Publications by authors named "Richard Casaburi"

180 Publications

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.

Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

Identifying a Heart Rate Recovery Criterion After a 6-Minute Walk Test in COPD.

Int J Chron Obstruct Pulmon Dis 2021 4;16:2545-2560. Epub 2021 Sep 4.

Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

Background: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.

Study Design And Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.

Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p<0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV%pred and negatively associated with airway wall thickness. An optimal HRR ≤10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58-0.66) for identifying FEV<30%pred. HRR≥11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤10 bt/min was associated with (p<0.001): ≥2 exacerbations in the previous year (OR=1.76[1.33-2.34]); CAT≥10 (OR=1.42[1.18-1.71]); mMRC≥2 (OR=1.42[1.19-1.69]); GOLD 4 (OR=1.98[1.44-2.73]) and GOLD D (OR=1.51[1.18-1.95]). HRR≤10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07-3.12], P=0.027).

Conclusion: HRR≤10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.
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http://dx.doi.org/10.2147/COPD.S311572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427685PMC
September 2021

Objectively Measured Physical Activity in Patients with COPD: Recommendations from an International Task Force on Physical Activity.

Chronic Obstr Pulm Dis 2021 08 25. Epub 2021 Aug 25.

Reval Rehabilitation Research Center, Biomed Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.

Physical activity (PA) is of key importance for health among healthy persons and individuals with COPD. PA has multiple dimensions that can be assessed and quantified objectively using activity monitors. Moreover, as shown in the published literature, variable methodologies have been used to date to quantify PA among individuals with COPD, precluding clear comparisons of outcomes across studies. The present paper aims to provide a summary of the available literature for the rationale behind using objectively measured PA and proposes a standardized methodology for assessment, including standard operating procedures for future research. The present paper therefore describes the concept of PA, reports on the importance of PA, summarizes the dimensions of PA, provides a standard operating procedure how to monitor PA using objective assessments and describes the psychometric properties of objectively measured PA. The present international task force recommends implementation of the standard operating procedure for PA data collection and reporting in the future. This should allow to further clarify the relationship between PA and clinical outcomes, to test the impact of treatment interventions on PA in individuals with COPD and to successfully propose a PA endpoint for regulatory qualification in the future.
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http://dx.doi.org/10.15326/jcopdf.2021.0213DOI Listing
August 2021

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.
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http://dx.doi.org/10.1183/23120541.00068-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311135PMC
July 2021

Objectively Measured Physical Activity as a COPD Clinical Trial Outcome.

Chest 2021 Jul 1. Epub 2021 Jul 1.

Department of Research and Development, CIRO, Horn, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.chest.2021.06.044DOI Listing
July 2021

Dynamic airway function during exercise in COPD assessed via impulse oscillometry before and after inhaled bronchodilators.

J Appl Physiol (1985) 2021 07 20;131(1):326-338. Epub 2021 May 20.

Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California.

