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1.  Validation of an administrative claims-based diagnostic code for pneumonia in a US-based commercially insured COPD population 
To estimate the accuracy of claims-based pneumonia diagnoses in COPD patients using clinical information in medical records as the reference standard.
Selecting from a repository containing members’ data from 14 regional United States health plans, this validation study identified pneumonia diagnoses within a group of patients initiating treatment for COPD between March 1, 2009 and March 31, 2012. Patients with ≥1 claim for pneumonia (International Classification of Diseases Version 9-CM code 480.xx–486.xx) were identified during the 12 months following treatment initiation. A subset of 800 patients was randomly selected to abstract medical record data (paper based and electronic) for a target sample of 400 patients, to estimate validity within 5% margin of error. Positive predictive value (PPV) was calculated for the claims diagnosis of pneumonia relative to the reference standard, defined as a documented diagnosis in the medical record.
A total of 388 records were reviewed; 311 included a documented pneumonia diagnosis, indicating 80.2% (95% confidence interval [CI]: 75.8% to 84.0%) of claims-identified pneumonia diagnoses were validated by the medical charts. Claims-based diagnoses in inpatient or emergency departments (n=185) had greater PPV versus outpatient settings (n=203), 87.6% (95% CI: 81.9%–92.0%) versus 73.4% (95% CI: 66.8%–79.3%), respectively. Claims-diagnoses verified with paper-based charts had similar PPV as the overall study sample, 80.2% (95% CI: 71.1%–87.5%), and higher PPV than those linked to electronic medical records, 73.3% (95% CI: 65.5%–80.2%). Combined paper-based and electronic records had a higher PPV, 87.6% (95% CI: 80.9%–92.6%).
Administrative claims data indicating a diagnosis of pneumonia in COPD patients are supported by medical records. The accuracy of a medical record diagnosis of pneumonia remains unknown. With increased use of claims data in medical research, COPD researchers can study pneumonia with confidence that claims data are a valid tool when studying the safety of COPD therapies that could potentially lead to increased pneumonia susceptibility or severity.
PMCID: PMC4516198
positive predictive value; pneumonia; validation; claims data; medical record review
2.  Clinical role of dual bronchodilation with an indacaterol–glycopyrronium combination in the management of COPD: its impact on patient-related outcomes and quality of life 
Chronic obstructive pulmonary disease (COPD) is the result of persistent and progressive pathologic abnormalities in the small airways, most often associated with alveolar loss. Smoking cessation is the most effective intervention to slow down the progression of COPD. Long-acting inhaled bronchodilators are prescribed for the symptomatic relief at any stage of disease severity. For patients whose COPD cannot be not sufficiently controlled with long-acting bronchodilator monotherapy, international guidelines suggest the possibility of associating a long-acting beta2 agonist (LABA) with a long-acting muscarinic antagonist (LAMA), ie, dual bronchodilation. This is not a new concept as the combination of short-acting agents has been popular in the past. In recent years, several fixed-dose combinations containing a LAMA and a LABA in a single inhaler have been approved by regulatory authorities in several countries. Among the new LAMA/LABA combinations, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg (QVA149) has been shown in a series of clinical trials to be as safe as the single components and placebo, and more effective than placebo and the single components with regard to lung function, symptoms, and patient-oriented outcomes. Furthermore, QVA149 achieved better bronchodilation than salmeterol 50 µg/fluticasone 500 µg twice daily. Compared with tiotropium, a well-recognized treatment for COPD, the percentage of patients that exceed the minimal clinical important difference for dyspnea and health-related quality of life measurements was superior with QVA149. Other patient-oriented outcomes, such as daily symptoms, night-time awakening, and use of rescue medication consistently favored QVA149. Finally, QVA149 was significantly superior to LAMAs for reducing all types of exacerbation. In conclusion, several years after introduction of dual bronchodilation, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg in a single inhaler for once-daily administration via the Breezhaler® device (QVA149) has been demonstrated to be a safe and effective treatment for COPD patients.
PMCID: PMC4516211
chronic obstructive pulmonary disease; long-acting bronchodilators; dual bronchodilation; indacaterol; glycopyrronium; patient-oriented outcomes
3.  Is dynamometry able to infer the risk of muscle mass loss in patients with COPD? 
Sarcopenia is characterized by a progressive and generalized decrease of strength and muscle mass. Muscle mass loss is prevalent in patients with chronic obstructive pulmonary disease (COPD) as a result of both the disease and aging. Some methods have been proposed to assess body composition (and therefore identify muscle mass loss) in this population. Despite the high accuracy of some methods, they require sophisticated and costly equipment.
The purpose of this study was to infer the occurrence of muscle mass loss measured by a sophisticated method (dual energy X-ray absorptiometry [DEXA]) using a more simple and affordable equipment (dynamometer).
Fifty-seven stable subjects with COPD were evaluated for anthropometric characteristics, lung function, functional exercise capacity, body composition, and peripheral muscle strength. A binary logistic regression model verified whether knee-extension strength (measured by dynamometry) could infer muscle mass loss (from DEXA).
