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Background: Alterations in body weight and composition are common in patients with chronic obstructive pulmonary disease (COPD) and are independent predictors for morbidity and mortality. Low vitamin D status is also more prevalent in patients with COPD compared to controls and has been related to lower lung function, muscle atrophy and impaired musculoskeletal function. This study aimed to evaluate the association between vitamin D levels and status with body composition (BC), as well as with its changes over time., Patients and Methods: Patients with COPD and controls without COPD, participating in the Individualized COPD Evaluation in relation to Ageing (ICE-Age) study, a prospective observational study, were included. Plasma 25-hydroxyvitamin D (25(OH)D) was measured at baseline and BC was measured by dual-energy X-ray absorptiometry scan, at baseline and after two years of follow-up. Multiple linear regression analyses were performed to assess the relationships between 25(OH)D (nmol/l) and longitudinal changes in BMI, fat-free mass index (FFMI), fat mas index (FMI) and bone mineral density (BMD)., Results: A total of 192 patients with COPD (57% males, mean ± SD age, 62 ± 7, FEV1, 49 ± 16% predicted) and 199 controls (45% males, mean ± SD age 61 ± 7) were included in this study. Vitamin D levels were significantly lower in patients with COPD (64 ± 26 nmol/L, 95% CI 60-68 nmol/L versus 75 ± 25 nmol/L, 95% CI 72-79 nmol/L) compared to controls. Both patients and controls presented a significant decline in FFMI and T-score hip, but vitamin D level or status did not determine differences in BC or changes in BC over time in either COPD or controls., Conclusion: Vitamin D status was not associated with BC or longitudinal changes in BC. However, vitamin D insufficiency and low BMD were more prevalent in patients with COPD compared to controls., Competing Interests: FF reports grants and personal fees from AstraZeneca, grants, and personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, personal fees from Pieris, grants and personal fees from Sanofi, outside the submitted work. MAS reports grants and/or fees from Netherlands Lung Foundation Netherlands, Stichting Astma Bestrijding, Boehringer Ingelheim, AstraZeneca, Chiesi, GSK, Sanofi and TEVA, all paid to the institution and all outside the submitted work. LEGWV reports personal fees for lectures and/or advisory boards from AstraZeneca, GSK, Chiesi, Pulmonx, Novartis, Boehringer, Menarini, Grifols and reports research grants from AstraZeneca paid to the institution, all outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Minter et al.)

Introduction: In patients with chronic obstructive pulmonary disease (COPD), loneliness and social isolation are associated with increased morbidity and decreased mobility, self-reliance, and health-related quality of life. Social support has been shown to improve these outcomes., Aims: This cross-sectional study aimed to investigate the level of experienced social support and the clinical outcomes associated with inadequate social support among patients with COPD with a resident loved one., Methods: Level of social support was assessed with the Medical Outcomes Study - Social Support Survey (MOS-SSS) in patients with COPD with a resident loved one. Patients were sub-grouped into adequate or inadequate social support. Multiple clinical outcomes were assessed, including lung function, degree of dyspnoea, health status, symptoms of anxiety and depression, the degree of care dependency, functional status, and mobility., Results: The study included 191 Dutch patients with COPD (53.4% men, age: 65.6 ± 8.9 years, FEV 1 : 47.3 ± 17.7% predicted). Eighteen percent of the patients reported inadequate social support. Patients with inadequate social support reported a significantly symptom severity of COPD (p = 0.004), a higher care dependency level (p = 0.04) and a higher level of depression (p = 0.004) compared to patients with adequate social support. Other traits were comparable for both groups., Conclusion: Patients with COPD with a resident loved one who perceive an inadequate level of social support are more likely to report a higher impact of COPD, a higher care dependency and symptoms of depression. Other characteristics are comparable with patients who perceive adequate social support., 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 Elsevier Ltd. All rights reserved.)

Rationale: A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life among patients with chronic obstructive pulmonary disease (COPD) that is not fully accepted in regulatory decision making, hampering drug development. Objectives: To demonstrate, as we previously asserted (Casaburi COPD 2022;9:252), that constant work rate cycling endurance time is an appropriate exercise endurance measure in patients with COPD. Methods: To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2,166 subjects) and 15 exercise training (3,488 subjects) studies (Casaburi COPD 2022;9:520). Results: Construct validity was demonstrated: 1 ) peak physiologic and perceptual responses were similar for constant work rate and incremental cycling; 2 ) after bronchodilator therapy, there were greater increases in endurance time in patients with more severe airflow limitation; 3 ) after exercise training, endurance time increases were similar across airflow limitation severities; and 4 ) there were correlations between changes in endurance time and changes in mechanistically related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points after the intervention. Responsiveness was confirmed, with significant increases in endurance time after active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation and after exercise training. On the basis of regression analysis using multiple anchor variables, the minimum important difference for endurance time increase is estimated to be approximately 1 minute. Conclusions: Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to the evaluation of treatment benefit supporting regulatory decision making and evidence-based therapeutic recommendations.