Assessing airway function during exercise provides useful information regarding mechanical properties of the airways and the extent of ventilatory limitation in COPD. The primary aim of this study was to use impulse oscillometry (IOS) to assess dynamic changes in airway impedance across a range of exercise intensities in patients with GOLD 1-4, before and after albuterol administration. A secondary aim was to assess the reproducibility of IOS measures during exercise. Fifteen patients with COPD (8 males/7 females; age = 66 ± 8 yr; prebronchodilator FEV = 54.3 ± 23.6%Pred) performed incremental cycle ergometry before and 90 min after inhaled albuterol. Pulmonary ventilation and gas exchange were measured continuously, and IOS-derived indices of airway impedance were measured every 2 min immediately preceding inspiratory capacity maneuvers. Test-retest reproducibility of exercise IOS was assessed as mean difference between replicate tests in five healthy subjects (3 males/2 females). At rest and during incremental exercise, albuterol significantly increased airway reactance (X) and decreased airway resistance (R, R-R), impedance (Z), and end-expiratory lung volume (60% ± 12% vs. 58% ± 12% TLC, main effect = 0.003). At peak exercise, there were moderate-to-strong associations between IOS variables and IC, and between IOS variables and concavity in the expiratory limb of the spontaneous flow-volume curve. Exercise IOS exhibited moderate reproducibility in healthy subjects which was strongest with R (mean diff. = -0.01 ± 0.05 kPa/L/s; ICC = 0.68), R-R (mean diff. = -0.004 ± 0.028 kPa/L/s; ICC = 0.65), and Z (mean diff. = -0.006 ± 0.021 kPa/L/s; ICC = 0.69). In patients with COPD, exercise evoked increases in airway resistance and decreases in reactance that were ameliorated by inhaled bronchodilators. The technique of exercise IOS may aid in the clinical assessment of dynamic airway function during exercise. This study provides a novel, mechanistic insight into dynamic airway function during exercise in COPD, before and after inhaled bronchodilators. The use of impulse oscillometry (IOS) to evaluate airway function is unique among exercise studies. We show strong correlations among IOS variables, dynamic hyperinflation, and shape-changes in the spontaneous expiratory flow-volume curve. This approach may aid in the clinical assessment of airway function during exercise.
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http://dx.doi.org/10.1152/japplphysiol.00148.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325613PMC
July 2021

Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels.

Respir Res 2021 May 8;22(1):142. Epub 2021 May 8.

UCLA David Geffen School of Medicine, Los Angeles, CA, USA.

Background: We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.

Methods: Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.

Results: In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.

Conclusion: In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.

Trial Registration: Clinicaltrials.gov NCT00683722.
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http://dx.doi.org/10.1186/s12931-021-01734-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106850PMC
May 2021

Defining Modern Pulmonary Rehabilitation. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2021 05;18(5):e12-e29

Pulmonary rehabilitation is a highly effective treatment for people with chronic lung disease but remains underused across the world. Recent years have seen the emergence of new program models that aim to improve access and uptake, including telerehabilitation and low-cost, home-based models. This workshop was convened to achieve consensus on the essential components of pulmonary rehabilitation and to identify requirements for successful implementation of emerging program models. A Delphi process involving experts from across the world identified 13 essential components of pulmonary rehabilitation that must be delivered in any program model, encompassing patient assessment, program content, method of delivery, and quality assurance, as well as 27 desirable components. Only those models of pulmonary rehabilitation that have been tested in clinical trials are currently considered as ready for implementation. The characteristics of patients most likely to succeed in each program model are not yet known, and research is needed in this area. Health professionals should use clinical judgment to determine those patients who are best served by a center-based, multidisciplinary rehabilitation program. A comprehensive patient assessment is critical for personalization of pulmonary rehabilitation and for effectively addressing individual patient goals. Robust quality-assurance processes are important to ensure that any pulmonary rehabilitation service delivers optimal outcomes for patients and health services. Workforce capacity-building and training should consider the skills necessary for emerging models, many of which are delivered remotely. The success of all pulmonary rehabilitation models will be judged on whether the essential components are delivered and on whether the expected patient outcomes, including improved exercise capacity, reduced dyspnea, enhanced health-related quality of life, and reduced hospital admissions, are achieved.
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http://dx.doi.org/10.1513/AnnalsATS.202102-146STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086532PMC
May 2021

The effect of long-acting dual bronchodilator therapy on exercise tolerance, dynamic hyperinflation, and dead space during constant work rate exercise in COPD.

J Appl Physiol (1985) 2021 06 29;130(6):2009-2018. Epub 2021 Apr 29.

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California.