Patients with decreased knee-extension strength were 5.93 times more likely to have muscle mass loss, regardless of sex, disease stage, and functional exercise capacity (P=0.045).
Knee-extension dynamometry was able to infer muscle mass loss in patients with COPD.
PMCID: PMC4516177
COPD; sarcopenia; peripheral muscle strength
4.  Constant-load exercise decreases the serum concentration of myeloperoxidase in healthy smokers and smokers with COPD 
There is an ongoing demand for easily accessible biomarkers related to pathophysiological processes in chronic obstructive pulmonary disease (COPD). Short-term intense exercise is known to increase the peripheral blood levels of cytokines. Therefore, we tested the potential and the repeatability of an exercise challenge to amplify seven serum biomarkers (interleukin 6 [IL6], C-reactive protein [CRP], myeloperoxidase [MPO], leukotriene B4, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and von Willebrand factor [VWF]) in smokers with and without COPD. Twenty-three smokers with moderate COPD (GOLD 2) and 23 sex- and age-matched healthy smokers underwent up to 30-minute submaximal, constant-load exercise (75% of maximum work load) on two occasions separated by 4 weeks (second challenge n=19/20). Serum samples were obtained before, 5 minutes after the start, at the end of exercise (maximum 30 minutes or until exhaustion), and after additional 20 minutes of rest. The median (interquartile range) exercise time until exhaustion in the two challenges was 10.0 (4.0) minutes and 10.0 (8.0) minutes in smokers with COPD and 22.0 (16.0) minutes and 26.5 (14.5) minutes in healthy smokers. The exercise challenge significantly increased the serum concentrations of IL6 and VWF, but decreased the concentrations of MPO. Healthy smokers showed a significantly greater increase (at the end of exercise compared to before exercise) in IL6 (P=0.01) and a larger decline (P=0.03) in MPO. The overall profile of the serum markers during the exercise challenge was shown to be repeatable in the second challenge. In summary, intense load exercise is capable of changing the concentration of inflammatory and endothelial function markers. Especially, the decline in the level of MPO, a marker closely related to cardiovascular risk, appears to be of clinical interest, as the exercise-induced decline might be related to the beneficial effects of physical activity in general.
PMCID: PMC4516189
serum biomarker; systemic inflammation; physical activity
5.  Smoking duration, respiratory symptoms, and COPD in adults aged ≥45 years with a smoking history 
The purpose of this study was to assess the relationship of smoking duration with respiratory symptoms and history of chronic obstructive pulmonary disease (COPD) in the South Carolina Behavioral Risk Factor Surveillance System survey in 2012.
Data from 4,135 adults aged ≥45 years with a smoking history were analyzed using multivariable logistic regression that accounted for sex, age, race/ethnicity, education, and current smoking status, as well as the complex sampling design.
The distribution of smoking duration ranged from 19.2% (1–9 years) to 36.2% (≥30 years). Among 1,454 respondents who had smoked for ≥30 years, 58.3% were current smokers, 25.0% had frequent productive cough, 11.2% had frequent shortness of breath, 16.7% strongly agreed that shortness of breath affected physical activity, and 25.6% had been diagnosed with COPD. Prevalence of COPD and each respiratory symptom was lower among former smokers who quit ≥10 years earlier compared with current smokers. Smoking duration had a linear relationship with COPD (P<0.001) and all three respiratory symptoms (P<0.001) after adjusting for smoking status and other covariates. While COPD prevalence increased with prolonged smoking duration in both men and women, women had a higher age-adjusted prevalence of COPD in the 1–9 years, 20–29 years, and ≥30 years duration periods.
These state population data confirm that prolonged tobacco use is associated with respiratory symptoms and COPD after controlling for current smoking behavior.
PMCID: PMC4516194
tobacco use; chronic obstructive pulmonary disease; respiratory symptoms; population-based study
6.  Self-reported alcohol intake and risk of acute exacerbations of chronic obstructive pulmonary disease: a prospective cohort study 
To evaluate the relationship between alcohol consumption and the risk of acute exacerbation of COPD (AECOPD).
Methods and measurements
We conducted a secondary analysis of data previously collected in a large, multicenter trial of daily azithromycin in COPD. To analyze the relationship between amount of baseline self-reported alcohol consumption in the past 12 months and subsequent AECOPD, we categorized the subjects as minimal (<1 drink/month), light-to-moderate (1–60 drinks/month), or heavy alcohol users (>60 drinks/month). The primary outcome was time to first AECOPD and the secondary outcome was AECOPD rate during the 1-year study period.
Of the 1,142 enrolled participants, 1,082 completed baseline alcohol questionnaires and were included in this analysis. Six hundred and forty-five participants reported minimal alcohol intake, 363 reported light-to-moderate intake, and 74 reported heavy intake. There were no statistically significant differences in median time to first AECOPD among minimal (195 days), light-to-moderate (241 days), and heavy drinkers (288 days) (P=0.11). The mean crude rate of AECOPD did not significantly differ between minimal (1.62 events per year) and light-to-moderate (1.44 events per year) (P=0.095), or heavy drinkers (1.68 events per year) (P=0.796). There were no significant differences in hazard ratios for AECOPD after adjustment for multiple covariates.
