my mHealth Limited that includes: employment. TMAW is Chief Science Officer and cofounder of my mHealth, the developer of the myCOPD app. He has a patent pending to my mHealth. AK is the Medical Director and Data Protection Officer of my mHealth. All other authors declare no competing interests in this work., (© 2023 Duckworth et al.)

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV 1 ) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV 1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV 1 and mean annual exacerbation rate., (© 2023. The Author(s).)

Background: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients., Objectives: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD., Methods: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life., Results: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes., Conclusions: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Rationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype., Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death., Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls)., Measurements: We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George's Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20., Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point -1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability., Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD., Competing Interests: CBC has consulted with PulmonX, has received research funding from Equinox Fitness Clubs, Amgen and was employed part-time by the GlaxoSmithKline Global Respiratory Franchise, and reports personal fees from GlaxoSmithKline, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, NHLBI and Department of Veterans Affairs, outside the submitted work. JLC is supported by Merit Review award I01 CX000911 from the Department of Veterans Affairs, and reports grants from the Department of Defense, the National Institutes of Health, and from MedImmune Corporation, Ltd., and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NIAID, grants from Department of Veterans Affairs, grants from Department of Defense, personal fees from AstraZeneca, outside the submitted work. REK has no conflicts other than NHLBI contracts. CHM has NIH grants NHLBI R01HL122438-02S1 and K23 HL128936-01; personal fees, non-financial support and COPD Ad Boards, Steering Committee (honoraria, travel support) from AtraZeneca, IPF Steering Committee (publication) from Afferent/Merck, personal fees, non-financial support and COPD Advisory Board (honorarium travel) support; ILD DSMB, IPF Steering Committee, Study presentations (honoraria, travel support, publication) from Boheringer Ingelheim, teleconference without compensation from Bristol Myers Squibb, COPD Ad Board (travel support) from Chiesi, personal fees and non-financial support from Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and COPD Ad Boards, Steering Committee, DSMB (honoraria and travel support) from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MDMagazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education, Steering Committee without compensation from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, DSMB and Steering Committee without compensation from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, teleconference without compensation from twoXR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and PF Ad Board (travel support) and NIH study in kind suppoRt from Zambon, non-financial support from ProTerrix Bio, personal fees from IQVIA, outside the submitted work. CM does not report any conflicts of interest. RB served on the advisory boards (GlaxoSmithKline, Boehringer Ingelheim, and Mylan Pharmaceuticals) and received research grants from GlaxoSmithKline and Boehringer Ingelheim, and reports personal fees from GlaxoSmithKline, personal fees from Boehringer Ingelheim, personal fees from Mylan Pharmaceuticals, grants from GlaxoSmithKline, grants from Boehringer Ingelheim, outside the submitted work. WO’N does not report any conflicts of interest. EAH a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, and reports personal fees from VIDA Diagnostics, during the conduct of the study. DC has grants from the NIH, reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study and no other conflicts. MQ reports no conflicts. GC reports grants from Boehringer-Ingelheim, Novartis, Astra Zeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, Pulmonx, personal fees from HE Health Care Solutions, Inc, Amirall, Boehringer-Ingelheim, Holaira. MTD reports receiving grants from the NIH, the Department of Defense, and the American Heart Association; consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Astra Zeneca, Yungjin, PneumRx/BTG, Pulmonx, Genentech, Boston Scientific, Quark Pharmaceuticals, Mereo and received grants from American Lung Association and NIH, and reports grants from NIH, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Boston Scientific, grants from American Lung Association, grants from Department of Defense, grants from Department of Veterans Affairs, personal fees from Mereo, personal fees from Quark, contracted clinical trial from Gala and Nuvaira, outside the submitted work. MKH has consulted for GSK, Boehringer Ingelheim and AstraZeneca, has received research support from Novartis and Sunovion and reports grants from NIH, NHLBI, and from COPD Foundation, during the conduct of the study; and Consulting for GSK, BI, Mylan, Merck and AstraZeneca, research support from Sunovion and Novartis. NNH reports grants and personal fees from AstraZeneca, GSK, Mylan, Boehringer Ingelheim, grants from NIH, COPD Foundation, outside the submitted work. JAK has received research grants from NIH and the Patient Centered Outcomes Research Institute. SCL reports grants from NIH/NHLBI, during the conduct of the study. SPP reports grants from MIH, HNLBI, during the conduct of the study. The authors report no other conflicts of interest in this work. RGB has grants from the NIH, Foundation for the NIH, COPD Foundation and Alpha-1 Foundation, and reports grants, personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. FJM reports grants from NHLBI, National Institutes of Health, personal fees from Continuing Education, personal fees from Forest Laboratories, Janssen, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, Puerto Rico Thoracic Society, outside the submitted work, and reports personal fees from Afferent/Merck, personal fees from American Thoracic Society, grants, personal fees, non-financial support from AstraZeneca, personal fees from Bayer, non-financial support, COPD Advisory Board (honorarium travel) support; ILD DSMB, IPF Steering Committee, Study presentations (honoraria, travel support, publication) from Boehringer Ingelehim, personal fees from ProTerrix Bio, personal fees from Bridge Biotherapeutics, personal fees, non-financial support from Chiesi, personal fees from Gala, personal fees, non-financial support, personal fees from Genentech, grants, personal fees, non-financial support from GlaxoSmithKline, grants, personal fees from Nitto, personal fees from ProMedior, personal fees from ProMetic, personal fees from Patara/Respivant, personal fees from Biogen, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees, non-financial support from Sunovion, personal fees, non-financial support from Teva, personal fees from Veracyte, teleconference without compensation from Bristol Myers Squibb, twoXR, personal fees and non-financial support from Canadian Respiratory Society, CME Outfitters, Inova Fairfax, MDMagazine, NYP Methodist Hospital Brooklyn, Miller Communications, Rare Diseases Healthcare Communications, Sanofi/Regeneron, CSL Behring, Novartis, WebMD/MedScape, personal fees from France Foundation, New York University, Rockpointe Communications, University of Birmingham Alabama, Vindico, Dartmouth University, DSMB and Steering Committee without compensation from Biogen, and IPF Ad Board (travel support) and NIH study in kind support from Zambon, during the conduct of the study. PGW reports personal fees from Glenmark Pharmaceuticals, personal fees from GSK, personal fees from NGM Pharma, personal fees from Amgen, Regeneron, 23andMe, Theravance, AstraZeneca, Sanofi, Glenmark Pharmaceuticals, Theravance, NGM Pharma, Amgen, and Genentech, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Cooper et al.)

