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1.  Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD 
Background
Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructive pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients with COPD.
Methods
PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10−10–10−6 M), with dexamethasone (10−10–10−6 M), or with both. Phosphorylated glucocorticoid receptor (GR) was measured by Western blot.
Results
Baseline (P<0.01) and LPS-induced (P<0.05) CXCL8 release was greater in PBMCs from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone (10−6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increased in PBMCs of COPD. GW856553 (10−9 and 10−10 M) synergistically increased the inhibitory effect of dexamethasone (10−8 and 10−6 M) on LPS-induced CXCL8 release in COPD. Similar results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.
Conclusion
p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
doi:10.2147/COPD.S72403
PMCID: PMC4322842
glucocorticoid receptor; p38 mitogen-activated protein kinase
2.  Detection of acute deterioration in health status visit among COPD patients by monitoring COPD assessment test score 
Background
The Chronic Obstructive Pulmonary Disease Assessment Test (CAT) could play a role in detecting acute deterioration in health status during monitoring visits in routine clinical practice.
Objective
To evaluate the discriminative property of a change in CAT score from a stable baseline visit for detecting acute deterioration in health status visits of chronic obstructive pulmonary disease (COPD) patients.
Methods
The CAT questionnaire was administered to stable COPD patients routinely attending the chest clinic of Chiang Mai University Hospital who were monitored using the CAT score every 1–3 months for 15 months. Acute deterioration in health status was defined as worsening or exacerbation. CAT scores at baseline, and subsequent visits with acute deterioration in health status were analyzed using the t-test. The receiver operating characteristic curve was performed to evaluate the discriminative property of change in CAT score for detecting acute deterioration during a health status visit.
Results
A total of 354 follow-up visits were made by 140 patients, aged 71.1±8.4 years, with a forced expiratory volume in 1 second of 47.49%±18.2% predicted, who were monitored for 15 months. The mean CAT score change between stable baseline visits, by patients’ and physicians’ global assessments, were 0.05 (95% confidence interval [CI], −0.37–0.46) and 0.18 (95% CI, −0.23–0.60), respectively. At worsening visits, as assessed by patients, there was significant increase in CAT score (6.07; 95% CI, 4.95–7.19). There were also significant increases in CAT scores at visits with mild and moderate exacerbation (5.51 [95% CI, 4.39–6.63] and 8.84 [95% CI, 6.29–11.39], respectively), as assessed by physicians. The area under the receiver operating characteristic curve of CAT score change for the detection of acute deterioration in health status was 0.89 (95% CI, 0.84–0.94), and the optimum cut-off point score was at 4, with a sensitivity, specificity, and accuracy of 76.8%, 83.6%, and 82.4%, respectively.
Conclusions
Change in CAT score during monitoring visits is useful for detecting acute deterioration in health status, and a change of 4 units could make a moderate prediction of acute deterioration in health status.
doi:10.2147/COPD.S76128
PMCID: PMC4322832
chronic obstructive pulmonary disease; health status; questionnaire
3.  COPD: balancing oxidants and antioxidants 
Chronic obstructive pulmonary disease (COPD) is one of the most common chronic illnesses in the world. The disease encompasses emphysema, chronic bronchitis, and small airway obstruction and can be caused by environmental exposures, primarily cigarette smoking. Since only a small subset of smokers develop COPD, it is believed that host factors interact with the environment to increase the propensity to develop disease. The major pathogenic factors causing disease include infection and inflammation, protease and antiprotease imbalance, and oxidative stress overwhelming antioxidant defenses. In this review, we will discuss the major environmental and host sources for oxidative stress; discuss how oxidative stress regulates chronic bronchitis; review the latest information on genetic predisposition to COPD, specifically focusing on oxidant/antioxidant imbalance; and review future antioxidant therapeutic options for COPD. The complexity of COPD will necessitate a multi-target therapeutic approach. It is likely that antioxidant supplementation and dietary antioxidants will have a place in these future combination therapies.
doi:10.2147/COPD.S42414
PMCID: PMC4321570
cigarette smoking; mucins; gene regulation; Chinese herbs; acupuncture; dietary antioxidants
4.  Cardiovascular and inflammatory effects of simvastatin therapy in patients with COPD: a randomized controlled trial 
Background
There is excess cardiovascular mortality in patients with chronic obstructive pulmonary disease. Aortic stiffness, an independent predictor of cardiovascular risk, and systemic and airway inflammation are increased in patients with the disease. Statins modulate aortic stiffness and have anti-inflammatory properties. A proof-of-principle, double-blind, randomized trial determined if 6 weeks of simvastatin 20 mg once daily reduced aortic stiffness and systemic and airway inflammation in patients with chronic obstructive pulmonary disease.