Among persons with COPD at high risk of exacerbation, we found no significant relationship between self-reported baseline alcohol intake and subsequent exacerbations. The number of patients reporting heavy alcohol intake was small and further study is needed to determine the effect of heavy alcohol intake on AECOPD risk.
PMCID: PMC4516185
pulmonary disease; chronic obstructive; ethanol; alcohol; alcoholism
7.  Characteristics of prevalent and new COPD cases in Greece: the GOLDEN study 
Greece has one of the highest rates of smoking and chronic obstructive pulmonary disease (COPD) in Europe.
The study aimed to record both the disease characteristics among a sample of Greek COPD patients and the nationwide rates of newly diagnosed COPD cases.
In this noninterventional, epidemiological cross-sectional study, a representative nationwide sample of 45 respiratory centers provided data on the following: 1) the demographic and clinical characteristics of COPD patients and 2) newly diagnosed COPD cases monitored over a period of 6 months by each physician.
Data from 6,125 COPD patients were collected. Advanced age (median age: 68 years), male predominance (71.3%), largely overweight status with median body mass index (BMI) =27.5 kg/m2, high percentage of current and ex-smokers (89.8%), and presence of comorbidities (81.9%) were evident in the sample. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 criteria, majority of the COPD patients had moderate or severe airflow limitation (61%). Severity of airflow limitation was significantly associated with older age, male sex, obesity, ex-smoking status, and presence of comorbidity (all P-values <0.001). A total of 61.3% of the patients received medication, mostly bronchodilators (64.4%) and fixed-dose combinations of long-acting β2-agonists and inhaled corticosteroids (39.9%), while 35.9% reported taking medication on demand. The majority (81.1%) of patients reported a preference for fewer inhalations of their bronchodilator therapy. Based on the mixed-effect Poisson model, the rate of newly diagnosed COPD cases was estimated to be 18.2% (95% confidence interval: 14.9–22.3) per pulmonologist/3 months. Of those newly diagnosed, the majority of patients had mild or moderate airflow limitation (78.2%).
The Greek Obstructive Lung Disease Epidemiology and health ecoNomics study reflected the real-life profile of COPD patients and provided evidence on the profile of new COPD cases in Greece. Various demographic factors were delineated, which can assist in designing more effective diagnostic and management strategies for COPD in Greece.
PMCID: PMC4516213
COPD; characteristics; newly diagnosed; epidemiology; prevalent cases; new cases; health care system; health care management; nationwide sampling
8.  Underdiagnosis and prognosis of chronic obstructive pulmonary disease after percutaneous coronary intervention: a prospective study 
Retrospective studies based on clinical data and without spirometric confirmation suggest a poorer prognosis of patients with ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) following percutaneous coronary intervention (PCI). The impact of undiagnosed COPD in these patients is unknown. We aimed to evaluate the prognostic impact of COPD – previously or newly diagnosed – in patients with IHD treated with PCI.
Patients with IHD confirmed by PCI were consecutively included. After PCI they underwent forced spirometry and evaluation for cardiovascular risk factors. All-cause mortality, new cardiovascular events, and their combined endpoint were analyzed.
A total of 133 patients (78%) male, with a mean (SD) age of 63 (10.12) years were included. Of these, 33 (24.8%) met the spirometric criteria for COPD, of whom 81.8% were undiagnosed. IHD patients with COPD were older, had more coronary vessels affected, and a greater history of previous myocardial infarction. Median follow-up was 934 days (interquartile range [25%–75%]: 546–1,160). COPD patients had greater mortality (P=0.008; hazard ratio [HR]: 8.85; 95% confidence interval [CI]: 1.76–44.47) and number of cardiovascular events (P=0.024; HR: 1.87; 95% CI: 1.04–3.33), even those without a previous diagnosis of COPD (P=0.01; HR: 1.78; 95% CI: 1.12–2.83). These differences remained after adjustment for sex, age, number of coronary vessels affected, and previous myocardial infarction (P=0.025; HR: 1.83; 95% CI: 1.08–3.1).
Prevalence and underdiagnosis of COPD in patients with IHD who undergo PCI are both high. These patients have an independent greater mortality and a higher number of cardiovascular events during follow-up.
PMCID: PMC4509531  PMID: 26213464
ischemic heart disease; mortality; myocardial infarction; prognosis
9.  Underrecognized comorbidities of chronic obstructive pulmonary disease 
COPD is associated with different comorbid diseases, and their frequency increases with age. Comorbidities severely impact costs of health care, intensity of symptoms, quality of life and, most importantly, may contribute to life span shortening. Some comorbidities are well acknowledged and established in doctors’ awareness. However, both everyday practice and literature searches provide evidence of other, less recognized diseases, which are frequently associated with COPD. We call them underrecognized comorbidities, and the reason why this is so may be related to their relatively low clinical significance, inefficient literature data, or data ambiguity. In this review, we describe rhinosinusitis, skin abnormalities, eye diseases, different endocrinological disorders, and gastroesophageal reflux disease. Possible links to COPD pathogenesis have been discussed, if the data were available.