Introduction: Patients with advanced emphysema eligible for bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBV) are characterized by severe static lung hyperinflation, which can be considered a treatable trait. Other treatable traits (TTs), which are assumed to be present in this highly selected patient group, have not been studied in detail nor how they may affect health-related quality of life (HRQL)., Aims: We aimed to evaluate a spectrum of TTs in COPD patients eligible for EBV treatment and their association with HRQL., Methods: The SoLVE study (NCT03474471) was a prospective multicenter randomized controlled trial to examine the impact of pulmonary rehabilitation in COPD patients receiving EBV. The presence/absence of 16 TTs was based on pre-defined thresholds. HRQL was assessed with the St. George's Respiratory Questionnaire (SGRQ). Subjects were stratified into two groups, using the median split method, into higher or lower SGRQ total score. Logistic regression assessed the odds ratio (OR) of having a higher SGRQ total score per TT., Results: Ninety-seven subjects were included, the mean number of TTs per patient was 8.1 ± 2.5. Low physical activity (95%), poor exercise capacity (94%) and severe fatigue (75%) were the most prevalent TTs. The sum of TTs present in a subject was associated with the SGRQ total score (r = 0.53; p < 0.001). Severe fatigue, depression, and anxiety were predictors of having a higher SGRQ total score., Conclusions: A high prevalence and co-occurrence of multiple TTs were identified in emphysema patients eligible for EBV. Patients with a higher number of TTs were more likely to have worse HRQL., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Evaluating variability and stability using measures for nonlinear dynamics may provide additional insight into the structure of the locomotor system, reflecting the neuromuscular system's organization of gait. This is in particular of interest when this system is affected by a respiratory disease and it's extrapulmonary manifestations. This study assessed stride-to-stride fluctuations and gait stability in patients with chronic obstructive pulmonary disease (COPD) during a self-paced, treadmill 6-minute walk test (6MWT) and its association with clinical outcomes. In this cross-sectional study, eighty patients with COPD (age 62±7y; forced expiratory volume in first second 56±19%predicted) and 39 healthy older adults (62±7y) were analyzed. Gait parameters including stride-to-stride fluctuations (coefficient of variation (CoV), predictability (sample entropy) and stability (Local Divergence Exponent (LDE)) were calculated over spatiotemporal parameters and center of mass velocity. Independent t-test, Mann-Whitney U test and ANCOVA analyses were conducted. Correlations were calculated between gait parameters, functional mobility using Timed Up and Go Test, and quadriceps muscle strength using dynamometry. Patients walked slower than healthy older adults. After correction for Speed, patients demonstrated increased CoV in stride length (F(1,116) = 5.658, p = 0.019), and increased stride length predictability (F(1,116) = 3.959, p = 0.049). Moderate correlations were found between mediolateral center of mass velocity LDE and normalized maximum peak torque (ρ = -0.549). This study showed that patients with COPD demonstrate alterations in stride length fluctuations even when adjusted for walking speed, highlighting the potential of nonlinear measures to detect alterations in gait function in patients with COPD. Association with clinical outcomes were moderate to weak, indicating that these clinical test are less discriminative for gait alterations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The influence of the ActiGraph® processing criteria on estimating step counts in chronic obstructive pulmonary disease (COPD) remains uncertain. This study aimed to assess the influence of filters, epoch lengths and non-wearing time (NWT) algorithms on steps/day in people with COPD. ActiGraph GT3X+ was worn on the waist for seven days. Steps were detected using different filters (normal and low-frequency extension [LFE]), epoch lengths (15s and 60s), and NWT algorithms (Choi and Troiano). Linear mixed-effects model was applied to assess the effects of filter, epoch length, NWT algorithm on steps/day. Lin's concordance correlation and Bland-Altman were used to measure agreement. A total of 136 people with COPD (107 male; 69 ± 8 years; FEV 1 51 ± 17% predicted) were included. Significant differences were found between filters ( p  < 0.001), but not between epoch lengths or NWT algorithms. The LFE increased, on average, approximately 7500 steps/day compared to the normal filter ( p  < 0.001). Agreement was poor (<0.3) and proportional bias was significant when comparing steps/day computed with different filters, regardless of the epoch length and NWT algorithm. Filter choice but not epoch lengths or NWT algorithms seem to impact measurement of steps/day. Future studies are needed to recommend the most accurate technique for measuring steps/day in people with COPD.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that is associated with significant morbidity, mortality, and healthcare costs. The burden of respiratory symptoms and airflow limitation can translate to reduced physical activity, in turn contributing to poor exercise capacity, muscle dysfunction, and body composition abnormalities. These extrapulmonary features of the disease are targeted during pulmonary rehabilitation, which provides patients with tailored therapies to improve the physical and emotional status. Patients with COPD can be divided into metabolic phenotypes, including cachectic, sarcopenic, normal weight, obese, and sarcopenic with hidden obesity. To date, there have been many studies performed investigating the individual effects of exercise training programs as well as nutritional and pharmacological treatments to improve exercise capacity and body composition in patients with COPD. However, little research is available investigating the combined effect of exercise training with nutritional or pharmacological treatments on these outcomes. Therefore, this review focuses on exploring the potential additional beneficial effects of combinations of exercise training and nutritional or pharmacological treatments to target exercise capacity and body composition in patients with COPD with different metabolic phenotypes., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: Bronchoscopic lung volume reduction (BLVR) is a novel and effective treatment for a specific phenotype of chronic obstructive pulmonary disease (COPD) characterized by advanced emphysema with static lung hyperinflation and severe breathlessness. This review aims to provide an overview of the recent advances made in BLVR., Recent Findings: For achieving optimal outcomes with BLVR, patient selection and target lobe identification is crucial. BLVR has recently also been established to improve pulmonary function, exercise capacity and quality of life in COPD patients falling outside the standard treatment criteria, including patients with moderate hyperinflation, chronic hypercapnic failure or with very low diffusion capacity. In a cluster analysis, target lobe characteristics like emphysema destruction, air trapping and perfusion were found to be important discriminators between responders and non-responders. A potential survival benefit has been demonstrated in BLVR-treated patients when compared to non-treated patients. Long-term outcomes showed sustained outcomes of BLVR; however, effects decline over time, probably due to disease progression., Summary: BLVR using one-way endobronchial valves has become a guideline treatment offered in specialized intervention centres for a specific subgroup of COPD patients. Recent studies further characterize responders, describe extrapulmonary effects of BLVR and show positive long-term outcomes and a potential survival benefit., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) can have a negative impact on functional capacity, symptoms and health-related quality of life (HRQOL). This study aimed to i) investigate the recovery of muscle strength, functional capacity, symptoms, and HRQOL in patients after a severe AECOPD; ii) compare with matched patients with stable COPD (SCOPD); and iii) assess whether these assessments at hospital discharge could discriminate patients' risk for future events., Methods: This observational study assessed patients with AECOPD during hospital discharge (T1) and one month after discharge (T2). Patients with SCOPD were assessed once. Quadriceps force, handgrip strength, short physical performance battery (SPPB), 6-min walk distance (6 MWD), COPD assessment test (CAT), London chest activity of daily living (LCADL), modified medical research council, checklist individual strength-fatigue, patient health questionnaire, and physical activity (Actigraph) were measured. Exacerbation-related readmission and mortality within six months and 1-year were collected., Results: Forty-four patients with AECOPD were matched with 44 patients with SCOPD. At T2, a significant improvement was found for the SPPB total score, 6 MWD, CAT score, and LCADL score. Compared to patients with SCOPD, a worse LCADL score was found at T2 in patients with AECOPD. Patients with AECOPD that were readmitted or died had a worse SPPB classification and five-repetition sit-to-stand test at T1., Conclusion: Patients after severe AECOPD improved in functional capacity and HRQOL one month after hospital discharge, but ADL performance was still worse compared to SCOPD. Patients who were readmitted or died had significantly worse scores on functional tests at hospital discharge., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Asthma and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. Despite all available diagnostics and treatments, these conditions pose a significant individual, economic and social burden. Artificial intelligence (AI) promises to support clinical decision-making processes by optimizing diagnosis and treatment strategies of these heterogeneous and complex chronic respiratory diseases. Its capabilities extend to predicting exacerbation risk, disease progression and mortality, providing healthcare professionals with valuable insights for more effective care. Nevertheless, the knowledge gap between respiratory clinicians and data scientists remains a major constraint for wide application of AI and may hinder future progress. This narrative review aims to bridge this gap and encourage AI deployment by explaining its methodology and added value in asthma and COPD diagnosis and treatment., Areas Covered: This review offers an overview of the fundamental concepts of AI and machine learning, outlines the key steps in building a model, provides examples of their applicability in asthma and COPD care, and discusses barriers to their implementation., Expert Opinion: Machine learning can advance our understanding of asthma and COPD, enabling personalized therapy and better outcomes. Further research and validation are needed to ensure the development of clinically meaningful and generalizable models.

Introduction: There is high heterogeneity of outcomes and measures reported in pulmonary rehabilitation (PR) trials of people with chronic obstructive pulmonary disease (COPD). This hinders study comparability and benchmarking of PR. We have developed a core outcome set (COS) to overcome these challenges., Methods: This study was informed by a systematic review and two qualitative studies and had patient involvement since its inception. A two-round Delphi survey was available in seven languages. Outcomes (n=63) scored 7-9 (crucial) by ≥70% of the participants and 1-3 (not that important) by ≤15% of participants from both groups in the Likert scale were automatically included in the COS, while outcomes that were considered crucial by only one of the groups were further discussed by the authors in a meeting., Results: A total of 299 people (n=229 healthcare professionals/researchers/policy-makers; n=70 people with COPD and informal caregivers) participated in the survey (83% retention), which covered 29 countries/five continents. After the second round, six outcomes were included and three were added in the meeting. The final COS contains dyspnoea, fatigue, functional exercise capacity, health-related quality of life, health behaviours/lifestyle, knowledge about the disease, lower limb muscle function, personal goals and problematic activities of daily living., Conclusion: A COS for PR of people with COPD is now available and can be used by different stakeholders to improve consistency and comparability of studies, benchmark PR and improve the quality of care provided. Future research should establish the core measures and investigate the uptake of this COS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Persistent dyspnea, functional limitations, and reduced quality of life (QoL) are common following pulmonary embolism (PE). Rehabilitation is a potential treatment option, but the scientific evidence is limited., Research Question: Does an exercise-based rehabilitation program improve exercise capacity in PE survivors with persistent dyspnea?, Study Design and Methods: This randomized controlled trial was conducted at two hospitals. Patients with persistent dyspnea following PE diagnosed 6 to 72 months earlier, without cardiopulmonary comorbidities, were randomized 1:1 to either the rehabilitation or the control group. The rehabilitation program consisted of two weekly sessions of physical exercise for 8 weeks and one educational session. The control group received usual care. The primary end point was the difference in Incremental Shuttle Walk Test between groups at follow-up. Secondary end points included differences in the Endurance Shuttle Walk Test (ESWT), QoL (EQ-5D and Pulmonary Embolism-QoL questionnaires) and dyspnea (Shortness of Breath questionnaire)., Results: A total of 211 subjects were included: 108 (51%) were randomized to the rehabilitation group and 103 (49%) to the control group. At follow-up, participants allocated to the rehabilitation group performed better on the ISWT compared with the control group (mean difference, 53.0 m; 95% CI, 17.7-88.3; P = .0035). The rehabilitation group reported better scores on the Pulmonary Embolism-QoL questionnaire (mean difference, -4%; 95% CI, -0.09 to 0.00; P = .041) at follow-up, but there were no differences in generic QoL, dyspnea scores, or the ESWT. No adverse events occurred during the intervention., Interpretation: In patients with persistent dyspnea following PE, those who underwent rehabilitation had better exercise capacity at follow-up than those who received usual care. Rehabilitation should be considered in patients with persistent dyspnea following PE. Further research is needed, however, to assess the optimal patient selection, timing, mode, and duration of rehabilitation., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03405480; URL: www., Clinicaltrials: gov., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Long-acting bronchodilators (LABD), in general, reduce respiratory symptoms, improve exercise endurance time and pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, there might be heterogeneity in improvement for several outcomes on an individual level. Therefore, we aimed to profile the multidimensional response in patients receiving tiotropium/olodaterol (T/O) using self-organizing maps (SOM)., Materials and Methods: This is a secondary analysis of the TORRACTO study: a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effects of T/O (2.5/5 and 5/5 μg) compared with placebo after 6 and 12 weeks of treatment in patients with COPD. In the current study, we used endurance time, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), inspiratory capacity (IC) at rest and IC at isotime (ICiso) to identify clusters by means of SOM in patients treated with T/O., Results: Six clusters with distinct response profiles were generated at week 12 in COPD patients receiving T/O (n = 268). Patients in cluster 1 improved significantly on all outcomes, whilst cluster 5 showed strong improvement in endurance time (357s); contrarily, FEV1, FVC, ICrest and ICiso decreased when compared to baseline., Conclusion: Individual responses on endurance time and pulmonary function after 12 weeks of T/O are heterogeneous. This study identified clusters in COPD patients with markedly different multidimensional response on LABD., (© 2023 Posthuma et al.)