Methods
Stable patients (n=70) were randomized to simvastatin (active) or placebo. Pre-treatment and post-treatment aortic stiffness, blood pressure, spirometry, and circulating and airway inflammatory mediators and lipids were measured. A predefined subgroup analysis was performed where baseline aortic pulse wave velocity (PWV) was >10 m/sec.
Results
Total cholesterol dropped in the active group. There was no significant change in aortic PWV between the active group and the placebo group (−0.7 m/sec, P=0.24). In those with aortic stiffness >10 m/sec (n=22), aortic PWV improved in the active group compared with the placebo group (−2.8 m/sec, P=0.03). Neither systemic nor airway inflammatory markers changed.
Conclusion
There was a nonsignificant improvement in aortic PWV in those taking simvastatin 20 mg compared with placebo, but in those with higher baseline aortic stiffness (a higher risk group) a significant and clinically relevant reduction in PWV was shown.
doi:10.2147/COPD.S76061
PMCID: PMC4321645
chronic obstructive pulmonary disease; arterial stiffness; statins
5.  Analysis of autonomic modulation after an acute session of resistance exercise at different intensities in chronic obstructive pulmonary disease patients 
Purpose
Physical exercises are employed as part of the treatment of patients with chronic obstructive pulmonary disease (COPD); however information regarding cardiac autonomic modulation after an acute session of resistance exercise (RE) is unknown. The aim of this study was to evaluate the cardiac autonomic modulation, via heart rate variability after an acute session of RE applied at different intensities in COPD patients.
Patients and methods
Twelve COPD patients underwent an acute session of RE with an intensity of 60% and another of 90% of the one repetition maximum test. For analysis of autonomic modulation, heart rate was recorded beat-by-beat for 20 minutes at rest and after the training session. Heart rate variability indexes were obtained in the time and frequency domains for the assessment of autonomic modulation.
Results
Regardless of exercise intensity, RE acute sessions influenced the autonomic modulation when the recovery period was compared with the baseline. An increase in standard deviation of normal to normal RR intervals was observed throughout recovery time after the RE, as compared to baseline in both protocols: 60% and 90% of the one repetition maximum test. The spectral component of low frequency index (ms) was higher throughout recovery when compared to baseline in both protocols. The same was also observed in the spectral component of high frequency index (ms) for the protocols of 60% and 90%.
Conclusion
RE sessions impact on the autonomic modulation of COPD patients by promoting differences in the recovery period compared to baseline, regardless of the intensity of the exercise performed.
doi:10.2147/COPD.S64345
PMCID: PMC4321648
heart rate variability; autonomic nervous system; sympathetic nervous system; parasympathetic nervous system; physical exercise
6.  Associated bone mineral density and obstructive sleep apnea in chronic obstructive pulmonary disease 
Background
Osteoporosis is an important issue for patients with chronic obstructive pulmonary disease (COPD). Worse systemic inflammation and reduced exercise capacity have been reported in COPD patients with obstructive sleep apnea (OSA), implying that OSA may be an independent factor for osteoporosis in COPD patients.
Methods
A total of 66 patients with bone mineral density (BMD) and polysomnography results from a previous COPD cohort (January 2008 to January 2013) were retrospectively enrolled. Clinical characteristics such as medication, pulmonary function, BMD, and results of polysomnography were analyzed.
Results
The BMD in those with OSA was significantly lower than in those without OSA (−1.99±1.63 versus −1.27±1.14, P=0.045). In univariate analysis, body mass index, forced expiratory volume in 1 second, percentage of predicted value, incremental shuttle walk test, apnea–hypopnea index, and oxygen desaturation index (ODI) were significantly associated with BMD. After multivariate linear regression analysis, the ODI was still an independent factor for BMD. In addition, smaller total lung capacity is significantly associated with higher ODI and lower BMD, which implies that lower BMD might cause severer OSA via decreased total lung capacity.
Conclusion
OSA may be an independent factor for BMD in patients with COPD, which implies a possible vicious cycle takes place in these patients.
doi:10.2147/COPD.S72099
PMCID: PMC4321657
chronic obstructive pulmonary disease; osteoporosis; total lung capacity
7.  Analysis of diaphragmatic movement before and after pulmonary rehabilitation using fluoroscopy imaging in patients with COPD 
Background
The diaphragm is the principal inspiratory muscle. The purpose of this study was to assess improvements in diaphragmatic movement before and after pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD), using a fluoroscopy-guided chest X-ray.