PMCID: PMC4507790  PMID: 26203239
COPD; comorbidities; rhinosinusitis; endocrinological disorders; GERD
10.  What pulmonologists think about the asthma–COPD overlap syndrome 
Some patients with COPD may share characteristics of asthma; this is the so-called asthma–COPD overlap syndrome (ACOS). There are no universally accepted criteria for ACOS, and most treatments for asthma and COPD have not been adequately tested in this population.
Materials and methods
We performed a survey among pulmonology specialists in asthma and COPD aimed at collecting their opinions about ACOS and their attitudes in regard to some case scenarios of ACOS patients. The participants answered a structured questionnaire and attended a face-to-face meeting with the Metaplan methodology to discuss different aspects of ACOS.
A total of 26 pulmonologists with a mean age of 49.7 years participated in the survey (13 specialists in asthma and 13 in COPD). Among these, 84.6% recognized the existence of ACOS and stated that a mean of 12.6% of their patients might have this syndrome. In addition, 80.8% agreed that the diagnostic criteria for ACOS are not yet well defined. The most frequently mentioned characteristics of ACOS were a history of asthma (88.5%), significant smoking exposure (73.1%), and postbronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 (69.2%). The most accepted diagnostic criteria were eosinophilia in sputum (80.8%), a very positive bronchodilator test (69.2%), and a history of asthma before 40 years of age (65.4%). Up to 96.2% agreed that first-line treatment for ACOS was the combination of a long-acting β2-agonist and inhaled steroid, with a long-acting antimuscarinic agent (triple therapy) for severe ACOS.
Most Spanish specialists in asthma and COPD agree that ACOS exists, but the diagnostic criteria are not yet well defined. A previous history of asthma, smoking, and not fully reversible airflow limitation are considered the main characteristics of ACOS, with the most accepted first-line treatment being long-acting β2-agonist/inhaled corticosteroids.
PMCID: PMC4507793  PMID: 25587219
asthma; COPD; ACOS; survey; guidelines
11.  Clinical significance of laryngopharyngeal reflux in patients with chronic obstructive pulmonary disease 
Although chronic obstructive pulmonary disease (COPD) is closely associated with gastroesophageal reflux disease (GERD), the clinical significance of laryngopharyngeal reflux (LPR) is not fully understood in COPD.
Prospective cohorts were established among 118 patients with COPD from March 2013 to July 2014. Thirty-two age-matched and sex-matched normal controls, who had routine health check-ups during the study period, were included. Laryngopharyngeal reflux finding scores (RFS) and reflux symptom index (RSI) for LPR were subjected to association analysis with severity and acute exacerbation of COPD during the 1-year follow-up.
The mean age of patients enrolled in the study was 69.2±8.8 years, with 93.2% being male. Positive RFS (>7) and RSI (>13) were observed in 51 (42.5%) and six patients (5.0%), respectively. RFS and RSI were significantly higher in patients with COPD than in normal, healthy patients (P<0.001). RFS was significantly correlated with residual volume/total lung capacity (%, P=0.048). Scores for diffuse laryngeal edema, erythema, and hyperemia were significantly higher in the high-risk group (Global Initiative for Chronic Obstructive Lung Disease classification C and D; P=0.025 and P=0.049, respectively), while RSI was significantly higher in the more symptomatic group (Global Initiative for Chronic Obstructive Lung Disease classification B and D; P=0.047). RSI and RFS were significant predictors for severe acute exacerbation of COPD (P=0.03 and P=0.047, respectively), while only RSI was associated with severity of dyspnea.
Laryngeal examination and evaluation of laryngeal reflux symptom could be a surrogate clinical indicator related to severe acute exacerbation of COPD. Further studies of LPR in COPD patients should be considered.
PMCID: PMC4507795  PMID: 26203240
COPD; acute exacerbation; laryngopharyngeal reflux; reflux symptom index; reflux finding score
12.  Pulmonary hemodynamic profile in chronic obstructive pulmonary disease 
Few data are available in regards to the prevalence of pulmonary hypertension (PH) in the broad spectrum of COPD. This study was aimed at assessing the prevalence of PH in a cohort of COPD patients across the severity of airflow limitation, and reporting the hemodynamic characteristics at rest and during exercise.
We performed a retrospective analysis on COPD patients who underwent right-heart catheterization in our center with measurements obtained at rest (n=139) and during exercise (n=85). PH was defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary capillary wedge pressure <15 mmHg. Exercise-induced PH (EIPH) was defined by a ratio of ΔmPAP/Δcardiac output >3.
PH was present in 25 patients (18%). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, PH prevalence in GOLD 2 was 7% (3 patients); 25% (14 patients) in GOLD 3; and 22% (8 patients) in GOLD 4. Severe PH (mPAP ≥35 mmHg) was identified in four patients (2.8%). Arterial partial oxygen pressure was the outcome most strongly associated with PH (r=−0.29, P<0.001). EIPH was observed in 60 patients (71%) and had a similar prevalence in both GOLD 2 and 3, and was present in all GOLD 4 patients. Patients with PH had lower cardiac index during exercise than patients without PH (5.0±1.2 versus 6.7±1.4 L/min/m2, respectively; P=0.001).