We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (V/V) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous [Formula: see text] (Tc[Formula: see text]) measurement was used for V/V estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV by 0.18 ± 0.21 L relative to placebo (PL; < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; = 0.013; confidence interval: 20-90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL ( ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, = 0.865). Isotime V/V did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering V/V. This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (V/V) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess V/V (transcutaneous carbon dioxide, Tc[Formula: see text]) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement.
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http://dx.doi.org/10.1152/japplphysiol.00774.2020DOI Listing
June 2021

Chronotropic Index and Acute Exacerbations of COPD: A Secondary Analysis of BLOCK COPD.

Ann Am Thorac Soc 2021 Mar 30. Epub 2021 Mar 30.

Minneapolis VA Health Care System, 20040, Pulmonary and Sleep Medicine (111N), Minneapolis, Minnesota, United States.

Rationale: Chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between chronotropic index and acute exacerbations of COPD (AECOPD) has not been evaluated.

Objective: Determine if higher chronotropic index during 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and if CI-6MW is a marker of susceptibility to adverse effects of metoprolol in COPD.

Methods: We analyzed data from the Beta-Blockers for the Prevention of Acute Exacerbations of COPD trial. We used Cox proportional hazards models to investigate the relationship between CI-6MW and time to AECOPD. We also tested for interactions between study group assignment (metoprolol vs placebo) and CI-6MW on time to AECOPD.

Results: 477 participants with exacerbation prone COPD (mean FEV1 41% of predicted) were included in this analysis. Higher CI-6MW was independently associated with a decreased risk of AECOPD of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% CI: 0.80 to 0.96), but not AECOPD requiring hospitalization (aHR 0.94; 95% CI: 0.81 to 1.05). There was a significant interaction by treatment assignment, and in stratified analysis the protective effects of a higher CI-6MW on AECOPD were negated by metoprolol use.

Conclusion: Higher CI-6MW is associated with decreased risk of AECOPD and may be an indicator of susceptibility to adverse effects of metoprolol.
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http://dx.doi.org/10.1513/AnnalsATS.202008-1085OCDOI Listing
March 2021

Respiratory exacerbations are associated with muscle loss in current and former smokers.

Thorax 2021 06 11;76(6):554-560. Epub 2021 Feb 11.

Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Objectives: Muscle wasting is a recognised extra-pulmonary complication in chronic obstructive pulmonary disease and has been associated with increased risk of death. Acute respiratory exacerbations are associated with reduction of muscle function, but there is a paucity of data on their long-term effect. This study explores the relationship between acute respiratory exacerbations and long-term muscle loss using serial measurements of CT derived pectoralis muscle area (PMA).

Design And Setting: Participants were included from two prospective, longitudinal, observational, multicentre cohorts of ever-smokers with at least 10 pack-year history.

Participants: The primary analysis included 1332 (of 2501) participants from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and 4384 (of 10 198) participants from Genetic Epidemiology of COPD (COPDGene) who had complete data from their baseline and follow-up visits.

Interventions: PMA was measured on chest CT scans at two timepoints. Self-reported exacerbation data were collected from participants in both studies through the use of periodic longitudinal surveys.

Main Outcome Measures: Age-related and excess muscle loss over time.

Results: Age, sex, race and body mass index were associated with baseline PMA. Participants experienced age-related decline at the upper end of reported normal ranges. In ECLIPSE, the exacerbation rate over time was associated with an excess muscle area loss of 1.3% (95% CI 0.6 to 1.9, p<0.001) over 3 years and in COPDGene with an excess muscle area loss of 2.1% (95% CI 1.2 to 2.8, p<0.001) over 5 years. Excess muscle area decline was absent in 273 individuals who participated in pulmonary rehabilitation.

Conclusions: Exacerbations are associated with accelerated skeletal muscle loss. Each annual exacerbation was associated with the equivalent of 6 months of age-expected decline in muscle mass. Ameliorating exacerbation-associated muscle loss represents an important therapeutic target.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222105PMC
June 2021

Transcutaneous PCO for Exercise Gas Exchange Efficiency in Chronic Obstructive Pulmonary Disease.