Patients and methods
Among 117 patients with COPD receiving pulmonary rehabilitation who underwent the initial fluoroscopy-guided chest X-ray and pulmonary function test, 37 of those patients who underwent both initial and follow-up fluoroscopy and pulmonary function tests were enrolled in this study. After hospital education, participants received pulmonary rehabilitation through regular home-based training for at least 3 months by the same physiatrist. We assessed the changes in diaphragm area with fluoroscopy-guided posteroanterior chest X-rays between pre- and postpulmonary rehabilitation. To minimize radiation hazards for subjects, the exposure time for fluoroscopy to take chest X-rays was limited to less than 5 seconds.
Results
There were significant improvements (2,022.8±1,548.3 mm2 to 3,010.7±1,495.6 mm2 and 2,382.4±1,475.9 mm2 to 3,315.9±1,883.5 mm2; right side P=0.001 and left side P=0.019, respectively) in diaphragmatic motion area during full inspiration and expiration in both lungs after pulmonary rehabilitation. Pulmonary function tests showed no statistically significant difference between pre- and postpulmonary rehabilitation.
Conclusion
The study suggests that the strategy to assess diaphragm movement using fluoroscopy is a relatively effective tool for the evaluation of pulmonary rehabilitation in COPD patients in terms of cost and time savings compared with computed tomography or magnetic resonance imaging.
doi:10.2147/COPD.S74438
PMCID: PMC4315303
COPD; pulmonary rehabilitation; fluoroscopy; diaphragmatic movement
8.  A score to predict short-term risk of COPD exacerbations (SCOPEX) 
Background
There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.
Methods
Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.
Results
The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).
Conclusion
SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.
doi:10.2147/COPD.S69589
PMCID: PMC4315304
chronic obstructive pulmonary disease; exacerbation; model; predictor; inhaled corticosteroids; bronchodilators
9.  Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls 
Purpose
To assess the importance of inflammation in chronic obstructive pulmonary disease (COPD) by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups.
Patients and methods
This was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures.
Results
The overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8), surfactant protein D (SP-D), and Krebs von den Lungen 6 (KL-6) in sputum and clara cell 16 (CC-16), high-sensitivity C-reactive protein (hs-CRP), and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; P<0.001), neutrophils and MMP-9 (P<0.001), macrophages and KL-6 (P<0.01), total cell count and IL-8 (P<0.05), neutrophils and IL-8 (P<0.05), and macrophages and MMP-9 (P<0.05). Significant correlations were also observed between some inflammatory cells in sputum and biomarkers in serum, with the most significant between serum CC-16 and both total cell count (P<0.005) and neutrophils (P<0.005) in sputum.
Conclusion
These results provide evidence for the first time that COPD in Japanese patients is a multicomponent disease, involving both airway and systemic inflammation, in addition to airway obstruction. Therefore, intervention with anti-inflammatory therapy may provide additional benefit in disease management of COPD in Japan.
doi:10.2147/COPD.S74557
PMCID: PMC4315175
chronic obstructive pulmonary disease; inflammatory cells; biomarkers; sputum; serum
10.  Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units 
Introduction
Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement. The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT).
Methods
Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1) <50% of predicted value from 27 secondary care respiratory units in Sweden. Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables.
Results
Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments. Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] −0.07 [−0.13 to −0.02]), EQ-5D VAS (−5.17 [−9.42 to −0.92]), and CAT (3.78 [2.35 to 5.20]). Musculoskeletal symptoms were significantly associated with worse EQ-5D index (−0.08 [−0.14 to −0.02]), osteoporosis with worse EQ-5D VAS (−4.65 [−9.27 to −0.03]), and depression with worse EQ-5D index (−0.10 [−0.17 to −0.04]). In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients.
Conclusion
The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD. Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL. We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD.
doi:10.2147/COPD.S74645
PMCID: PMC4310343  PMID: 25653516
chronic bronchitis; EQ-5D; CAT; osteoporosis; depression; musculoskeletal symptoms
11.  Continuing to Confront COPD International Surveys: comparison of patient and physician perceptions about COPD risk and management 
Purpose
Using data from the Continuing to Confront COPD International Physician and Patient Surveys, this paper describes physicians’ attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) prognosis, and compares physician and patient perceptions with respect to COPD.
Methods
In 12 countries worldwide, 4,343 patients with COPD were identified through systematic screening of population samples, and 1,307 physicians who regularly saw patients with COPD were sampled from in-country professional databases. Both patients and physicians completed surveys about their COPD knowledge, beliefs, and perceptions; physicians answered further questions about diagnostic methods and treatment choices for COPD.