Background: Alterations in body composition, including a low fat-free mass index (FFMI), are common in patients with COPD and occur regardless of body weight., Research Question: Is the impact of low FFMI on exercise capacity, health-related quality of life (HRQL), and systemic inflammation different among patients with COPD stratified in different BMI classifications?, Study Design and Methods: We analyzed baseline data of patients with COPD from the COPD and Systemic Consequences-Comorbidities Network (COSYCONET) cohort. Assessments included lung function, bioelectrical impedance analysis, 6-min walk distance (6MWD), HRQL, and inflammatory markers. Patients were stratified in underweight, normal weight (NW), preobese, and obese according to BMI and as presenting low, normal, or high FFMI using 25th and 75th percentiles of reference values. Linear mixed models were used to investigate the associations between fat-free mass (FFM) and fat mass with secondary outcomes in each BMI group., Results: Two thousand one hundred thirty-seven patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages 1-4; 61% men; mean ± SD age, 65 ± 8 years; mean ± SD FEV 1 , 52.5 ± 18.8% predicted) were included. The proportions of patients in underweight, NW, preobese, and obese groups were 12.3%, 31.3%, 39.6%, and 16.8%, respectively. The frequency of low FFMI decreased from lower to higher BMI groups (underweight, 81%; NW, 53%; preobese, 42%; and obese, 39%). FFM was associated with the 6MWD in the underweight group, even when adjusting for a broad set of covariates (P < .05). HRQL was not associated with FFM after adjustment for lung function or dyspnea (P > .32). Fat mass was associated with higher systemic inflammation in the NW and preobese groups (P < .05)., Interpretation: In patients with COPD with lower weight, such as underweight patients, higher FFMI is associated independently with better exercise capacity. In contrast, in preobese and obese patients with COPD, a higher FFMI was not consistently associated with better outcomes., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) play a pivotal role in the burden and progressive course of chronic obstructive pulmonary disease (COPD). As such, disease management is predominantly based on the prevention of these episodes of acute worsening of respiratory symptoms. However, to date, personalised prediction and early and accurate diagnosis of AECOPD remain unsuccessful. Therefore, the current study was designed to explore which frequently measured biomarkers can predict an AECOPD and/or respiratory infection in patients with COPD. Moreover, the study aims to increase our understanding of the heterogeneity of AECOPD as well as the role of microbial composition and hostmicrobiome interactions to elucidate new disease biology in COPD., Methods and Analysis: The 'Early diagnostic BioMARKers in Exacerbations of COPD' study is an exploratory, prospective, longitudinal, single-centre, observational study with 8-week follow-up enrolling up to 150 patients with COPD admitted to inpatient pulmonary rehabilitation at Ciro (Horn, the Netherlands). Respiratory symptoms, vitals, spirometry and nasopharyngeal, venous blood, spontaneous sputum and stool samples will be frequently collected for exploratory biomarker analysis, longitudinal characterisation of AECOPD (ie, clinical, functional and microbial) and to identify host-microbiome interactions. Genomic sequencing will be performed to identify mutations associated with increased risk of AECOPD and microbial infections. Predictors of time-to-first AECOPD will be modelled using Cox proportional hazards' regression. Multiomic analyses will provide a novel integration tool to generate predictive models and testable hypotheses about disease causation and predictors of disease progression., Ethics and Dissemination: This protocol was approved by the Medical Research Ethics Committees United (MEC-U), Nieuwegein, the Netherlands (NL71364.100.19)., Trial Registration Number: NCT05315674., Competing Interests: Competing interests: KWS, SMJVK, DP and SHW declare no conflicts of interest in relation to the submitted work. AD, JB, KO, UG, BRS and TK are employees of AstraZeneca and may hold stock in the company. MAS has received grants from the Netherlands Lung Foundation, Stichting Asthma Bestrijding, AstraZeneca, Boehringer Ingeheim, TEVA and Chiesi outside the submitted work. SOS has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Chiesi outside the submitted work. FMEF has received grants and personal fees from AstraZeneca, Chiesi, Boehringer Ingelheim, Glaxosmithkline, Novartis and MSD outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Introduction: Studies suggest that people with chronic obstructive pulmonary disease (COPD) who are worse at baseline respond better to pulmonary rehabilitation (PR). Identifying treatable traits (TTs) may help to distinguish responders from non-responders. We explored the impact of PR on extra-pulmonary traits of people with COPD and whether the presence of TT influences the type of response to PR., Methods: A comprehensive assessment of 9 TT including symptoms (dyspnoea, fatigue, anxiety and depression), functional capacity, deconditioning, balance, impact of the disease and health-related quality of life was conducted before and after a 12-week community-based PR programme. Pre-post differences between people with or without each TT at baseline were compared with independent samples t-tests or Mann-Whitney U tests. Proportion of responders between groups were explored with chi-square tests and odds ratio., Results: 102 people with COPD were included (70 [65; 75] years old, 78% male, FEV 1 47 [36; 60] %predicted). They had a median of 3 (out of 9) TTs per person and each patient responded on average to 5 (out of 9) outcomes of PR. People with TT were more responsive than those without them in all outcomes (p < 0.05) except for the 1-min sit-to-stand test. The presence of TT increased 4 to 20 times the likelihood of being a good responder., Conclusions: Identification of baseline extra-pulmonary TT in people with COPD showed the potential to inform on PR responsiveness and might therefore be an important strategy for patient prioritization, treatment personalisation (i.e., activation of the most suitable components) and optimisation., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cardiovascular disease is a significant cause of morbidity and mortality in COPD. Endothelial dysfunction is suggested to be involved in cardiovascular disease pathogenesis, and multiple studies report endothelial dysfunction in COPD. This article summarized the current knowledge on endothelial function in COPD patients., Areas Covered: Databases were screened until November 2022 for studies using ultrasound-based flow-mediated dilation in patients with stable COPD. Pooled effect sizes were calculated using random effects model. Meta-regression analyses assessed the effects of demographic and clinical variables., Expert Opinion: 34 studies were identified (1365 COPD patients; 617 controls). Pooled analysis demonstrated an impaired endothelial-dependent (-2.33%; 95%CI -3.30/-1.35; p < 0.001) and endothelial-independent dilation (-3.11%; 95%CI -5.14/-1.08; p = 0.003) in COPD patients when compared to non-COPD controls. Meta-regression identified that higher age, worse severity of airflow obstruction, and current smoking were significantly associated with impaired endothelial function. Studies evaluating the effects of pharmacological and non-pharmacological interventions on endothelial function in COPD patients demonstrated conflicting results.