COPD 2021 02 17;18(1):16-25. Epub 2021 Jan 17.

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (V/V). Noninvasive methods for accurate V/V assessment during exercise in patients are lacking. The current study sought to compare transcutaneous PCO (TcPCO) with the gold standard-arterial PCO (PaCO)-and other available methods (end tidal CO and the Jones equation) for estimating V/V during incremental exercise in COPD. Ten COPD patients completed a symptom limited incremental cycle exercise. TcPCO was measured by a heated electrode on the ear-lobe. Radial artery blood was collected at rest, during unloaded cycling (UL) and every minute during exercise and recovery. Ventilation and gas exchange were measured breath-by-breath. Bland-Altman analysis examined agreement of PCO and V/V calculated using PaCO, TcPCO, end-tidal PCO (PCO) and estimated PaCO by the Jones equation (PaCO-Jones). Lin's Concordance Correlation Coefficient (CCC) was assessed. 114 measurements were obtained from the 10 COPD subjects. The bias between TcPCO and PaCO was 0.86 mmHg with upper and lower limit of agreement ranging -2.28 mmHg to 3.99 mmHg. Correlation between TcPCO and PaCO during rest and exercise was r=0.907 ( < 0.001; CCC = 0.941) and V/V using TcPCO vs. PaCO was r=0.958 ( < 0.0001; CCC = 0.967). Correlation between PaCO-Jones and PCO vs. PaCO were r=0.755, 0.755, ( < 0.001; CCC = 0.832, 0.718) and for V/V calculation (r=0.793, 0.610;  < 0.0001; CCC = 0.760, 0.448), respectively. The results support the accuracy of TcPCO to reflect PaCO and calculate V/V during rest and exercise, but not in recovery, in COPD patients, enabling improved accuracy of noninvasive assessment of gas exchange inefficiency during incremental exercise testing.
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http://dx.doi.org/10.1080/15412555.2020.1858403DOI Listing
February 2021

Interview with Prof. Dr Richard Casaburi, Presidential Awardee 2020.

Breathe (Sheff) 2020 Dec;16(4):200249

Rehabilitation Clinical Trials Center, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, USA.

https://bit.ly/3j2aSdr.
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http://dx.doi.org/10.1183/20734735.0249-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792851PMC
December 2020

Effects of Tiotropium/Olodaterol on Activity-Related Breathlessness, Exercise Endurance and Physical Activity in Patients with COPD: Narrative Review with Meta-/Pooled Analyses.

Adv Ther 2021 02 11;38(2):835-853. Epub 2020 Dec 11.

Kingston General Hospital, Kingston, ON, Canada.

One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life. A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD. Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo. In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life. We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment. We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change.
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http://dx.doi.org/10.1007/s12325-020-01557-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889690PMC
February 2021

Response.

Chest 2020 11;158(5):2232

Division of Respiratory and Critical Care Physiology and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

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http://dx.doi.org/10.1016/j.chest.2020.06.063DOI Listing
November 2020

Airflow dynamics and exhaled-breath temperature following cold-water ingestion.

Respir Physiol Neurobiol 2021 02 24;284:103564. Epub 2020 Oct 24.

Institute of Respiratory Medicine and Exercise Physiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States.

Introduction: Drinking cold water evokes decreases in spirometric indices of lung function. We studied whether this could be explained by changes in exhaled-breath temperature (EBT), airflow dynamics, and spirometer measurement sensitivity.

Methods: In a randomized/crossover design, 10 healthy adults consumed 1000 mL refrigerated water (2.1 ± 0.64 °C) or water at room temperature (19.4 ± 0.5 °C), with EBT assessed at baseline and at 5, 10, 15 and 30-min post-ingestion. The influence of EBT on pneumotachograph measurement characteristics was modelled using computational fluid dynamics (CFD).