Results
Most physicians (79%) responded that the long-term health outlook for patients with COPD has improved over the past decade, largely attributed to the introduction of better medications. However, patient access to medication remains an issue in many countries, and some physicians (39%) and patients (46%) agreed/strongly agreed with the statement “there are no truly effective treatments for COPD”. There was strong concordance between physicians and patients regarding COPD management practices, including the use of spirometry (86% of physicians and 76% of patients reporting they used/had undergone a spirometry test) and smoking cessation counseling (76% of physicians reported they counseled their smoking patients at every clinic visit, and 71% of smoking patients stated that they had received counseling in the past year). However, the groups differed in their perception about the role of smoking in COPD, with 78% of physicians versus 38% of patients strongly agreeing with the statement “smoking is the cause of most cases of COPD”.
Conclusion
The Continuing to Confront COPD International Surveys demonstrate that while physicians and patients largely agreed about COPD management practices and the need for more effective treatments for COPD, a gap exists about the causal role of smoking in COPD.
doi:10.2147/COPD.S74315
PMCID: PMC4310342  PMID: 25653515
chronic obstructive pulmonary disease; physician survey; patient survey; beliefs; perceptions
12.  Dynamic hyperinflation and dyspnea during the 6-minute walk test in stable chronic obstructive pulmonary disease patients 
The purpose of this study was to investigate the relationship between dynamic hyperinflation and dyspnea and to clarify the characteristics of dyspnea during the 6-minute walk test (6MWT) in chronic obstructive pulmonary disease patients. Twenty-three subjects with stable moderate chronic obstructive pulmonary disease (age 73.8±5.8 years, all male) took part in this study. During the 6MWT, ventilatory and gas exchange parameters were measured using a portable respiratory gas analysis system. Dyspnea and oxygen saturation were recorded at the end of every 2 minute period during the test. There was a significant decrease in inspiratory capacity during the 6MWT. This suggested that dynamic hyperinflation had occurred. Dyspnea showed a significant linear increase, and there was a significant negative correlation with inspiratory capacity. It was suggested that one of the reasons that dyspnea developed during the 6MWT was the dynamic hyperinflation. Even though the tidal volume increased little after 2 minutes, dyspnea increased linearly to the end of the 6MWT. These results suggest that the mechanisms generating dyspnea during the 6MWT were the sense of respiratory effort at an early stage and then the mismatch between central motor command output and respiratory system movement.
doi:10.2147/COPD.S73717
PMCID: PMC4304629  PMID: 25632228
field walking test; chronic respiratory diseases; respiratory gas analysis; inspiratory capacity; IC; inspiratory reserve volume; IRV; Borg CR-10 scale; COPD
13.  EGLN2 and RNF150 genetic variants are associated with chronic obstructive pulmonary disease risk in the Chinese population 
Purpose
Chronic obstructive pulmonary disease (COPD) is a major and an increasingly prevalent health problem worldwide. It has been reported that genetic variation may play a role in the development and severity of COPD. The purpose of this study was to investigate whether single nucleotide polymorphisms in multiple genetic variants were associated with COPD in a Chinese population from Hainan province.
Methods
In this case-control study, including 200 COPD patients and 401 controls, we genotyped 14 tag single nucleotide polymorphisms and evaluated their association with COPD using the χ2 test and genetic model analysis.
Results
The polymorphism, rs10007052, in the RNF150 gene was significantly associated with COPD risk at a 5% level (odds ratio =1.43, 95% confidence interval, 1.06–1.95, P=0.020). In the log-additive model, the minor allele (C) of rs10007052 in the RNF150 gene (P=0.026) and the minor allele (C) of rs3733829 in the EGLN2 gene (P=0.037) were associated with COPD risk after adjustment for age, sex, and smoking status. Further haplotype analysis revealed that the “CT” haplotype composed of the mutant allele (C) of rs7937, rs3733829 in the EGLN2 gene, was associated with increased COPD risk (odds ratio =1.55; 95% confidence interval, 1.05–2.31; P=0.029).
Conclusion
Our findings indicated that rs10007052 in the RNF150 and rs3733829 in the EGLN2 gene were significantly associated with the risk of COPD in Chinese populations of Hainan province. These data may provide novel insights into the pathogenesis of COPD, although further studies with larger numbers of participants worldwide are needed for validation of our conclusions.
doi:10.2147/COPD.S73031
PMCID: PMC4298296  PMID: 25609945
case-control studies; COPD; tag single-nucleotide polymorphism
14.  Whole-body vibration improves functional capacity and quality of life in patients with severe chronic obstructive pulmonary disease (COPD): a pilot study 
Background
Exercise intolerance is a common development in patients with chronic obstructive pulmonary disease (COPD). There is little data on the use of an isolated program using vibration platform training on functional capacity in these patients, which is an area that deserves investigation.