Background: Beta-alanine (BA) supplementation increases muscle carnosine, an abundant endogenous antioxidant and pH buffer in skeletal muscle. Carnosine loading promotes exercise capacity in healthy older adults. As patients with chronic obstructive pulmonary disease (COPD) suffer from elevated exercise-induced muscle oxidative/carbonyl stress and acidosis, and from reduced muscle carnosine stores, it was investigated whether BA supplementation augments muscle carnosine and induces beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress in patients with COPD., Methods: In this double-blind, randomized, placebo (PL)-controlled trial (clinicaltrials.gov identifier: NCT02770417), 40 patients (75% male) with COPD (mean ± standard deviation: age 65 ± 6 years; FEV 1 % predicted 55 ± 14%) were assigned to 12 weeks oral BA or PL supplementation (3.2 g/day). The primary outcome, i.e. muscle carnosine, was quantified from m. vastus lateralis biopsies obtained before and after intervention. Co-primary outcomes, i.e. incremental and constant work rate cycle capacity, were also assessed. Linear mixed model analyses were performed. Compliance with and side effects of supplement intake and secondary outcomes (quadriceps strength and endurance, and muscle oxidative/carbonyl stress) were also assessed., Results: Beta-alanine supplementation increased muscle carnosine in comparison with PL in patients with COPD (mean difference [95% confidence interval]; +2.82 [1.49-4.14] mmol/kg wet weight; P < 0.001). Maximal incremental cycling capacity (VO 2 peak: +0.5 [-0.7 to 1.7] mL/kg/min; P = 0.384, Wpeak: +5 [-1 to 11] W; P = 0.103) and time to exhaustion on the constant work rate cycle test (+28 [-179 to 236] s; P = 0.782) did not change significantly. Compliance with supplement intake was similar in BA (median (quartile 1-quartile 3); 100 (98-100)%) and PL (98 (96-100)%) (P = 0.294) groups, and patients did not report side effects possibly related to supplement intake. No change was observed in secondary outcomes., Conclusions: Beta-alanine supplementation is efficacious in augmenting muscle carnosine (+54% from mean baseline value) without side effects in patients with COPD in comparison with PL. However, accompanied beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress were not observed., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Isokinetic testing of peripheral muscle function is valid and reliable in patients with chronic obstructive pulmonary disease (COPD)., Objective: To evaluate whether and to what extent isokinetic testing of quadriceps function meets pre-defined test criteria in patients with COPD; to determine the response to pulmonary rehabilitation (PR), and to calculate minimal important differences (MIDs) of isokinetic quadriceps function., Methods: Retrospective analysis of 2033 patients with COPD (age: 65±9 years, body mass index: 26±6 kg/m 2 , FEV 1 : 49±22% predicted) who followed a comprehensive PR program. Pre and post PR isokinetic quadriceps function was assessed with 30 maximal extension-flexion contractions at an angular speed of 90°/s on a computerized dynamometer. The chosen anchors were 6-min walk test and COPD assessment test., Results: Pre PR, 27% of the patients performed the isokinetic test incorrectly. In male and female patients with a correct pre and post PR isokinetic test, peak torque (Δ=10±13 Nm or 9% and Δ=7±9 Nm or 10%, respectively) and total work (Δ=263±270 J or 14% and Δ=198±190 J or 15%, respectively) improved significantly. There was no change in work fatigue index following PR. Using distribution-based calculations, MID estimates for peak torque and total work ranged between 6-7 Nm and 97-135 J in males and between 4-5 Nm and 62-99 J in females., Conclusions: Based on the current test criteria, three in four patients with COPD performed the isokinetic quadriceps test correctly during baseline PR assessment. Furthermore, peak torque and total work, but not work fatigue index, were responsive to PR and sex-specific MIDs were established., Competing Interests: Conflict of interest The BASES consortium is financially supported by Lung Foundation, the Netherlands [#5.1.18.232]. Drs. Jana De Brandt is funded by the Flemish government. The Research of FWO Aspirant Jana De Brandt is sponsored by FWO-grant [#11B4718N]. Dr. F.M.E. Franssen is supported by grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from TEVA, outside the submitted work. Dr. B. van den Borst is supported by personal lecture fees from AstraZeneca and Boehringer Ingelheim bv. Drs. A.A.F. Stoffels, R. Meys, Dr. H.W.H. van Hees, A.J. van ‘t Hul, P.H. Klijn, A.W. Vaes, J. De Brandt and Prof. Dr. C. Burtin and M.A. Spruit declare that they do not have a conflict of interest, (Copyright © 2022 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: There is high heterogeneity of outcomes and measures reported in the literature for pulmonary rehabilitation (PR), which might limit benchmarking and an effective evidence synthesis. A core outcome set (COS) can minimise this problem. It is however unclear which outcomes and measures are most important and suitable for different stakeholders., Methods: A multicentre qualitative study with one-to-one semi-structured interviews with people with chronic obstructive pulmonary disease (COPD), healthcare professionals (HCPs), researchers and policy makers was conducted. Manifest content analysis was conducted to explore the frequency of outcomes viewed as crucial or not. Thematic analysis was performed to better understand stakeholders' views., Results: 37 participants (17 people with COPD and 20 HCPs/researchers/policy makers) from 14 countries and 4 continents were included. Participants expressed that i) core outcomes need to be meaningful to people with COPD and show PR benefits; ii) there should be comprehensive assessment and similar outcomes across settings; iii) a balance between optimal and practical measures is needed; iv) the COS is needed to benchmark PR and advance knowledge; and v) reluctance to change outcomes/measures used by HCPs and using the COS as a maximum set of outcomes might be the pitfalls. 28 outcomes were identified as crucial, and 12 as not crucial., Conclusions: This study provided important insights into outcome measurement in PR from the perspectives of different key international stakeholders and a list of outcomes that will inform a future consensus study., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inspiratory muscle training (IMT) improves inspiratory muscle strength, exercise capacity and health status in patients with chronic obstructive pulmonary disease (COPD). However, there is no additional effect on top of comprehensive pulmonary rehabilitation (PR). It is unclear whether patients with different baseline degrees of static hyperinflation respond differentially to IMT as part of a PR program. Therefore, the aim was to study the effects of IMT as an add-on on PR after stratification for baseline degrees of static hyperinflation., Methods: In this single center retrospective study data were extracted between June 2013 and October 2020 of COPD patients who participated in a comprehensive PR program including IMT. IMT was performed twice daily, one session consisted of 3 series of 10 breaths and training intensity was set initially at a load of approximately 50% of patients' maximal static inspiratory mouth pressure (MIP). The primary outcome measure was MIP. Secondary outcomes were the distance achieved on the 6-min walk test (6MWD), endurance cycling exercise capacity at 75% of the peak work rate (CWRT) and disease-specific health status using the COPD assessment test., Results: 754 patients with COPD were screened for eligibility and 328 were excluded because of repeated PR programs, missing data or baseline residual volume (RV) > 350%. In total, 426 COPD patients were categorized into RV categories 50-130% (n = 84), 131-165% (n = 86), 166-197% (n = 86), 198-234% (n = 85) and 235-349% (n = 85). In the whole sample, MIP, endurance exercise capacity and health status improved significantly. The change in 6MWD was higher in the lowest baseline degree of static hyperinflation [+ 39 (9-92) m] compared with the baseline highest degree of static hyperinflation [+ 11 (- 18-54) m] (p < 0.05)., Conclusions: IMT as part of a PR program in patients with COPD with different baseline degrees improved MIP irrespective of the degree of static lung hyperinflation. Improvement in functional exercise capacity was significantly higher in the group with the lowest degree of static hyperinflation compared with the patients with the highest degree of static hyperinflation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The 6-minute walking test (6MWT) is a widely used measure to assess functional status of people with chronic obstructive pulmonary disease (COPD). However, it requires a long hallway and might be time-consuming. Other simple measures might be useful as a first screening tool. We explored the predictive ability of the 1-minute sit-to-stand test (1-min STS) in discriminating people with COPD with or without functional impairment., Methods: A receiver operating characteristics (ROC) curve analysis was performed. We determined a threshold for the 1-min STS to identify functional impairment based on different cut-offs of the 6MWT (300, 350, 400 and 450 m)., Results: A total of 135 people with COPD were included. Except for the <450 m cut-off of the 6MWT, all other cut-offs identified 19.5 repetitions as the optimal cut-off point for the 1-min STS. All AUCs showed excellent discrimination (AUCs = 0.812-0.901). The best AUC (<300 m cut-off) had an outstanding discrimination (0.901; 95%CI: 0.84-0.96; other AUCs 0.812-0.836) between people with or without functional impairment, with 86% specificity and 83% sensitivity., Conclusion: A cut-off of 19.5 repetitions in the 1-min STS discriminates accurately people with COPD with a functional impairment. Future studies may validate our treatable trait candidate in other samples and investigate its utility in predicting other meaningful outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Physical capacity (PC; "can do") and physical activity (PA; "do do") are prognostic indicators in COPD and can be used to subdivide patients with COPD into four exclusive subgroups (the so-called "can do, do do" quadrants). This concept may be useful to understand better the impact of PC and PA on all-cause mortality in patients with COPD., Research Question: What is the 6-year all-cause mortality risk of the "can do, do do" quadrants of patients with COPD?, Study Design and Methods: This retrospective study used data from patients with COPD who underwent a comprehensive assessment at their first-ever outpatient consultation. PC was assessed using the 6-min walk distance and physical activity was assessed using an accelerometer (steps per day). All-cause mortality data were obtained from the Municipal Personal Records Database. Receiver operating characteristic curves were used to determine threshold values for PC and PA to predict 6-year all-cause mortality. Using the derived threshold values, male and female patients were divided into the four "can do, do do" quadrants., Results: Data from 829 patients were used for analyses. Best discriminatory values for 6-year mortality were 404 m and 4,125 steps/day for men and 394 m and 4,005 steps/day for women. During a median follow-up of 55 months (interquartile range, 37-71 months), 129 patients (15.6%) died. After controlling for established prognostic factors, patients in the "can do, don't do" quadrant and "can do, do do" quadrant showed significantly lower mortality risk compared with patients in the "can't do, don't do" quadrant: hazard ratios of 0.36 (95% CI, 0.14-0.93) and 0.24 (95% CI, 0.09-0.61) for men and 0.37 (95% CI, 0.38-0.99) and 0.29 (95% CI, 0.10-0.87) for women, respectively. No significant differences were found between the "can't do, do do" and "can't do, don't do" quadrants., Interpretation: Patients with COPD with a preserved PC seem to have a significantly lower 6-year mortality risk compared with patients with a decreased PC, regardless of physical activity level., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The magnitude of response to pulmonary rehabilitation (PR) is influenced by the selection of outcomes and measures., Objectives: This systematic review aimed to review all outcomes and measures used in clinical trials of PR for individuals with chronic obstructive pulmonary disease (COPD)., Methods: The review involved a search of Scopus, Web of Knowledge, Cochrane Library, EBSCO, Science Direct and PubMed databases for studies of stable individuals with COPD undergoing PR. Frequency of reporting for each domain, outcome and measure was synthesized by using Microsoft Excel., Results: We included 267 studies (43153 individuals with COPD). A broad range of domains (n = 22), outcomes (n = 163) and measures (n = 217) were reported. Several measures were used for the same outcome. The most reported outcomes were exercise capacity (n = 218) assessed with the 6-min walk test (n = 140), health-related quality of life (n = 204) assessed with the Saint George's respiratory questionnaire (n = 99), and symptoms (n = 158) assessed with the modified Medical Research Council dyspnoea scale (n = 56). The least reported outcomes were comorbidities, adverse events and knowledge., Conclusions: This systematic review reinforces the need for a core outcome set for PR in individuals with COPD because of high heterogeneity in reported outcomes and measures. Future studies should assess the importance of each outcome for PR involving different stakeholders., Prospero Id: CRD42017079935., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD., Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups., Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients., Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy., Clinical Trial Registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344., Competing Interests: Maud Koopman reports no real or perceived conflict of interest. Frits M.E. Franssen reports grants and personal fees from AstraZeneca and Novartis; personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and TEVA, outside the submitted work. Swetlana Gaffron works at Viscovery. Viscovery provides analysis services to Ciro+. Henrik Watz reports personal fees from AZ, during the conduct of the study; grants and/or personal fees from AZ, GSK, Chiesi, Boehringer Ingelheim Novartis, and Menarini, outside the submitted work. Thierry Troosters reports personal fees from AstraZeneca, Boehringer Ingelheim, and Chiesi, outside the submitted work. Judith Garcia-Aymerich reports consulting and lecture fees from AstraZeneca (outside the submitted work) and lecture fees from Esteve and Chiesi (outside the submitted work). Pierluigi Paggiaro reports grants and/or personal fees from ALK, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Guidotti, Menarini, and Mundipharma, outside the submitted work. Eduard Molins, Miguel Moya, Lindy van Burk, and Esther Garcia Gil are AstraZeneca employees. Dieter Maier works at Biomax. Biomax provides data management and analysis services to CIRO+. Emiel F.M. Wouters reports no real or perceived conflict of interest. Lowie E.G.W. Vanfleteren reports grants and/or personal fees from AstraZeneca, Novartis, GSK, Chiesi, Menarini, Pulmonx, Fisher&Paykel, and Boehringer, outside the submitted work. Martijn A. Spruit reports grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, GSK, Boehringer Ingelheim, AstraZeneca, TEVA, and Chiesi, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Koopman et al.)