PH has a similar prevalence in COPD patients with severe and very-severe airflow limitation, being associated with the presence of arterial hypoxemia. In contrast, EIPH is highly prevalent, even in moderate COPD, and might contribute to limiting exercise tolerance.
PMCID: PMC4507485  PMID: 26203238
pulmonary hypertension; right heart catheterization; cardiac index; GOLD
13.  The inspiratory capacity/total lung capacity ratio as a predictor of survival in an emphysematous phenotype of chronic obstructive pulmonary disease 
Forced expiratory volume in 1 second (FEV1) grades severity of COPD and predicts survival. We hypothesize that the inspiratory capacity/total lung capacity (IC/TLC) ratio, a sensitive measure of static lung hyperinflation, may have a significant association with survival in an emphysematous phenotype of COPD.
To access the association between IC/TLC and survival in an emphysematous phenotype of COPD.
We performed a retrospective analysis of a large pulmonary function (PF) database with 39,050 entries, from April 1978 to October 2009. Emphysematous COPD was defined as reduced FEV1/forced vital capacity (FVC), increased TLC, and reduced diffusing capacity of the lungs for carbon monoxide (DLCO; beyond 95% confidence intervals [CIs]). We evaluated the association between survival in emphysematous COPD patients and the IC/TLC ratio evaluated both as dichotomous (≤25% vs >25%) and continuous predictors. Five hundred and ninety-six patients had reported death dates.
Univariate analysis revealed that IC/TLC ≤25% was a significant predictor of death (hazard ratio [HR]: 2.39, P<0.0001). Median survivals were respectively 4.3 (95% CI: 3.8–4.9) and 11.9 years (95% CI: 10.3–13.2). Multivariable analysis revealed age (HR: 1.19, 95% CI: 1.14–1.24), female sex (HR: 0.69, 95% CI: 0.60–0.83), and IC/TLC ≤25% (HR: 1.69, 95% CI: 1.34–2.13) were related to the risk of death. Univariate analysis showed that continuous IC/TLC was associated with death, with an HR of 1.66 (95% CI: 1.52–1.81) for a 10% decrease in IC/TLC.
Adjusting for age and sex, IC/TLC ≤25% is related to increased risk of death, and IC/TLC as a continuum, is a significant predictor of mortality in emphysematous COPD patients.
PMCID: PMC4506024  PMID: 26203237
emphysema; pulmonary function testing; mortality
14.  Pathological and radiological correlation in an autopsy case of combined pulmonary fibrosis and emphysema 
We report an educational autopsy case of combined pulmonary fibrosis and emphysema. Radiological patterns of the upper lung were considered as mostly emphysema, but pathological observation revealed significant interstitial fibrosis of usual interstitial pneumonia as a major pathology. The patient eventually developed acute exacerbation of background interstitial pneumonia. Careful radiological and pathological correlation of the current case indicates that regions with distal acinar emphysema on computed tomography image may possess histologically marked dense fibrosis of lethal interstitial pneumonia.
PMCID: PMC4501445  PMID: 26185436
interstitial pneumonia; CPFE; AEF; smoking; CT
15.  Evaluating inhaler use technique in COPD patients 
Poor inhalation techniques are associated with decreased medication delivery and poor disease control in chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate techniques for using inhaler devices in COPD patients.
A prospective cross-sectional study was conducted to assess patient compliance with correct techniques for using inhaler devices across four regimens, ie, the pressurized metered-dose inhaler (pMDI), the pMDI with a spacer, the Accuhaler®, and the Handihaler®. The percentage of compliance with essential steps of correct device usage for each regimen was recorded without prior notification when COPD patients presented for a routine visit, and 1 month after receiving face-to-face training. We compared the percentage of compliance between the devices and risk factors related to incorrect techniques using logistic regression analysis. Percentage of patient compliance with correct techniques was compared between the two visits using the chi-square test. Statistical significance was set at P<0.05.
A total of 103 COPD patients (mean age 71.2±9.2 years, males 64.1%, low education level 82.5%, and percent predicted forced expiratory volume in 1 second 51.9±22.5) were evaluated. Seventy-seven patients (74.8%) performed at least one step incorrectly. Patients using the Handihaler had the lowest compliance failure (42.5%), and the odds ratio for failure with the other devices compared with the Handihaler were 4.6 (95% confidence interval [CI] 1.8–11.8) for the pMDI, 3.1 (95% CI 1.2–8.2) for the pMDI with a spacer, and 2.4 (95% CI 1.1–5.2) for the Accuhaler. Low education level was the single most important factor related to incorrect technique (adjusted odds ratio 4.1, 95% CI 1.2–13.4, P=0.022). Formal training resulted in a statistically significant decrease in percentage of incorrect techniques for all devices and for the pMDI (59.4% vs 48.6%, P<0.001; 72.4% vs 48.3%, P=0.039, respectively).
Inhalation technique in COPD patients without face-to-face training was mostly unsatisfactory, especially in patients with low education levels. The Handihaler was the inhaler device associated with the lowest technique failure. Face-to-face inhalation technique training significantly increased technique compliance for the pMDI.