Aim
To investigate the effect of training on a vibrating platform (whole-body vibration [WBV]) on functional performance and quality of life of subjects with COPD.
Methods
A randomized controlled crossover pilot study with eleven subjects with COPD (forced expiratory volume in 1 second [FEV1]% predicted =14.63±11.14; forced vital capacity [FVC]% predicted =48.84±15.21; FEV1/FVC =47.39±11.63) underwent a 12-week WBV training program. Participants were randomized into the intervention group (IG) undergoing three sessions per week for a total of 12 weeks and control group (CG) without intervention. We evaluated the 6-minute walk test (6MWT), distance walked (DW), duration of the walk (TW), and index of perceived exertion (IPE), quality of life using St George’s Respiratory Questionnaire (SGRQ) and developed a 12-week program of training on a vibrating platform.
Results
The mean age was 62.91±8.82 years old (72.7% male). The DW increased at the end of training with a difference between groups of 75 m; all domains of the SGRQ improved at the end of training. The effect size Cohen’s d ranged from small to large for all the measured results.
Conclusion
These preliminary results suggest that WBV may potentially be a safe and feasible way to improve functional capacity in the 6MWT of patients with COPD undergoing a training program on the vibrating platform as well as in all domains of the SGRQ quality of life. However, further studies with a larger number of patients are needed to establish the long-term effect on functional capacity and quality of life in these patients.
doi:10.2147/COPD.S73751
PMCID: PMC4296910  PMID: 25624756
pulmonary rehabilitation; exercise training; exercise tolerance; SGRQ
15.  Long-term efficacy of intensive cycle ergometer exercise training program for advanced COPD patients 
Background
Exercise training has been incorporated into the international guidelines for the treatment of chronic obstructive pulmonary disease (COPD). However, the long-term efficacy of the training program for patients with advanced COPD has never been evaluated in Thailand.
Purpose
To determine the long-term efficacy of intensive cycle ergometer exercise program on various clinical parameters of patients with advanced COPD.
Materials and methods
The patients with advanced COPD were separated into two groups: the intensive ergometer exercise program group and the control group. The clinical parameters of all the patients were assessed at baseline, every month for the first 3 months, and then every 3 months until they had completed the 24-month follow-up. Mann–Whitney U test was used to compare baseline mean differences between the groups. Repeated measure analysis was applied to determine the progress in all parameters during the entire follow-up period. Mean incase imputation method was applied to estimate the parameters of dropout cases.
Results
A total of 41 patients were enrolled: 27 in the intensive ergometer exercise program group and 14 in the control group. The intensive cycle ergometer exercise program group showed statistically significant improvements in muscle strength (from month 1 till the end of the study, month 24), endurance time (from month 1 till the end of measurement, month 12) and clinically significant improvements in 6-minute walk distance (from month 2 until month 9), dyspnea severity by transitional dyspnea index (from month 1 till the end of the study, month 24), and quality of life (from month 1 till the end of the study, month 24). There was no significant difference in survival rates between the groups.
Conclusion
The intensive ergometer exercise training program revealed meaningful long-term improvements in various clinical parameters for up to 2 years. These promising results should encourage health care professionals to promote exercise training for patients with advanced COPD who have limited daily activities despite optimal medication control.
doi:10.2147/COPD.S73398
PMCID: PMC4296915  PMID: 25624757
chronic obstructive pulmonary disease; pulmonary rehabilitation; ergometer training; physical endurance; strength training
16.  Continuing to Confront COPD International Physician Survey: physician knowledge and application of COPD management guidelines in 12 countries 
Aim
Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.
Materials and methods
Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face. Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.
Results
Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P<0.001) to diagnose COPD and frequently included validated patient-reported outcome measures (PCPs 67%, respiratory specialists 81%; P<0.001). Respiratory specialists were more likely than PCPs to report awareness of the GOLD global strategy (93% versus 58%, P<0.001); however, when presented with patient scenarios, they did not always perform better than PCPs with regard to recommending GOLD-concordant treatment options. The proportion of PCPs and respiratory specialists providing first- or second-choice treatment options concordant with GOLD strategy for a GOLD B-type patient was 38% versus 67%, respectively. For GOLD C and D-type patients, the concordant proportions for PCPs and respiratory specialists were 40% versus 38%, and 57% versus 58%, respectively.