Background & Aim: Patients with early-onset severe COPD are often female and characterized by severe emphysema. Extrapulmonary disease manifestations have not yet been investigated in this clinical phenotype. Therefore, this study aimed to study the physical and mental health profile of patients with early-onset severe COPD., Methods: This is a cross-sectional analysis including 1058 patients with COPD who were referred for pulmonary rehabilitation between July 2013 and August 2018. Based on a forced expiratory volume in 1 s (FEV 1 ) <50%predicted and age <55 years, 78 patients were identified having early-onset severe COPD. Using propensity score matching, these patients were matched to 54 early-onset mild-to-moderate, 158 older severe and 103 older mild-to-moderate COPD patients based on FEV 1 %predicted, age and gender. An extensive panel of pulmonary and extrapulmonary disease markers (i.e. body composition, physical performance and mental health) was compared between these groups., Results: Pulmonary manifestations as well as physical and mental health were similar in patients with early-onset severe COPD compared to older severe patients, despite a mean age difference of 15.8 years. Remarkably, a high prevalence of depression was observed in early-onset severe COPD which was significantly higher compared to older severe patients (51.9 vs 32.7%, p = 0.029). In line with a large difference in FEV 1 (33.9 (25.1-41.5) vs 71.8 (61.3-85.4), p < 0.001), patients with early-onset severe COPD had lower exercise performance, indicated by a lower 6-min walking distance and peak work rate (mean difference 71.1 m, p = 0.001, and 25.9%predicted, p < 0.001, respectively), compared to patients with early-onset mild-to-moderate COPD. Interestingly, body composition and isokinetic muscle strength were not different between these comparable age groups., Conclusion: Pulmonary and physical health limitations are generally comparable between younger and older patients with severe airflow limitation, while more younger patients might have mental problems. These data suggest the need for early identification of subjects at risk for early-onset severe COPD., Competing Interests: Conflicts of interest FF reports grants and personal fees from Novartis, AstraZeneca and Chiesi and personal fees from GlaxoSmithKline, Boehringer, Mundipharma and TEVA, outside the submitted work. All other authors report no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Clusters of COPD patients have been reported in order to individualize the treatment program. Neither co-morbidity clusters, nor integrated respiratory physiomics clusters contributed to a better prediction of outcomes. Based on a thoroughly assessed set of pulmonary and extra-pulmonary traits at the start of a pulmonary rehabilitation (PR) program, we recently described seven clusters of COPD patients. The aims of this study are to confirm multidimensional differential response and to assess the potential of pulmonary and extra-pulmonary traits-based clusters to predict this multidimensional response to PR pulmonary in COPD patients., Methods: Outcomes of a 40-session PR program for COPD patients, referred by a chest physician, were evaluated based on the minimal clinically important difference (MCID) for 6-minute walk distance (6MWD), cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression scores, MRC dyspnea grade and St George's Respiratory Questionnaire. The aforementioned response indicators were used to calculate the overall multidimensional response and patients were grouped in very good, good, moderate and poor responders. In the same way, responses to pulmonary rehabilitation were compared based on seven previously identified pulmonary and extra-pulmonary traits-based clusters., Results: Of the whole sample, drop out was 19% and 419 patients (55.4% males, age: 64.3 ± 8.8, FEV1% of predicted: 48.9 ± 20) completed the pulmonary rehabilitation program. Very good responders had significantly worse baseline characteristics with a higher burden of disease, a higher proportion of rollator-users, higher body mass index (BMI), more limitations of activities in daily life, emotional dysfunction, higher symptoms of dyspnea and worse quality of life. Of the seven pre-identified clusters, 'the overall best functioning cluster' and 'the low disease burden cluster' both including the best 6MWD, the lowest dyspnea score and the overall best health status, demonstrated attenuated outcomes, while in 'the cluster of disabled patients', 76% of the patients improved health status with at least 2 times MCID. This 'cluster of disabled patients' as well as 'the multimorbid cluster', 'the emotionally dysfunctioning cluster', 'the overall worst-functioning cluster' and 'the physically dysfunctioning cluster' all demonstrated improvements in performance and satisfaction for occupational activities (more than 65% of patients improved with > 1MCID), emotional functioning (more than 50% of patients improved with > 1 MCID) and overall health status (more than 58%)., Conclusion: The current study confirms the differential response to pulmonary rehabilitation based on multidimensional response profiling. Cluster analysis of baseline traits illustrates that non-linear, clinically important differences can be achieved in the most functionally and emotionally impaired clusters and that 'the overall best functional cluster' as well as 'the low disease burden cluster' had an attenuated outcome., Competing Interests: The following authors are affiliated with CIRO+: Ingrid Augustin, Frits Franssen, Sarah Houben-Wilke, Daisy Janssen, Martijn Spruit. The following author is an employee of Viscovery Software GmbH: Swetlana Gaffron. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Falls risk is elevated in chronic obstructive pulmonary disease (COPD). However, there is a lack of evidence regarding the contributing factors. Here, we examined the feasibility of, and initial responses to, large walking perturbations in COPD, as well as the adaptation potential of people with COPD to repeated walking perturbations that might indicate potential for perturbation-based balance training in COPD., Methods: 12 participants with COPD undergoing inpatient pulmonary rehabilitation and 12 age-gender-matched healthy control participants walked on an instrumented treadmill and experienced repeated treadmill-belt acceleration perturbations (leading to a forward balance loss). Three-dimensional motion capture was used to quantify the stability of participants body position during perturbed walking. Feasibility, stability following the initial perturbations and adaptation to repeated perturbations were assessed., Findings: Using perturbations in this manner was feasible in this population (no harness assists and participants completed the minimum number of perturbations). No clear, specific deficit in reactive walking stability in COPD was found (no significant effects of participant group on stability or recovery step outcomes). There were mixed results for the adaptability outcomes which overall indicated some adaptability to repeated perturbations, but not to the same extent as the healthy control participants., Interpretation: Treadmill-based perturbations during walking are feasible in COPD. COPD does not appear to result in significant deficits in stability following sudden perturbations and patients do demonstrate some adaptability to repeated perturbations. Perturbation-based balance training may be considered for fall prevention in research and practice in people with COPD., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Regular exercise positively affects cardiovascular physiology, translating into the adequate capacity of microvascular blood vessels to dilate in response to acute bouts of exercise. However, this remains unstudied in patients with chronic obstructive pulmonary disease (COPD), who often suffer from cardiovascular comorbidity. Therefore, we studied acute changes in retinal blood vessel diameters in response to high-intensity exercise in patients with COPD. The effect of an exercise-based 8-week pulmonary rehabilitation (PR) program was evaluated. We consider changes in these retinal metrics as an indicator of microvascular reactivity., Methods: Demographics and clinical characteristics of 41 patients were collected at the start and end of the PR program. Patients performed a high-intensity exercise test on a cycle ergometer at the start and end of the PR program, during which we collected retinal images. Fundus images were taken immediately before and 0, 5, 10, 15, and 30 min after the ergometer test. Widths of retinal blood vessels, represented as Central Retinal Arteriolar and Venular Equivalents (CRAE and CRVE), were calculated., Results: Thirty patients with COPD completed the study protocol (57% males; mean age: 64 ± 7 years; mean FEV 1 : 45 ± 17%pred). We did not observe a change in retinal vessel widths following the ergometer test at the start of the PR program. This null result remained at the end of the 8-week PR program. Our observations did not alter when considering responders and non-responders to PR., Conclusion: Retinal blood vessel diameters of patients with COPD did not change following an exercise test on an ergometer. The exercise-based PR program of eight weeks did not counteract the blunted retinal microvascular response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients with pulmonary hypertension present limited tolerance to exercise and aerobic capacity; which is reflected in the reduction in peak oxygen consumption and their functional performance. This intolerance to exercise has traditionally been attributed to cardiac and respiratory dysfunction. However, as it happens in other chronic diseases, lower-limb and respiratory muscle alterations are also involved in patients with pulmonary hypertension. Increasing evidence suggests that physical exercise training is an efficient and safe strategy. The recommendation for light and moderate-intensity exercise is made within the framework of pulmonary rehabilitation, and its benefits have been previously described. In diseases such as COPD, lower-limb muscle function, exercise tolerance and quality of life improve following exercise training. And just as with COPD, it is necessary to promote evidence-based interventions with pulmonary hypertension. This narrative review focuses on the evaluation, safety and efficacy of training the respiratory muscles and the muscles of upper and lower extremities in patients with pulmonary hypertension., Competing Interests: Conflict of interests: The authors declare no conflict of interest, (Copyright © 2021 Colombia Medica.)