Results: At 5-min post-ingestion, EBT was lower (p < 0.001) following the ingestion of cold water versus water at room-temperature (31.7 ± 1.1 vs. 33.0 ± 0.9 °C), and remained lower until 30-min post-ingestion. At a flow of 8 L s, a decrease in EBT of 2.1 °C (as observed following cold-water ingestion) was modelled to underpredict lung volume by 0.7%.

Conclusions: Cold water reduces EBT below baseline but effects pneumotachograph measurements only negligibly. Therefore, decreased lung function following cold-water ingestion likely has a physiological explanation which warrants further study.
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http://dx.doi.org/10.1016/j.resp.2020.103564DOI Listing
February 2021

Long-Term Benefits of Pulmonary Rehabilitation in Patients With COPD: A 2-Year Follow-Up Study.

Chest 2021 03 22;159(3):967-974. Epub 2020 Oct 22.

Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX.

Background: Pulmonary rehabilitation (PR) improves exercise capacity in patients with COPD in the short term.

Research Question: In patients with COPD, does 8 weeks of PR confer long-term benefits on symptoms of dyspnea, anxiety, and depression, and on quality of life, 2 years after completion?

Study Design And Methods: One hundred and sixty-five patients with COPD completed an 8-week, community-based, comprehensive PR program, comprising 2-h sessions twice weekly. Sessions included aerobic exercise and an educational program. Patients were encouraged to perform daily walking exercise up to 30 min at home. We evaluated a number of outcome measures at baseline, 8 weeks, and 2 years, including the following: dyspnea measured with the modified Medical Research Council (mMRC) questionnaire, quality of life assessed with the St. George's Respiratory Questionnaire (SGRQ), and anxiety measured with the Anxiety Inventory for Respiratory Disease (AIR) and the Depression Anxiety Stress Scale (DASS). In addition, we measured exercise capacity, using the Incremental Shuttle Walk Test (ISWT), at baseline and 8 weeks.

Results: Mean age (SD) was 72 (8.6) years; 55% were men. At 8 weeks, improvements in mMRC, SGRQ, ISWT, DASS, and AIR were all statistically significant (P < .001). During the 2-year follow-up, changes observed at 8 weeks were maintained for anxiety symptoms, and for symptoms, impact, and total SGRQ scores. In multivariate analysis, initial elevated levels of dyspnea, depression, anxiety, and decreased exercise capacity predicted greater quality of life improvement at 2 years (all P < .001).

Interpretation: Over a 2-year period, an effective 8-week PR program provides sustained improvement in anxiety and quality of life. Short-term improvements in dyspnea, depression, and stress symptoms at 8 weeks were not maintained at 2 years.
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http://dx.doi.org/10.1016/j.chest.2020.10.032DOI Listing
March 2021

Serum Amyloid A in Stable COPD Patients is Associated with the Frequent Exacerbator Phenotype.

Int J Chron Obstruct Pulmon Dis 2020 30;15:2379-2388. Epub 2020 Sep 30.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, People's Republic of China.

Background: We sought to determine whether circulating inflammatory biomarkers were associated with the frequent exacerbator phenotype in stable COPD patients ie, those with two or more exacerbations in the previous year.

Methods: Eighty-eight stable, severe, COPD patients (4 females) were assessed for exacerbation frequency, pulmonary function, fraction of expired nitric oxide (FNO); inflammatory variables were measured in venous blood. Logistic regression assessed associations between the frequent exacerbator phenotype and systemic inflammation.