Conclusion
This survey of physicians in 12 countries practicing in the primary care and respiratory specialty settings showed high awareness of COPD-management guidelines. Frequent use of guideline-recommended COPD diagnostic practices was reported; however, gaps in the application of COPD-treatment recommendations were observed, warranting further evaluation to understand potential barriers to adopt guideline recommendations.
doi:10.2147/COPD.S70162
PMCID: PMC4284025  PMID: 25565799
chronic obstructive pulmonary disease; physician beliefs; adherence to guidelines
17.  Smoking-associated fibrosis and pulmonary asbestosis 
The diagnosis of pulmonary asbestosis is most often established based on clinical criteria and has both clinical and legal implications. Unfortunately, one of the confounding features in the diagnosis may be a history of cigarette abuse, which can produce interstitial opacities on chest imaging as well as diffusion defects on pulmonary function testing, criteria that are used in the diagnosis of pulmonary asbestosis. The objective of the present study was to evaluate the correlation of radiographically detected pulmonary fibrosis with fibrosis established histopathologically as attributable to asbestos, in a cohort referred for diagnosis of an asbestos-related malignancy in the context of litigation. We examined the slides of 186 cases with reported asbestos exposure, referred in consultation for asbestos-related malignancy and the presence of pulmonary fibrosis. Sixty-five cases had what was judged to be adequate tissue sampling for histopathologic evaluation of asbestosis as well as an existing radiologic assessment of pulmonary fibrosis by B-reader report. Of 24 cases judged to have asbestosis radiographically, which had sufficient tissue for pathologic examination, six showed asbestosis histopathologically. The remaining 18 cases (mean smoking history of 53 pack-years) showed interstitial fibrosis that was judged to be most consistent with smoking-associated pulmonary fibrosis. We conclude that the clinical diagnosis of mild asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers.
doi:10.2147/COPD.S74643
PMCID: PMC4279669  PMID: 25565798
asbestos; smoking; pulmonary fibrosis
18.  The added value of hybrid ventilation/perfusion SPECT/CT in patients with stable COPD or apparently healthy smokers. Cancer-suspected CT findings in the lungs are common when hybrid imaging is used 
Ventilation/perfusion (V/P) single-photon emission computed tomography (SPECT) is recognized as a diagnostic method with potential beyond the diagnosis of pulmonary embolism. V/P SPECT identifies functional impairment in diseases such as heart failure (HF), pneumonia, and chronic obstructive pulmonary disease (COPD). The development of hybrid SPECT/computed tomography (CT) systems, combining functional with morphological imaging through the addition of low-dose CT (LDCT), may be useful in COPD, as these patients are prone to lung cancer and other comorbidities. The aim of this study was to investigate the added value of LDCT among healthy smokers and patients with stable COPD, when examined with V/P SPECT/CT hybrid imaging. Sixty-nine subjects, 55 with COPD (GOLD I–IV) and 14 apparently healthy smokers, were examined with V/P SPECT and LDCT hybrid imaging. Spirometry was used to verify COPD grade. Only one apparently healthy smoker and three COPD patients had a normal or nearly normal V/P SPECT. All other patients showed various degrees of airway obstruction, even when spirometry was normal. The same interpretation was reached on both modalities in 39% of the patients. LDCT made V/P SPECT interpretation more certain in 9% of the patients and, in 52%, LDCT provided additional diagnoses. LDCT better characterized the type of emphysema in 12 patients. In 19 cases, tumor-suspected changes were reported. Three of these 19 patients (ie, 4.3% of all subjects) were in the end confirmed to have lung cancer. The majority of LDCT findings were not regarded as clinically significant. V/P SPECT identified perfusion patterns consistent with decompensated left ventricular HF in 14 COPD patients. In 16 patients (23%), perfusion defects were observed. HF and perfusion defects were not recognized with LDCT. In COPD patients and long-time smokers, hybrid imaging had added value compared to V/P SPECT alone, by identifying patients with lung malignancy and more clearly identifying emphysema. V/P SPECT visualizes comorbidities to COPD not seen with LDCT, such as pulmonary embolism and left ventricular HF.
doi:10.2147/COPD.S73423
PMCID: PMC4279608  PMID: 25565797
lung; lung cancer; V/P SPECT; ventilation/perfusion; single-photon emission computed tomography; computed tomography
19.  Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study 
Background
Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney.
Objectives
To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol.
Methods
Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 μg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 μg.
Results
No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%–93%) and 89% (81%–93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 μg and umeclidinium/vilanterol 125/25 μg administration, respectively. Treatments were well tolerated in both populations.