Background: Little is known regarding treatment of urinary incontinence (UI) in women with chronic obstructive pulmonary disease (COPD). The aim of the study was to explore the efficacy of pelvic floor muscle training (PFMT) or cough-suppression techniques (CST) on UI in women with COPD., Methods: A three-armed, two-centred, single-blinded, randomised controlled study was performed. Subjects were randomised to (a) PFMT for 16 weeks, (b) 2-3 educational sessions in CST, or (c) written information only. All participants completed questionnaires about UI, cough symptoms, and health status and underwent clinical examinations to evaluate the strength of the pelvic floor muscles and exercise capacity. Daily physical activity levels were measured using an activity monitor and lung function with spirometry. With a significance level of 5% and an 80% chance of detecting a significant difference between groups of 2.5 points on the ICIQ UI SF score, our sample size calculation showed that a total of 78 women, 26 in each group, was required to complete the study., Results: During the period 2016 to 2018, 95 women were invited to the study. A total of 42 were recruited, three were excluded and 10 (24%) dropped out during the follow-up period. Mean ICIQ-UI SF total baseline score was 9.6 (range: 1-17) and 7.0 (range: 0-16) at follow-up. Changes in subjective UI as measured with the ICIQ-UI SF questionnaire were seen in the PFMT group and control group, but not in the CST group., Conclusion: Due to the low number of available participants and recruitment difficulties including practical issues such as travel distance, lack of interest, poor state of health, and high number of comorbidities, our results are inconclusive. However, reduced subjective UI was observed in the PFMT and control groups with a trend towards best effect in the PFMT group. Screening for UI is advisable in all women with COPD to be able to identify and treat these women to reduce symptom burden and improve quality of life. Future studies should focus on barriers to recruitment as well as randomised controlled studies with larger sample sizes., Trial Registration: ClinicalTrials.gov NCT02614105. 25th November 2015., (© 2021. The Author(s).)

Background: Reduced physical activity is common in COPD and is associated with poor outcomes. Physical activity is therefore a worthy target for intervention in clinical trials; however, trials evaluating physical activity have used heterogeneous methods., Research Question: What is the available evidence on the efficacy and/or effectiveness of various interventions to enhance objectively measured physical activity in patients with COPD, taking into account the minimal preferred methodologic quality of physical activity assessment?, Study Design and Methods: In this narrative review, the COPD Biomarker Qualification Consortium (CBQC) task force searched three scientific databases for articles that reported the effect of an intervention on objectively measured physical activity in COPD. Based on scientific literature and expert consensus, only studies with ≥ 7 measurement days and ≥ 4 valid days of ≥ 8 h of monitoring were included in the primary analysis., Results: Thirty-seven of 110 (34%) identified studies fulfilled the criteria, investigating the efficacy and/or effectiveness of physical activity behavior change programs (n = 7), mobile or electronic-health interventions (n = 9), rehabilitative exercise (n = 9), bronchodilation (n = 6), lung volume reduction procedures (n = 3), and other interventions (n = 3). Results are generally variable, reflecting the large differences in study characteristics and outcomes. Few studies show an increase beyond the proposed minimal important change of 600 to 1100 daily steps, indicating that enhancing physical activity levels is a challenge., Interpretation: Only one-third of clinical trials measuring objective physical activity in people with COPD fulfilled the preset criteria regarding physical activity assessment. Studies showed variable effects on physical activity even when investigating similar interventions., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the response to a pulmonary rehabilitation (PR) program and minimal important differences (MIDs) for the Short Physical Performance Battery (SPPB) subtests and SPPB summary score in patients with chronic obstructive pulmonary disease (COPD)., Design: Retrospective analysis using distribution- and anchor-based methods., Setting: PR center in the Netherlands including a comprehensive 40-session 8-week inpatient or 14-week outpatient program., Participants: A total of 632 patients with COPD (age, 65±8y; 50% male; forced expiratory volume in the first second=43% [interquartile range, 30%-60%] predicted)., Interventions: Not applicable., Main Outcome Measure: Baseline and post-PR results of the SPPB, consisting of 3 balance standing tests, 4-meter gait speed (4MGS), and 5-repetition sit-to-stand (5STS). The chosen anchors were the 6-Minute Walk Test and COPD Assessment Test. Patients were stratified according to their SPPB summary scores into low-performance, moderate-performance, and high-performance groups., Results: 5STS (∆=-1.14 [-4.20 to -0.93]s) and SPPB summary score (∆=1 [0-2] points) improved after PR in patients with COPD. In patients with a low performance at baseline, balance tandem and 4MGS significantly increased as well. Based on distribution-based calculations, the MID estimates ranged between 2.19 and 6.33 seconds for 5STS and 0.83 to 0.96 points for SPPB summary score., Conclusions: The 5STS and SPPB summary score are both responsive to PR in patients with COPD. The balance tandem test and 4MGS are only responsive to PR in patients with COPD with a low performance at baseline. Based on distribution-based calculations, an MID estimate of 1 point for the SPPB summary score is recommended in patients with COPD. Future research is needed to confirm MID estimates for SPPB in different centers., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Low fat-free mass (FFM) is common in patients with chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality. Few studies have evaluated longitudinal changes in body composition in patients with COPD compared with non-COPD controls. This study aimed to compare longitudinal changes in total and regional body composition between patients with COPD and non-COPD controls and investigate predictors of changes in body composition in COPD., Methods: Patients with COPD and non-COPD controls participating in the Individualized COPD Evaluation in relation to Ageing (ICE-Age) study, a single-centre, longitudinal, observational study, were included. Subjects were assessed at baseline and after 2 years of follow-up. Among other procedures, body composition was measured by dual-energy X-ray absorptiometry scan. The number of exacerbations/hospitalizations 1 year before inclusion and during follow-up were assessed in patients with COPD., Results: A total of 405 subjects were included (205 COPD, 87 smoking and 113 non-smoking controls). Patients with COPD and smoking controls presented a significant decline in total FFM (mean [95% CI]: -1173 [-1527/-820] g and -486 [-816/-156] g, respectively) while body composition remained stable in non-smoking controls. In patients with COPD, the decline in FFM was more pronounced in legs (-174 [-361/14] g) and trunk (-675 [-944/406] g) rather than in arms (54 [-19/126] g). The predictors of changes in total and regional FFM in patients with COPD were gender, number of previous hospitalizations, baseline values of FFM and BMI., Conclusion: Patients with COPD present a significant decline in FFM after 2 years of follow-up, this decline is more pronounced in their legs and trunk., (© 2021 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Introduction: The understanding of whether and to what extent employment status affects readmission and mortality is limited in patients with COPD., Aim: To explore how employment status affects readmission and mortality after first admission to the hospital with acute exacerbation of COPD (AECOPD)., Methods: This study used Danish national registry-based data. All patients admitted for the first time to the hospital between 1999 and 2014 with a diagnosis of AECOPD, age 35-59, without a previous asthma diagnosis were included in the study. Employment status effect on 30-, 90-, and 365-day readmission and mortality was examined using logistic regression, adjusting for relevant confounders., Results: A total of 11,850 COPD patients were included in the study of which 3563 (30%) were working, 1368 (12%) unemployed, 840 (7%) on sick leave, and 6079 (51%) receiving early retirement. Patients receiving early retirement had, compared to patients working, an adjusted increased likelihood of readmission at 30, 90, and 365 days (odds ratio (OR) 1.26 (CI 95% (1.06-1.49)), 1.33 (CI 95% (1.16-1.53)), and 1.48 (CI 95% (1.33-1.66)), respectively). An increased likelihood was also seen in unemployed at 365 days follow-up (OR 1.44 (CI 95% (1.22-1.68))). Early retirement was associated with an increased mortality at 30, 90, and 365 days (OR 1.39 (CI 95% (1.07-1.80)) 1.37 (CI 95% (1.09-1.79)) and 1.48 (CI 95% (1.25-1.75)), respectively). An increased likelihood was also seen in patients receiving sick leave (OR 1.57 (CI 95% (1.21-2.04)))., Conclusion: Patients with COPD who are not working at the time of first admission have a higher likelihood of readmission and mortality., Competing Interests: Dr Kristian Hay Kragholm reports personal fees from Novartis, outside the submitted work. Dr Christian Torp-Pedersen reports grant for randomised study from Bayer and grant for epidemiological study from Novo Nordisk, during the conduct of the study. Dr Daisy JA Janssen reports lecture fees from Novartis and Boehringer Ingelheim, outside the submitted work. The authors have no other conflicts of interest to declare with regard to the content of this manuscript., (© 2021 Jacobsen et al.)