Results: Compared with infrequent exacerbators, frequent exacerbators (n=10; 11.4%) had greater serum concentration (median (25th-75th quartile)) of serum amyloid A (SAA; 134 (84-178) vs 71 (38-116) ng/mL; P=0.024), surfactant protein D (SP-D; 15.6 (9.0-19.3) vs 8.5 (3.6-14.9) ng/mL; P=0.049) and interleukin-4 (IL-4; 0.12 (0.08-1.44) vs 0.03 (0.01-0.10) pg/mL; P=0.001). SAA, SP-D and IL-4 were not significantly correlated with FEV%predicted or FVC %predicted. After adjusting for sex, age, BMI, FEV/FVC and smoking pack-years, only SAA remained independently associated with the frequent exacerbator phenotype (OR 1.49[1.09-2.04]; P=0.012). The odds of being a frequent exacerbator was 18-times greater in the highest SAA quartile (≥124.1 ng/mL) than the lowest SAA quartile (≤44.1 ng/mL) (OR 18.34[1.30-258.81]; P=0.031), and there was a significant positive trend of increasing OR with increasing SAA quartile (P=0.008). For SAA, the area under the receiver operating characteristic curve was 0.721 for identification of frequent exacerbators; an SAA cut-off of 87.0 ng/mL yielded an 80% sensitivity and 61.5% specificity.

Conclusion: In stable COPD patients, SAA was independently associated with the frequent exacerbator phenotype, suggesting that SAA may be a useful serum biomarker to inform progression or management in COPD.
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http://dx.doi.org/10.2147/COPD.S266844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535123PMC
June 2021

A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Chronic Obstr Pulm Dis 2020 Oct;7(4):346-361

University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.

Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.

Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.

Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883903PMC
October 2020

Comparative measurement properties of constant work rate cycling and the endurance shuttle walking test in COPD: the TORRACTO clinical trial.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620926858

Rehabilitation Clinical Trial Centre, Los Angeles Biomedical Research Institute at Harbour-UCLA Medical Centre, Torrance, CA, USA.

Background: Exercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE.

Methods: This analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 μg or T/O 5/5 μg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed.

Results: The intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37-0.71] and 0.75 (95% CI 0.63-0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT ( <0.0001). Both tests were responsive to bronchodilator treatment: there was a 19% increase in endurance time from baseline at week 6 ( = 0.0006) assessed with CWRCE, and a 20% increase in endurance time assessed with ESWT ( = 0.0013).

Conclusions: Both exercise tests performed well in a multicentre clinical trial. Although the locus of symptom limitation differed between the two tests, both were reliable and responsive to bronchodilation. For future clinical trials, the choice of test should depend on the study requirements.

Clinicaltrials.gov Identifier: NCT01525615.
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http://dx.doi.org/10.1177/1753466620926858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268161PMC
June 2021

Serum IgG Levels and Risk of COPD Hospitalization: A Pooled Meta-analysis.

Chest 2020 10 19;158(4):1420-1430. Epub 2020 May 19.

Department of Medicine, University of Maryland, Baltimore, MD.

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations.

Research Question: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD.

Study Design And Methods: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status.

Results: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001.

Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.
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http://dx.doi.org/10.1016/j.chest.2020.04.058DOI Listing
October 2020

Chicken Soup in the Time of COVID.

Chest 2020 09 6;158(3):864-865. Epub 2020 May 6.

Division of Respiratory and Critical Care Physiology and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

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http://dx.doi.org/10.1016/j.chest.2020.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201233PMC
September 2020

Heme metabolism genes Downregulated in COPD Cachexia.

Respir Res 2020 May 1;21(1):100. Epub 2020 May 1.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Introduction: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

Methods: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m among women and < 17 kg/m among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.

Results: The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).

Discussion: Several replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.
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http://dx.doi.org/10.1186/s12931-020-01336-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193359PMC
May 2020

Muscle Oxidative Capacity Is Reduced in Both Upper and Lower Limbs in COPD.

Med Sci Sports Exerc 2020 10;52(10):2061-2068

Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.

Introduction: Skeletal muscle atrophy, weakness, mitochondrial loss, and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction occurs in both upper and lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in upper and lower limbs of COPD patients compared with controls.

Methods: Oxidative capacity of the forearm and medial gastrocnemius was measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min) in 20 COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2/3/4, n = 7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps per day and vector magnitude units per minute (VMU·min) were assessed using triaxial accelerometry. Differences between group and limb were assessed by two-way ANOVA.