Conclusion
Umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment.
doi:10.2147/COPD.S68094
PMCID: PMC4279609  PMID: 25565796
chronic obstructive pulmonary disease; exposure; GSK573719; long-acting beta2 agonist; long-acting muscarinic antagonist
20.  Association of genetic polymorphisms with chronic obstructive pulmonary disease in the Hainan population: a case-control study 
Purpose
Chronic obstructive pulmonary disease (COPD) is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. Recently, variants in the hypoxia-inducible factor 1α (HIF1A), cholinergic receptor, neuronal nicotinic, alpha polypeptide-5, and iron-responsive element-binding protein 2 gene (IREB2) genes were found to be associated with COPD. This study aims to identify whether the variations in these genes are related to COPD in the Hainan population of the People’s Republic of China.
Patients and methods
We genotyped 12 single nucleotide polymorphisms in a case-control study with 200 COPD cases and 401 controls from Hainan, People’s Republic of China. Odds ratios and 95% confidence intervals were estimated using the chi-squared (χ2) test, genetic model analysis, haplotype analysis, and stratification analysis.
Results
In the genetic model analysis, we found that the genotype T/T of rs13180 of IREB2 decreased the COPD risk by 0.52-fold (P=0.025). But in the further stratification analysis, we failed to find the association between the selected single nucleotide polymorphisms with COPD risk in Han population. In addition, the haplotype analysis of HIF1A gene also was not found to be the possible haplotype associated with COPD risk.
Conclusion
Our results support that IREB2 rs13180 is associated with COPD in Hainan population. And this is the first time the HIF1A polymorphisms in COPD in a Chinese population has been reported, although we failed to find any significant result.
doi:10.2147/COPD.S73042
PMCID: PMC4279605  PMID: 25565795
single nucleotide polymorphism (SNP); IREB2; HIF1A
21.  Knowledge about COPD among users of primary health care services 
Background
Chronic obstructive pulmonary disease (COPD) is often underdiagnosed, which might be attributable to a lack of knowledge about the disease among the general population. The objective of this study was to evaluate COPD-related knowledge among primary care users in an urban area in Brazil.
Methods
This study was carried out at primary care clinics (PCCs), including 12 general PCCs and 26 family health PCCs, in the city of Goiânia, Brazil. Between May 2013 and February 2014, we interviewed 674 PCC users, applying a questionnaire designed to assess COPD-related knowledge. Satisfactory knowledge of COPD was defined as knowing at least two of its symptoms and that smoking is a risk factor for the disease.
Results
Of the 674 users interviewed, only 9.2% recognized the term “COPD”, 75.1% recognized the term “emphysema”, and 15.7% did not recognize either term. We found that recognizing either term was associated with a higher level of education (P<0.001). The prevalence of satisfactory knowledge of COPD was 16.2%, and having such knowledge was associated with being over 60 years of age. The COPD symptom known by the greatest proportion of users (70.6%) was dyspnea, and most (87.5%) knew that smoking is a risk factor, whereas only a few (4.9%) knew that exposure to wood smoke is also a risk factor. The most frequently cited sources of knowledge were the media (43.1%) and a relative with COPD (36.4%).
Conclusion
Most of the PCC users evaluated did not know the term “COPD” but were familiar with the term “emphysema”. The level of basic knowledge about the disease was low in this population. These results should alert health care administrators to the need for interventions aimed at increasing the diagnosis rate and thus promoting the early treatment of COPD.
doi:10.2147/COPD.S71152
PMCID: PMC4279667  PMID: 25565794
primary care; underdiagnosis; health professional; perception
22.  The clinical use of regenerative therapy in COPD 
Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation.
doi:10.2147/COPD.S49519
PMCID: PMC4271722  PMID: 25548520
chronic obstructive pulmonary disease; stem cells; regenerative therapy; all-trans retinoic acid; photobiostimulation
23.  The concept of control of COPD in clinical practice 
Treatment of chronic obstructive pulmonary disease (COPD) requires a personalized approach according to the clinical characteristics of the patients, the level of severity, and the response to the different therapies. Furthermore, patients with the same level of severity measured by the degree of airflow obstruction or even with multidimensional indices may have very different symptoms and limitations for daily activities. The concept of control has been extensively developed in asthma but has not been defined in COPD. Here, we propose a definition of COPD control based on the concepts of impact and stability. Impact is a cross-sectional concept that can be measured by questionnaires such as the COPD Assessment Test or the Clinical COPD Questionnaire. Alternatively, impact can be assessed by the degree of dyspnea, the use of rescue medication, the level of physical activity, and sputum color. Stability is a longitudinal concept that requires the absence of exacerbations and deterioration in the aforementioned variables or in the COPD Assessment Test or Clinical COPD Questionnaire scores. Control is defined by low impact (adjusted for severity) and stability. The concept of control in COPD can be useful in the decision making regarding an increase or decrease in medication in the stable state.