Hyaluronic acid (HA) is a key component of the extracellular matrix. HA and its metabolism are suggested to be altered in the lungs of patients with chronic obstructive pulmonary disease (COPD). The present study explored systemic HA, and its metabolic regulators, in patients with clinically stable COPD and smoking and non-smoking controls. Furthermore, associations of HA with acute exacerbations (AECOPD), airway-related hospitalizations, systemic inflammation and cardiovascular risk were studied. In total, 192 patients with moderate to very severe COPD [aged 62.3 y (± SD 7.0)], 84 smoking controls [aged 61.8 y (± 5.7)], and 107 non-smoking controls [aged 60.1 y (± 7.0)] were included. Plasma HA was reduced in patients with COPD compared to non-smoking controls (p = 0.033), but was comparable after adjusting for age and sex. Expression of HAS-3 did not differ between groups, but was substantially less detectable in more patients with COPD than (non)smoking controls (p < 0.001). Expression of HYAL-2 was enhanced in patients with COPD versus smoking (p = 0.019) and non-smoking (p < 0.001) controls, also in the age- and sex- adjusted model (p < 0.001). Plasma HA was not associated with AECOPD, airway-related hospitalizations in the previous year, or systemic inflammation in COPD. Arterial pulse wave velocity explained some of the variance (< 10%) in plasma HA (p = 0.006). Overall, these results indicate that expression of HYAL-2, but not plasma HA nor HAS-3, is enhanced in patients with COPD compared to (non)smoking controls. Furthermore, HA was not associated with clinical outcomes, yet, cardiovascular risk might play a role in its systemic regulation in stable COPD., (© 2021. The Author(s).)

Background: Optimizing self-management is a key element in multidisciplinary pulmonary rehabilitation in patients with asthma or COPD. This observational study aimed to investigate the changes in self-management following pulmonary rehabilitation in subjects with chronic lung disease., Methods: Data were prospectively and routinely gathered at initial assessment and discharge in subjects taking part in a 12-week multidisciplinary out-patient pulmonary rehabilitation program. Measures of self-management included the Patient Activation Measure (PAM), the Health Education Impact Questionnaire (HEIQ) (8 subscales), a Self-Efficacy Questionnaire (2 subscales), the Lung Information Needs Questionnaire (LINQ), and the Health Literacy Questionnaire (HLQ) (9 subscales). Mean differences with 95% CI and effect sizes were computed., Results: A total of 70 subjects (62.9% women) were included, with a median age of 63.5 y; most of the subjects had been diagnosed with COPD (77%). Between admission and discharge, all measures of self-management increased significantly except for the HEIQ subscales of constructive attitudes and approaches, social integration and support, and health services navigation; and the HLQ subscale of social support for health. The largest improvements (effect size > 0.55) were seen for the PAM (0.57); the HEIQ subscales of health-directed behavior (0.71), self-monitoring and insight (0.62), and skill and technique acquisition (1.00); the HLQ subscales of having sufficient information to manage my health (1.21) and actively managing my health (0.66); and the LINQ (1.85)., Conlcusions: Self-management, including activation, improved significantly in subjects with asthma or COPD who took part in a multidisciplinary pulmonary rehabilitation program., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

Purpose: Not all patients with chronic obstructive pulmonary disease (COPD) experience similar benefits after pulmonary rehabilitation (PR). This pre-post PR study used a large sample of patients with COPD to determine whether PR-induced changes of oxygen uptake (V˙O2) kinetics and exercise responses of V˙O2, carbon dioxide output (V˙CO2), minute ventilation (V˙E), V˙E/V˙CO2, breathing frequency, and tidal volume differed between responders and nonresponders to PR., Methods: Responders to PR were defined as patients with a minimal clinically important increase in endurance time of 105 s. Isotime (=180 s) values of V˙O2, V˙CO2, V˙E, V˙E/V˙CO2, breathing frequency, and tidal volume; gains of V˙O2, V˙CO2, and V˙E; and V˙O2 mean response time of 183 patients with COPD (forced expiratory volume in 1 s: 56% ± 19% predicted) were compared between pre- and post-PR constant work rate tests., Results: After PR, only the group of responders significantly decreased V˙O2 mean response time (P < 0.05), V˙CO2 gain, V˙E gain, and isotime values of V˙CO2, V˙E, and V˙E/V˙CO2 (all, P < 0.001), while also improving their breathing pattern (e.g., decreased breathing frequency isotime value; P < 0.0001). These changes were not observed in the group of nonresponders. Changes in physiological exercise responses were correlated with changes in physical performance (e.g., correlation between changes in V˙O2 mean response time and endurance time: P = 0.0002, r = -0.32)., Conclusions: PR-induced changes in physiological exercise responses differed between responders and nonresponders. Physiological changes are relevant to explain the variable improvements of physical performance after PR in patients with COPD., (Copyright © 2020 by the American College of Sports Medicine.)

Objectives: The BODE (BMI, Obstruction - FEV 1 , Dyspnoea - mMRC, Exercise - 6-MWT) and the ADO (Age, Dyspnoea - mMRC, Obstruction - FEV 1 ) indices are widely used prognosis assessment tools for long-term mortality prediction in COPD patients but subject to limitations for use in daily clinical practice. The aim of this research was to construct a prognostic instrument that prevents these limitations and which would serve as a complementary prognostic tool for clinical use in these patients., Methods and Participants: The data of 699 COPD subjects were extracted from the Czech Multicentre Research Database (CMRD) of COPD patients (the derivation cohort) and analysed to identify factors associated with the long-term risk of mortality. These were entered into the ROC analysis and reclassification analysis. Those with the strongest discriminative power were used to construct the new index (CADOT). The new index was validated on 187 patients of the CIROCO+ cohort (Netherlands; the validation cohort)., Results: The CADOT was constructed by adding two newly identified prognosis-determining factors, chronic heart failure (CHF) and TL CO , to the ADO index. In a head-to-head comparison, the CADOT index showed highest c-statistic values compared to the BODE and ADO indices (0.701 vs 0.677 vs 0.644, respectively). The prognostic power was more definitive when applied to the Dutch validation (CIROCO+) cohort (0.842 vs 0.799 vs 0.825, respectively)., Conclusions: The CADOT index has comparable prognostic power to the BODE and ADO indices. The CADOT is complementary/an alternative to the BODE (if 6-MWT is not feasible) and ADO (with less dependence on the age factor) indices., Trial Registration: ClinicalTrials.gov (NCT01923051).

Introduction: Patients with COPD are vulnerable to workforce detachment. Better knowledge of features associated with paid work loss might be of help to design and select appropriate interventions., Method: This cross-sectional study aimed to explore the presence of treatable traits in COPD patients without paid work. Patients with COPD below 65 years at first referral to a hospital-based patient clinic were included. Using binary logistic regression analysis, the relationship between paid work and the following characteristics was explored: low daily physical activity, exercise, active smoking, Medical Research Council dyspnea scale (MRC), poor nutritional status, exacerbations, and fatigue (checklist individual strength (CIS)). Variables were adjusted for age, sex, forced expiratory volume in 1 s (FEV 1), and education level., Results: In total, 191 patients (47.3%) were without paid work. The following treatable traits were related to not being in paid work: < 5000 steps/day (OR 2.36, 95% CI (1.52-3.68)), MRC ≥ 3 (OR 1.78, 95%CI (1.14-2.77)), CIS ≥ 36 points (OR 1.78, 95% CI (1.10-2.87)), six-minute walk distance (6MWD) < 70% of predicted (OR 2.62, 95% CI (1.69-4.06)), and ≥ 2 exacerbations per year (OR 1.80, 95% CI (1.12-2.92)). Significant differences were also seen in age (OR 1.06, 95% CI (1.02-1.10) per year), FEV 1% predicted (OR 0.98, 95% CI (0.97-1.00) per % predicted increase), and medium/high education level (OR 0.62, 95% CI (0.41-0.93)). When adjusting for all variables the only treatable trait that remained significant was 6MWD., Conclusion: Patients without paid work are more likely to have treatable traits with 6MWD revealing the most significant association.