Results: There was a significant main effect of group (F = 11.2, ηp = 0.13, P = 0.001): k was lower in both upper and lower limb muscles in COPD (1.01 ± 0.17 and 1.05 ± 0.24 min) compared with CON (1.29 ± 0.49 and 1.54 ± 0.60 min). There was no effect on k of limb (F = 1.8, ηp = 0.02, P = 0.18) or group-limb interaction (P = 0.35). (VMU·min) was significantly lower in COPD (-38%; P = 0.042). Steps per day did not differ between COPD (4738 ± 3194) and CON (6372 ± 2107; P = 0.286), although the difference exceeded a clinically important threshold (>600-1100 steps per day).

Conclusions: Compared with CON, muscle oxidative capacity was lower in COPD in both upper (-20%) and lower (-30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles.
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http://dx.doi.org/10.1249/MSS.0000000000002364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497478PMC
October 2020

Association of Guideline-Recommended COPD Inhaler Regimens With Mortality, Respiratory Exacerbations, and Quality of Life: A Secondary Analysis of the Long-Term Oxygen Treatment Trial.

Chest 2020 08 9;158(2):529-538. Epub 2020 Apr 9.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA; Health Services Research & Development Center of Innovation for Veteran-centered and Value-driven Care, VA Puget Sound Healthcare System, Seattle, WA.

Background: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear.

Research Question: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?

Study Design And Methods: We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site.

Results: The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66).

Interpretation: Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.
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http://dx.doi.org/10.1016/j.chest.2020.02.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417382PMC
August 2020

Low FVC/TLC in Preserved Ratio Impaired Spirometry (PRISm) is associated with features of and progression to obstructive lung disease.

Sci Rep 2020 03 20;10(1):5169. Epub 2020 Mar 20.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

One quarter of individuals with Preserved Ratio Impaired Spirometry (PRISm) will develop airflow obstruction, but there are no established methods to identify these individuals. We examined the utility of FVC/TLC in identifying features of obstructive lung disease. The ratio of post-bronchodilator FVC and TLC from chest CT (FVC/TLC) among current and former smokers with PRISm (FEV/FVC ≥ 0.7 and FEV1 < 80%) in COPDGene was used to stratify subjects into quartiles: very high, high, low, and very low. We examined the associations between FVC/TLC quartiles and (1) baseline characteristics, (2) respiratory exacerbations, (3) progression to COPD at 5 years, and (4) all-cause mortality. Among participants with PRISm at baseline (n = 1,131), the very low FVC/TLC quartile was associated with increased gas trapping and emphysema, and higher rates of progression to COPD at 5 years (36% versus 17%; p < 0.001) relative to the very high quartile. The very low FVC/TLC quartile was associated with increased total (IRR = 1.65; 95% CI [1.07-2.54]) and severe (IRR = 2.24; 95% CI [1.29-3.89]) respiratory exacerbations. Mortality was lower in the very high FVC/TLC quartile relative to the other quartiles combined. Reduced FVC/TLC ratio in PRISm is associated with increased symptoms, radiographic emphysema and gas trapping, exacerbations, and progression to COPD.
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http://dx.doi.org/10.1038/s41598-020-61932-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083974PMC
March 2020

Survey of Exercise Prescription in US Pulmonary Rehabilitation Programs.

J Cardiopulm Rehabil Prev 2020 03;40(2):116-119

Department of Medicine, University of California San Francisco (Mr Garvey); Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California (Dr Casaburi); REVAL-Rehabilitation Research Center, BIOMED-Biomedical Research Institute, Faculty of Rehabilitation Sciences and Physiotherapy, Hasselt University, Diepenbeek, Belgium (Dr Spruit and Ms De Brandt); Department of Research and Education, CIRO+, Center of Expertise for Chronic Organ Failure, Horn, the Netherlands (Dr Spruit); and Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands (Dr Spruit).