doi:10.2147/COPD.S71370
PMCID: PMC4271723  PMID: 25548521
COPD; control; CAT; CCQ; exacerbations; prognosis
24.  Use of time in people with chronic obstructive pulmonary disease – a systematic review 
“Physical inactivity” and “sedentary lifestyles” are phrases often used when describing lifestyles of people with chronic obstructive pulmonary disease (COPD). Evidence suggests activity types, independent of energy expenditure, influence health outcomes, so understanding patterns of time use is important, particularly in chronic disease. We aimed to identify reports of time use in people with COPD. Predefined search strategies were used with six electronic databases to identify individual activity reports (including frequencies and/or durations) in which community-dwelling people with COPD engaged. Eligible studies were assessed independently against predefined criteria and data were extracted by two reviewers. Data synthesis was achieved by aggregating activity reports into activity domains (sports/exercise, screen time, transport, quiet time, self-care, sociocultural, work/study, chores, and sleep). Twenty-six publications reported 37 specific daily activities. People with COPD were found to spend extended periods in sedentary behaviors (eg, standing [194 min/day]; sitting [359 min/day]; lying [88 min/day]), have limited engagement in physical activity (eg, walking [51 min/day]; exercising [1.2 episodes per week {ep/w}, 13 min/day]), have high health care needs (medical appointments [1.0 ep/w]), and experience difficulties associated with activities of daily living (eg, showering [2.5 ep/w, 60 minutes per episode]; preparing meals [4.7 ep/w]). Little data could be found describing how people with COPD use their time, and data synthesis was problematic because of variations in methodologies, population differences, and research emphases. Identified data largely referred to posture and were skewed according to country, assessment methods, and disease severity. Comparisons with age-matched population data showed people with COPD spent less time engaged in personal-care activities (self-care and sleeping) and chores than people in similar age groups. The incorporation of time-use outcomes in future research designs should be encouraged. Ideally, these tools should use consistent frameworks and comparable outcome measures in order to provide clearer descriptions of time use in chronic disease.
doi:10.2147/COPD.S74298
PMCID: PMC4271726  PMID: 25548519
activities of daily living; human activities; leisure activities; sedentary lifestyles
25.  Ease-of-use preference for the ELLIPTA® dry powder inhaler over a commonly used single-dose capsule dry powder inhaler by inhalation device-naïve Japanese volunteers aged 40 years or older 
Background
In patients receiving inhaled medication, dissatisfaction with and difficulty in using the inhaler can affect treatment adherence. The incidence of handling errors is typically higher in the elderly than in younger people. The aim of the study was to assess inhaler preference for and handling errors with the ELLIPTA® dry powder inhaler (DPI), (GSK), compared with the established BREEZHALER™, a single-dose capsule DPI (Novartis), in inhalation device-naïve Japanese volunteers aged ≥40 years.
Methods
In this open-label, nondrug interventional, crossover DPI preference study comparing the ELLIPTA DPI and BREEZHALER, 150 subjects were randomized to handle the ELLIPTA or BREEZHALER DPIs until the point of inhalation, without receiving verbal or demonstrative instruction (first attempt). Subjects then crossed over to the other inhaler. Preference was assessed using a self-completed questionnaire. Inhaler handling was assessed by a trained assessor using a checklist. Subjects did not inhale any medication in the study, so efficacy and safety were not measured.
Results
The ELLIPTA DPI was preferred to the BREEZHALER by 89% of subjects (odds ratio [OR] 70.14, 95% confidence interval [CI] 33.69–146.01; P-value not applicable for this inhaler) for ease of use, by 63% of subjects (OR 2.98, CI 1.87–4.77; P<0.0001) for ease of determining the number of doses remaining in the inhaler, by 91% for number of steps required, and by 93% for time needed for handling the inhaler. The BREEZHALER was preferred to the ELLIPTA DPI for comfort of the mouthpiece by 64% of subjects (OR 3.16, CI 1.97–5.06; P<0.0001). The incidence of handling errors (first attempt) was 11% with ELLIPTA and 68% with BREEZHALER; differences in incidence were generally similar when analyzed by age (< or ≥65 years) or sex.
Conclusion
These data, obtained in an inhalation device-naïve population, suggest that the ELLIPTA DPI is preferred to an established alternative based on its ease-of-use features and is associated with fewer handling errors.
doi:10.2147/COPD.S72762
PMCID: PMC4267517  PMID: 25525354
chronic obstructive pulmonary disease; dry powder inhaler; ELLIPTA®; BREEZHALER™

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