PMCID: PMC4501446  PMID: 26185435
chronic obstructive pulmonary disease; inhalation; technique; compliance
16.  Prevalence of chronic kidney diseases in patients with chronic obstructive pulmonary disease: assessment based on glomerular filtration rate estimated from creatinine and cystatin C levels 
Cardiovascular diseases, osteoporosis, and depression are identified comorbidities of chronic obstructive pulmonary disease (COPD), but there have been few reports of chronic kidney disease (CKD) as a comorbidity of COPD. The objective of this study was to investigate the prevalence of CKD in COPD patients using estimated glomerular filtration rate (eGFR) based on creatinine (Cr) and cystatin C (Cys) levels.
The prevalence of CKD and the values of various CKD-related parameters were compared between 108 stable COPD outpatients (COPD group) and a non-COPD control group consisting of 73 patients aged 60 years or more without a history of COPD or kidney disease. CKD was defined as an eGFR less than 60 mL/min/1.73 m2.
The Cr level was significantly higher in the COPD group, but eGFR based on serum Cr (eGFRCr) was not significantly different between the two groups (73.3±25.3 vs 79.7±15.5 mL/min/1.73 m2). The Cys level was significantly higher and eGFR based on serum Cys (eGFRCys) was significantly lower in the COPD group (60.0±19.4 vs 74.0±13.5 mL/min/1.73 m2, P<0.0001). The prevalence of CKD evaluated based on eGFRCr was 31% in the COPD group and 8% in the non-COPD group with an odds ratio of 4.91 (95% confidence interval, 1.94–12.46, P=0.0008), whereas the evaluated prevalence based on eGFRCys was 53% in the COPD group and 15% in the non-COPD group with an odds ratio of 6.30 (95% confidence interval, 2.99–13.26, P<0.0001), demonstrating a higher prevalence of CKD when based on eGFRCys rather than on eGFRCr.
CKD is a comorbidity that occurs frequently in COPD patients, and we believe that renal function in Japanese COPD patients should preferably be evaluated based not only on Cr but on Cr in combination with Cys.
PMCID: PMC4500615  PMID: 26185434
CKD; comorbidity; COPD; eGFR
17.  Effects of pharmacologic treatment based on airflow limitation and breathlessness on daily physical activity in patients with chronic obstructive pulmonary disease 
Improvement in the daily physical activity (PA) is important for the management of chronic obstructive pulmonary disease (COPD). However, the effects of pharmacologic treatment on PA are not well understood. We evaluated the effects of additional medications, including bronchodilator with or without inhaled corticosteroid, based on airflow limitation and breathlessness on the PA in COPD patients and the factors that could predict or affect the improvement in PA.
A prospective non-randomized observational study was employed. Twenty-one COPD subjects without any other diseases that might reduce PA were recruited. The PA was measured with a triaxial accelerometer for 2 weeks, and pulmonary function tests and incremental shuttle walking tests were administered before and after 4-week treatment with an additional medication.
Bronchodilation was obtained by additional medication. The mean values of PA evaluated by metabolic equivalents (METs) at ≥3.0 METs and the duration of PA at ≥3.0 METs and ≥3.5 METs were improved by medication. The % change in the duration of PA at ≥3.5 METs was significantly correlated with the baseline functional residual capacity (FRC), residual volume, and inspiratory capacity/total lung capacity. However, the % change in the duration of PA at any intensity was not correlated with the % changes of any values of the pulmonary function tests or incremental shuttle walking test except the PA at ≥2.5 METs with FRC.
Medication could improve the PA in patients with COPD, especially at a relatively high intensity of activity when medication was administered based on airflow limitation and breathlessness. The improvement was seen in the patients with better baseline lung volume, but was not correlated with the improvements in the pulmonary function tests or exercise capacity.
PMCID: PMC4498718  PMID: 26170656
COPD; accelerometer; bronchodilator; pulmonary function; predictor
18.  Prediction of short term re-exacerbation in patients with acute exacerbation of chronic obstructive pulmonary disease 
The objective of the study is to develop a scoring system for predicting a 90-day re-exacerbation in hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).
A total of 176 consecutive hospitalized patients with AECOPD were included. The sociodemographic characteristics, status before acute exacerbation (AE), presentations of and treatment for the current AE, and the re-exacerbation in 90 days after discharge from hospital were collected.
The re-exacerbation rate in 90 days was 48.9% (86 out of 176). It was associated with the degree of lung function impairment (Global initiative for chronic Obstructive Lung Disease [GOLD] grades), frequency of AE in the previous year, and parameters of the current AE, including pleural effusion, use of accessory respiratory muscles, inhaled long-acting β-2-agonists, inhaled corticosteroids, controlled oxygen therapy, noninvasive mechanical ventilation, and length of hospital stay, but was not associated with body mass index, modified Medical Research Council scale, or chronic obstructive pulmonary disease assessment test. A subgroup of ten variables was selected and developed into the re-exacerbation index scoring system (age grades, GOLD grades, AE times in the previous year, pleural effusion, use of accessory respiratory muscles, noninvasive mechanical ventilation, controlled oxygen therapy, inhaled long-acting β-2-agonists and inhaled corticosteroids, and length of hospital stay). The re-exacerbation index showed good discrimination for re-exacerbation, with a C-statistic of 0.750 (P<0.001).