Nighttime symptoms are important indicators of impairment for many diseases and particularly for respiratory diseases such as chronic obstructive pulmonary disease (COPD). The use of wearable sensors to assess sleep in COPD has mainly been limited to the monitoring of limb motions or the duration and continuity of sleep. In this paper we present an approach to concisely describe sleep patterns in subjects with and without COPD. The methodology converts multimodal sleep data into a text representation and uses topic modeling to identify patterns across the dataset composed of more than 6000 assessed nights. This approach enables the discovery of higher level features resembling unique sleep characteristics that are then used to discriminate between healthy subjects and those with COPD and to evaluate patients' disease severity and dyspnea level. Compared to standard features, the discovered latent structures in nighttime data seem to capture important aspects of subjects sleeping behavior related to the effects of COPD and dyspnea., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The endurance shuttle walk test (ESWT) is used to evaluate exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). The recommended pre-intervention tolerated duration (Tlim) is between 3-8 minutes for optimal interpretation of treatment effects. However, this window may be exceeded and factors determining ESWT Tlim are not completely understood. Therefore, we aimed to determine whether pulmonary function, physical and incremental shuttle walk test (ISWT) performance measures are associated with ESWT Tlim in COPD patients., Methods: Assessment data from patients eligible for pulmonary rehabilitation was retrospectively analyzed. Inclusion criteria were: diagnosis of COPD and complete data availability regarding ESWT and ISWT. Patients performed an ESWT at 85% of ISWT speed and were divided into three groups (ESWT Tlim: <3 minutes, 3-8 minutes, >8 minutes). Subject characteristics, severity of complaints, pulmonary function, physical capacity and activity, exercise tolerance and quadriceps muscle strength were evaluated., Results: 245 COPD patients (FEV1 38 (29-52)% predicted) were included. Median ESWT Tlim was 6.0 (3.7-10.3) minutes, 41 (17%) patients walked <3 minutes and 80 (33%) patients walked >8 minutes. Body mass index, maximal oxygen consumption, Tlim on constant work rate cycle test, physical activity level, maximal ISWT speed, dyspnoea Borg score at rest and increase of leg fatigue Borg score during ISWT independently predicted Tlim in multivariate regression analysis (R2 = 0.297, p<0.001)., Conclusion: This study reported a large variability in ESWT Tlim in COPD patients. Secondly, these results demonstrated that next to maximal ISWT speed, other ISWT performance measures as well as clinical measures of pulmonary function, physical capacity and physical activity were independent determinants of ESWT Tlim. Nevertheless, as these determinants only explained ~30% of the variability, future studies are needed to establish whether additional factors can be used to better adjust individual ESWT pace in order to reduce ESWT Tlim variability., Competing Interests: The authors have read the journal’s policy and have the following competing interests: F.M.E. Franssen is supported by grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from TEVA, outside the submitted work. B. van den Borst is supported by personal lecture fees from AstraZeneca and Boehringer Ingelheim bv. A.A.F. Stoffels, R. Meys, H.W.H. van Hees, P. Klijn, C. Burtin, M.A. Spruit, H.A.C. van Helvoort, J.B. Peters, M.P.M. Klaassen and A.J. van ‘t Hul declare that they do not have a conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: Fatigue is a distressing symptom in patients with COPD. Little is known about the factors that contribute to fatigue in COPD. This review summarises existing knowledge on the prevalence of fatigue, factors related to fatigue and the instruments most commonly used to assess fatigue in COPD., Methods: Pubmed, PsycINFO, EMBASE, Cochrane and CINAHL databases were searched for studies from inception up to 7 January 2020 using the medical subject headings "COPD" and "Fatigue". Studies were reviewed in accordance with PRISMA guidelines., Results: 196 studies were evaluated. The prevalence of fatigue ranged from 17-95%. Age (r=-0.23 to r=0.27), sex (r=0.11), marital status (r=-0.096), dyspnoea (r=0.13 to r=0.78), forced expiatory volume in 1 s % predicted (r=-0.55 to r=-0.076), number of exacerbations (r=0.27 to r=0.38), number of comorbidities (r=0.10), number of medications (r=0.35), anxiety (r=0.36 to r=0.61), depression (r=0.41 to r=0.66), muscle strength (r=-0.78 to r=-0.45), functional capacity (r=-0.77 to r=-0.14) and quality of life (r=0.48 to r=0.77) showed significant associations with fatigue., Conclusions: Fatigue is a prevalent symptom in patients with COPD. Multiple physical and psychological factors seem to be associated with fatigue . Future studies are needed to evaluate these underlying factors in integral analyses in samples of patients with COPD., Competing Interests: Conflict of interest: Z. Ebadi has nothing to disclose. Conflict of interest: M.J. Goërtz has nothing to disclose. Conflict of interest: M. Van Herck has nothing to disclose. Conflict of interest: D.A.J. Janssen reports personal fees from Novartis, Boehringer Ingelheim and AstraZeneca, outside the submitted work. Conflict of interest: M.A. Spruit reports grants from Netherlands Lung Foundation, Stichting Astma Bestrijding, Boehringer Ingelheim and AstraZeneca, during the conduct of the study; and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work. Conflict of interest: C. Burtin has nothing to disclose. Conflict of interest: M.S.Y. Thong has nothing to disclose. Conflict of interest: J. Muris has nothing to disclose. Conflict of interest: J. Otker has nothing to disclose. Conflict of interest: M. Looijmans has nothing to disclose. Conflict of interest: C. Vlasblom has nothing to disclose. Conflict of interest: J. Bastiaansen has nothing to disclose. Conflict of interest: J. Prins has nothing to disclose. Conflict of interest: E.F.M. Wouters has nothing to disclose. Conflict of interest: J.H. Vercoulen has nothing to disclose. Conflict of interest: J.B. Peters has nothing to disclose., (©The authors 2021.)

Background: Cut offs for fat-free mass index (FFMI) and appendicular skeletal muscle mass index (ASMI) are available for diagnosing low muscle mass in patients with COPD. This study aimed to investigate: (1) the frequency of low muscle mass (FFMI and ASMI) applying different cut-offs and (2) the functional translation (clinical impact) of low muscle mass, in patients with COPD stratified into BMI categories., Methods: Patients with COPD were assessed regarding body composition, exercise capacity, quadriceps muscle strength, symptoms of anxiety and depression, dyspnea and quality of life upon referral to pulmonary rehabilitation. The proportion of patients with low muscle mass was compared among BMI categories. Clinical outcomes between patients with normal and low muscle mass within each BMI category were compared., Results: 469 patients with COPD were included for analyses. The frequency of patients classified as low FFMI varied significantly according to the choice of cut-off (32 to 54%; P < 0.05), whereas the frequency of patients with low ASMI was 62%. When applying age-gender-BMI-specific cut-offs, 254 patients (54%) were classified as low FFMI. The choice of the cut-off affected the frequency of patients with low muscle mass in all BMI categories. Overweight and obese patients with low muscle mass were more frequently males and presented worse pulmonary function, exercise capacity and muscle strength compared with overweight and obese patients with normal muscle mass., Conclusions: Approximately half of the overweight and obese patients with COPD have low muscle mass when applying age-gender-BMI-specific cut-offs. Low muscle mass is associated with worse functional outcomes in overweight and obese COPD patients.

Background.: Occupational therapy (OT) may be an important intervention in patients with COPD, but studies show conflicting results., Purpose.: To evaluate the effectiveness of home-based monodisciplinary OT in COPD patients., Method.: We conducted an observational clinical study. Main outcomes were the mean differences in the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores, pre and post intervention., Findings.: Pre- and postintervention data were obtained from 41 patients. Statistically significant increases were observed in COPM performance (5.0 ± 1.1 versus 6.9 ± 0.9; P<0.001) and satisfaction (4.6 ± 1.3 versus 6.9 ± 1.0; P<0.001). The most frequently reported occupational performance problems were found in the domains of productivity (47%) and mobility (40%), fewer in self-care (10%) and the least in leisure (3%)., Implications.: Home-based monodisciplinary OT can contribute significantly to the improvement of daily functioning of patients with COPD. OT should therefore be considered more often as part of the integrated management of these patients.

Background: Healthcare needs are complex and heterogeneous in advanced chronic organ failure. However, based on symptom clusters, groups of patients with similar quality of life, care dependency and life-sustaining treatment preferences can be identified., Aims: To evaluate the stability of symptom-based clusters over time, and whether and to what extent the clusters are able to predict patients' 2-year survival and hospitalization rates., Methods: This is a secondary analysis of a longitudinal observational study including 95 outpatients with chronic obstructive pulmonary disease (COPD) GOLD stage III-IV, 80 outpatients with chronic heart failure (CHF) NYHA stage III-IV and 80 outpatients with chronic renal failure (CRF) requiring dialysis. Patients were clustered into three groups applying K-means algorithm on baseline symptoms' severity and were then longitudinally evaluated. 2-year survival and hospital admissions during 1 year were estimated using Kaplan-Meier curves and Cox models. 1-year tendencies in symptom variation, using mixed linear models, and clusters comparison over time were performed., Results: The three clusters were unable to predict patients' survival and hospital admissions. Noteworthy, they show different trajectories of symptom variation, with Cluster 1 patients experiencing a worsening of symptoms, associated with an increased care dependency, and Cluster 2 and Cluster 3 patients being stable or having a relief in some symptoms. Although Cluster 1 is becoming more similar to Cluster 2, the three clusters preserve the overall characteristics and differences., Discussion: Symptom-based clusters might help to identify patients with different trajectories of symptom variations., Conclusion: Symptom clusters do not predict survival and hospital admissions and are stable over time.