COPD is associated with significant morbidity and is one of the leading causes of death worldwide. Periods of exacerbation, the acute worsening of symptoms, are interspersed throughout the disease's natural history and can result in increased treatment burden and hospitalization for patients with COPD. The frequency of exacerbations varies between countries, with both epidemiological studies and randomized controlled trials (RCTs) showing significant differences in observed prevalence rates. Differences in study design and the healthcare setting are likely to contribute to differences in exacerbation frequency, however the perceived rate of exacerbations in Japan is currently lower then the rest of the world. This review identified nine cohort studies and five RCTs that reported COPD annual exacerbation rates in Japan in the ranges of 0.1-2.1 and 0.33-1.79, respectively. The difference in exacerbation rate between studies appeared greater than the difference between Japan and Western countries, likely because of disparities between settings, design, and inclusion criteria. Of these, only one (Understanding the Long-Term Impacts of Tiotropium) had uniform inclusion criteria across different regions. This study found that the annual rate of exacerbation events per patient in Japan was 0.61, compared with 0.85 worldwide in the placebo groups. This review summarizes the published rates of COPD exacerbations in Japan and the rest of the world and explores the hypotheses as to why rates in Japan might be lower than other countries. These include access to medical care, variance in the associated morbidity profile, environmental factors, diagnostic crossover with related diseases, and differences in study design (including the underreporting of COPD exacerbations in Japan). Understanding the reasons why COPD exacerbation rates appear lower in Japan could help clinicians to recognize and modify treatment behaviors, which may lead to improved patient outcomes in all populations., Competing Interests: Disclosure TI, AA, MJ, and PJ are employees of GlaxoSmithKline (GSK) and hold stock/shares in GSK. MN has received research grants from Nippon Boehringer Ingelheim, AstraZeneca, and Novartis Japan, as well as personal fees from Nippon Boehringer Ingelheim. The authors report no other conflicts of interest in this work.

In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol., (Copyright © 2016 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd.)

Objective: To determine the effect of changing anticholinergic therapy in patients with COPD from ipratropium to tiotropium on pulmonary function., Methods: We examined records of patients prescribed high-dose ipratropium, who were subsequently converted to tiotropium. Spirometric values were obtained within 2 days of the change in medication and after 56 to 224 days of the switch to tiotropium., Results: 15 subjects were documented to have filled a prescription for ipratropium-containing medications the month prior to the change. Medication compliance over the 6 months prior to the switch in these patients was 72% +/- 31% (mean +/- SD) for ipratropium compared to 87% +/- 14% for tiotropium over the 6-month period after the switch (P = 0.1). FEV(1) improved from 1.12 +/- 0.39 L at baseline to 1.37 +/- 0.49 L after the change to tiotropium (P = 0.01). FVC also improved from 2.45 +/- 0.73 L at baseline to 2.72 +/- 0.69 L after the change (P = 0.04). Maximal voluntary ventilation was also increased from 39.67 +/- 10.7 L/min to 45.13 +/- 15.8 L/min (P = 0.045)., Conclusions: We conclude that replacing high-dose ipratropium with tiotropium therapy significantly improves pulmonary function in a clinical setting.