A comprehensive assessment integrating parameters of stable chronic obstructive pulmonary disease, clinical presentations at exacerbation, and treatment showed a strong predictive capacity for short-term outcome in patients with AECOPD. Further studies are required to verify these findings.
PMCID: PMC4494178  PMID: 26170655
chronic obstructive pulmonary disease; acute exacerbation; treatment; re-exacerbation
19.  Systemic signs of neutrophil mobilization during clinically stable periods and during exacerbations in smokers with obstructive pulmonary disease 
It is still unclear whether signs of neutrophil mobilization in the blood of patients with chronic obstructive pulmonary disease represent true systemic events and how these relate to bacterial colonization in the airways. In this study, we evaluated these issues during clinically stable periods and during exacerbations in smokers with obstructive pulmonary disease and chronic bronchitis (OPD-CB).
Over a period of 60 weeks for each subject, blood samples were repeatedly collected from 60 smokers with OPD-CB during clinically stable periods, as well as during and after exacerbations. Myeloperoxidase (MPO) and neutrophil elastase (NE) protein and mRNA, growth of bacteria in sputum, and clinical parameters were analyzed. Ten asymptomatic smokers and ten never-smokers were included as controls.
We found that, during clinically stable periods, neutrophil and NE protein concentrations were increased in smokers with OPD-CB and in the asymptomatic smokers when compared with never-smokers. During exacerbations, neutrophil and MPO protein concentrations were further increased in smokers with OPD-CB, without a detectable increase in the corresponding mRNA during exacerbations. However, MPO and NE protein and mRNA displayed positive correlations. During exacerbations, only increased neutrophil concentrations were associated with growth of bacteria in sputum. Among patients with low transcutaneous oxygen saturation during exacerbations, PaO2 (partial oxygen pressure) correlated with concentrations of MPO and NE protein and neutrophils in a negative manner.
There are signs of systemic neutrophil mobilization during clinically stable periods and even more so during exacerbations in chronic obstructive pulmonary disease. In this condition, MPO and NE may share a cellular origin, but its location remains uncertain. Factors other than local bacteria, including hypoxemia, may be important for driving systemic signs of neutrophil mobilization.
PMCID: PMC4493974  PMID: 26170654
C-reactive protein; COPD; elastase; infection; myeloperoxidase; oxygen
20.  Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity 
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of “contig” alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.
PMCID: PMC4493967  PMID: 26170653
lung; cigarette smoking; SNP; GOLD; Mexican population
21.  Postural control in chronic obstructive pulmonary disease: a systematic review 
Patients with chronic obstructive pulmonary disease (COPD) fall frequently, although the risk of falls may seem less important than the respiratory consequences of the disease. Nevertheless, falls are associated to increased mortality, decreased independence and physical activity levels, and worsening of quality of life. The aims of this systematic review was to evaluate information in the literature with regard to whether impaired postural control is more prevalent in COPD patients than in healthy age-matched subjects, and to assess the main characteristics these patients present that contribute to impaired postural control.
Five databases were searched with no dates or language limits. The MEDLINE, PubMed, EMBASE, Web of Science, and PEDro databases were searched using “balance”, “postural control”, and “COPD” as keywords. The search strategies were oriented and guided by a health science librarian and were performed on March 27, 2014. The studies included were those that evaluated postural control in COPD patients as their main outcome and scored more than five points on the PEDro scale. Studies supplied by the database search strategy were assessed independently by two blinded researchers.
A total of 484 manuscripts were found using the “balance in COPD or postural control in COPD” keywords. Forty-three manuscripts appeared more than once, and 397 did not evaluate postural control in COPD patients as the primary outcome. Thus, only 14 studies had postural control as their primary outcome. Our study examiners found only seven studies that had a PEDro score higher than five points. The examiners’ interrater agreement was 76.4%. Six of those studies were accomplished with a control group and one study used their patients as their own controls. The studies were published between 2004 and 2013.
Patients with COPD present postural control impairment when compared with age-matched healthy controls. Associated factors contributing to impaired postural control were muscle weakness, physical inactivity, elderly age, need for supplemental oxygen, and limited mobility.
PMCID: PMC4493971  PMID: 26170652
posture; balance; chronic obstructive pulmonary disease; postural control; systematic review
22.  Improving outcomes in chronic obstructive pulmonary disease: the role of the interprofessional approach 
Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, places substantial time and cost burden on the health care system, and is now the third leading cause of death in the US. Many interventions are available to appropriately manage patients with COPD; however, fully implementing these strategies to help improve outcomes may be difficult. Collaboration between an interprofessional team of health care professionals (which includes physicians, nurses, respiratory therapists, physical therapists, dietitians, pharmacists, and many others) and COPD patients and caregivers is necessary to optimally manage these patients and to truly impact outcomes in this devastating disease. Prescribing evidence-based non-pharmacological and pharmacological therapies is an important start, but a true team-based approach is critical to successfully implement comprehensive care in patients with COPD. The goal of this review is to employ a case-based approach to provide practical information regarding the roles of the interprofessional team in implementing strategies to optimally manage COPD patients.