Purpose: Pulmonary rehabilitation (PR) is the standard of care for chronic, symptomatic lung disease. Current scientific and clinical guidelines recommend PR to improve dyspnea, functional capacity, and quality of life. Several PR guidelines provide recommendations about the mode, intensity, duration, frequency, and progression of exercise-based interventions. There are variations in the components of PR exercise prescription that may influence the response to PR, as well as variations in how the exercise prescription and its components are determined and monitored. Therefore, the purpose of this investigation was to identify current PR exercise prescription practices via survey sent to 1758 PR programs in the United States.

Methods: The American Association of Cardiovascular and Pulmonary Rehabilitation administered surveys in 2013 and 2016 to US-based PR providers.

Results: Responses were returned from 371 PR providers (vs 380 in 2013). There was an increase in responses for all options describing exercise prescription methodology in the 2016 survey, with each element (frequency, intensity, time [duration], and type [mode]; FITT) demonstrating significant increase in use. There was a significant increase in 3 methods of determining exercise goals in 2016 versus 2013: duration (P = .017), distance (P = .010), and metabolic equivalents of task (P ≤ .001).

Conclusions: The 2016 survey responses show a greater use of guideline-based exercise prescription methodology, with an increase in use of FITT methodology for exercise prescription.
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http://dx.doi.org/10.1097/HCR.0000000000000467DOI Listing
March 2020

Virtual Reality Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

Int J Chron Obstruct Pulmon Dis 2020 13;15:117-124. Epub 2020 Jan 13.

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.

Purpose: This study compared the effects of inpatient-based rehabilitation program of patients with chronic obstructive pulmonary disease (COPD) using non-immersive virtual reality (VR) training with a traditional pulmonary rehabilitation program. The aims of this study were to determine 1) whether rehabilitation featuring both VR as well as exercise training provides benefits over exercise training (ET) alone and 2) whether rehabilitation featuring VR training instead of exercise training provides equivalent benefits.

Patients And Methods: The study recruited 106 patients with COPD to a 2-week high-intensity, five times a week intervention. Randomized into three groups, 34 patients participated in a traditional pulmonary rehabilitation program including endurance exercise training (ET), 38 patients participated in traditional pulmonary rehabilitation, including both endurance exercise training and virtual reality training (ET+VR) and 34 patients participated in pulmonary rehabilitation program including virtual reality training but no endurance exercise training (VR). The traditional pulmonary rehabilitation program consisted of fitness exercises, resistance respiratory muscle and relaxation training. Xbox 360 and Kinect Adventures software were used for the VR training of lower and upper body strength, endurance, trunk control and dynamic balance. Comparison of the changes in the Senior Fitness Test was the primary outcome. Analysis was performed using linear mixed-effects models.

Results: The comparison between ET and ET+VR groups showed that ET+VR group was superior to ET group in Arm Curl (p<0.003), Chair stand (p<0.008), Back scratch (p<0.002), Chair sit and reach (p<0.001), Up and go (p<0.000), 6-min walk test (p<0.011). Whereas, the comparison between ET and VR groups showed that VR group was superior to ET group in Arm Curl (p<0.000), Chair stand (p<0.001), 6-min walk test (p<0.031).

Conclusion: Results suggest that pulmonary rehabilitation program supplemented with VR training is beneficial intervention to improve physical fitness in patients with COPD.
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http://dx.doi.org/10.2147/COPD.S223592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968810PMC
February 2021

Machine Learning Characterization of COPD Subtypes: Insights From the COPDGene Study.

Chest 2020 05 28;157(5):1147-1157. Epub 2019 Dec 28.

Department of Epidemiology, University of Colorado, Denver, Aurora, CO.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.
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http://dx.doi.org/10.1016/j.chest.2019.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242638PMC
May 2020
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