PMCID: PMC4492629  PMID: 26170651
optimal care; shared decision-making; co-morbidities
23.  COPD in patients with stable heart failure in the primary care setting 
Presence of chronic obstructive pulmonary disease (COPD) in heart failure (HF) has prognostic and therapeutic implications. Exact prevalence estimates are lacking because most previous studies estimated the prevalence of COPD among HF patients while unstable and in the presence of pulmonary congestion.
Community-dwelling patients with an established diagnosis of HF and in a stable phase of their disease were invited for spirometry. COPD was defined according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification and considered present if the ratio of the post-bronchodilator forced expiratory volume in 1 second and forced vital capacity was below 0.7.
Thirty of the 106 patients with HF (mean age 76 [standard deviation] 11.9 years, 57% male) had COPD (prevalence 28.3% [95% confidence interval (CI) 19.7%–36.9%]), with similar rates among those with HF and a reduced ejection fraction (18 individuals; prevalence 28.6% [95% CI 20.0%–37.2%]) and HF with preserved ejection fraction (12 individuals; prevalence 27.9% [95% CI 19.4–36.4]). Twenty-one (70%) of the 30 participants were newly detected cases of COPD.
More than a quarter of the patients with HF concomitantly have COPD, with the large majority being previously unrecognized. Coexistence of COPD should be considered more often in these patients.
PMCID: PMC4492658  PMID: 26170650
heart failure; COPD; prevalence; comorbidity; spirometry; diagnosis; primary care
24.  Peak expiratory flow rate as a surrogate for forced expiratory volume in 1 second in COPD severity classification in Thailand 
There are limited studies directly comparing correlation and agreement between peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1) for severity classification of COPD. However, clarifying the role of PEFR as a surrogate of COPD severity classification instead of FEV1 is essential in situations and areas where spirometry is not routinely available.
To evaluate the agreement between FEV1 and PEFR using Global initiative for chronic Obstructive Lung Disease (GOLD) severity classification criteria.
Materials and methods
This cross-sectional study included stable COPD patients. Both absolute values and % predicted FEV1 and % predicted PEFR were obtained from the same patients at a single visit. The severity of COPD was classified according to GOLD criteria. Pearson’s correlation coefficient was used to examine the relationship between FEV1 and PEFR. The agreement of % predicted FEV1 and % predicted PEFR in assigning severity categories was calculated using Kappa statistic, and identification of the limits of agreement was by Bland–Altman analysis. Statistical significance was set at P-value <0.05.
Three hundred stable COPD patients were enrolled; 195 (65.0%) male, mean age 70.4±9.4 years, and mean % predicted FEV1 51.4±20.1. Both correlations between the % predicted FEV1 and PEFR as well as the absolute values were strongly significant (r=0.76, P<0.001 and r=0.87, P<0.001, respectively). However, severity categories of airflow limitation based on % predicted FEV1 or PEFR intervals were concordant in only 179 patients (59.7%). The Kappa statistic for agreement was 0.41 (95% confidence interval, 0.34–0.48), suggesting unsatisfied agreement. The calculated limits of agreement were wide (+27.1% to −28.9%).
Although the correlation between FEV1 and PEFR measurements were strongly significant, the agreement between the two tests was unsatisfied and may influence inappropriate clinical decision making in diagnosis, severity classification, and management of COPD.
PMCID: PMC4485793  PMID: 26150713
chronic obstructive pulmonary disease; spirometry; agreement
25.  Relationship between nutritional risk and exercise capacity in severe chronic obstructive pulmonary disease in male patients 
The nutritional status of chronic obstructive pulmonary disease (COPD) patients is associated with their exercise capacity. In the present study, we have explored the relationship between nutritional risk and exercise capacity in severe male COPD patients.
A total of 58 severe COPD male patients were enrolled in this study. The patients were assigned to no nutritional risk group (n=33) and nutritional risk group (n=25) according to the Nutritional Risk Screening (NRS, 2002) criteria. Blood gas analysis, conventional pulmonary function testing, and cardiopulmonary exercise testing were performed on all the patients.
Results showed that the weight and BMI of the patients in the nutritional risk group were significantly lower than in the no nutritional risk group (P<0.05). The pulmonary diffusing capacity for carbon monoxide of the no nutritional risk group was significantly higher than that of the nutritional risk group (P<0.05). Besides, the peak VO2 (peak oxygen uptake), peak O2 pulse (peak oxygen pulse), and peak load of the nutritional risk group were significantly lower than those of the no nutritional risk group (P<0.05) and there were significantly negative correlations between the NRS score and peak VO2, peak O2 pulse, or peak load (r<0, P<0.05).
The association between exercise capacity and nutritional risk based on NRS 2002 in severe COPD male patients is supported by these results of this study.
PMCID: PMC4484657  PMID: 26150712
nutritional risk; exercise capacity; chronic obstructive pulmonary disease; conventional pulmonary function testing; cardiopulmonary exercise testing

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