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1.  Differences in Adjustment between Individuals with Alpha-1 Antitrypsin Deficiency (AATD) Associated COPD and Non-AATD COPD 
COPD  2013;10(2):226-234.
Smokers who have severe alpha-1 antitrypsin deficiency (AATD) are at risk for developing COPD earlier in life than smokers without AATD, and are likely to experience challenges adjusting to their illness because they are in a highly productive life stage when they are diagnosed with COPD. This study examined whether individuals with AATD-associated COPD differ from individuals with non-AATD COPD with regard to depression, anxiety, dyspnea, and health-related quality of life (HRQL). Cross-sectional data were collected via self-report questionnaires completed by 480 individuals with non-AATD COPD and 578 individuals with AATD-associated COPD under protocols with IRB approval. Multiple linear regression models were used to test whether individuals with non-AATD COPD differed from individuals with AATD-associated COPD with regard to depression, anxiety, dyspnea, and HRQL. All models adjusted for demographic and health characteristics. Individuals with AATD-associated COPD did not report more symptoms of depression or anxiety; however, they did report more dyspnea (B = 0.31, 95% CI = 0.16 to 0.47, p < 0.001) and impairment in HRQL (B = 4.75, 95% CI = 2.10 to 7.41, p < 0.001) than other individuals with COPD. Individuals with AATD-associated COPD were more likely to be a member of a couple (rather than single) and had a higher level of education when compared to individuals with non-AATD COPD. Resources available to persons with AATD-associated COPD, such as being in a serious relationship and having higher education, may offset the effect of age when considering symptoms of depression and anxiety in patients with COPD.
doi:10.3109/15412555.2012.719049
PMCID: PMC3616400  PMID: 23547634
Alpha-1 Antitrypsin Deficiency; Anxiety; Depression; Dyspnea; Health Status; Psychological Adjustment
2.  Use of Spirometry in the Diagnosis of COPD: A Qualitative Study in Primary Care 
COPD  2013;10(4):444-449.
Guidelines that recommend spirometry to confirm airflow obstruction among patients with suspected COPD are not routinely followed. We conducted a qualitative study to identify attitudes and barriers of primary care physicians to performing spirometry for patients with possible COPD. We conducted four focus groups, each with three primary care physicians (PCPs) who practice in an urban, academic medical center. In general, PCPs believed that spirometry was not necessary to confirm the diagnosis of COPD. Compared to other co-morbid conditions, in a patient with a diagnosis of COPD without self-reported symptoms, COPD was not a priority during a clinic visit. This was in part due to the belief that there was lack of evidence that medication used in COPD lead to improved outcomes and that there was no point of care measure for COPD compared to other co-morbid conditions such as diabetes mellitus or hypertension. Health system barriers specific to spirometry use was not identified. In conclusion, in our sample of PCPs, there was skepticism that spirometry is warranted to diagnose and manage COPD. Availability of spirometry was not a perceived barrier. Our results explain, in part, why previous interventions to improve access to spirometry and diagnosis of COPD in primary care settings have been difficult to conduct and/or have had marginal success. Our findings strongly suggest that a first step toward increasing the use of spirometry among primary care physicians is to have them believe in its utility in the diagnosis of COPD.
doi:10.3109/15412555.2013.766683
PMCID: PMC3938329  PMID: 23537230
chronic disease; diagnosis; pulmonary diseases; qualitative research
3.  Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: The Cardiovascular Health Study 
COPD  2013;10(5):588-596.
Background:
High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.
Methods:
We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing ≥1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic comorbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.
Results:
The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.
Conclusions:
Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
doi:10.3109/15412555.2013.781148
PMCID: PMC3903127  PMID: 23819728
Chronic airflow obstruction; instrumental activities of daily living; disability; disablement process
4.  Randomized Trial of Zileuton for Treatment of COPD Exacerbations Requiring Hospitalization 
COPD  2011;8(1):21-29.
Rationale
Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
Objective
We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
Methods
Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
Main Findings
Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75±2.19 vs. 3.86±3.06 days for zileuton vs. placebo, p=0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p=0.63) despite a decline in urinary LTE4 levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine −1.38± 1.19 vs. 0.14±1.51, p<0.0001) and 72 hours (−1.32±2.08 vs. 0.26±1.93, p<0.006). Adverse events were similar in both groups.
Principal Conclusions
While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE4 levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
doi:10.3109/15412555.2010.540273
PMCID: PMC3775706  PMID: 21299475
Chronic Obstructive Pulmonary Disease (COPD); Acute exacerbation of COPD (AECOPD); Leukotrienes; Zileuton; Clinical trial
5.  Demographic, Physiologic and Radiographic Characteristics of COPD Patients Taking Chronic Systemic Corticosteroids 
COPD  2012;9(1):29-35.
Long-term therapy with systemic corticosteroids is not recommended in the treatment of chronic obstructive pulmonary disease (COPD). However, experience demonstrates that some patients receive low dose therapy. Our objective was to describe the demographic, physiologic and radiologic characteristics of COPD patients treated with chronic systemic corticosteroids. We analyzed COPD subjects with GOLD I–IV disease in the COPDGene® study. Subjects were divided into two groups based on whether they reported using chronic oral steroids or not. 1264 subjects were included. 58 (4.5%) reported chronic systemic corticosteroid use. There were no differences in age, race, comorbid conditions (other than asthma), or body mass index between the groups. There was a greater proportion of GOLD III (41% vs. 26%) and IV (41% vs. 13%) subjects in the group using chronic systemic corticosteroids. This group used more respiratory medications, required more oxygen (2.31±0.21 vs. 0.59±0.05 L/min; p<0.0001), and walked less distance (245.4±17.4 vs. 367.2±3.9 meters; p<0.0001). They reported more total (1.7±0.16 vs. 0.62±0.03; p<0.0001) and severe exacerbations per year (0.41±0.05 vs. 0.18 ± 0.01; p<0.0001). BODE (5.0±0.3 vs. 2.6±0.1; p<0.0001), MMRC (3.31±0.19 vs. 1.90±0.04; p<0.0001) and SGRQ scores (54.9±2.9 vs 53.3±0.6; p<0.0001) were higher. They also had a higher percentage of emphysema (22.4±1.9 vs. 14.0±0.4; %, p=<0.0001) on CT scan. COPD patients that report using chronic systemic corticosteroids have more severe clinical, physiologic, and radiographic disease.
doi:10.3109/15412555.2011.634454
PMCID: PMC3764986  PMID: 22292596
Emphysema; Prednisone; Phenotype
6.  A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation 
COPD  2012;9(2):151-159.
The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring
Methods
Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were fifty-eight observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements.
Results
Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively.
Conclusions
Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.
doi:10.3109/15412555.2012.654923
PMCID: PMC3752926  PMID: 22429093
7.  Alcohol Use Predicts ER Visits in Individuals with Alpha-1 Antitrypsin Deficiency (AATD) Associated COPD 
COPD  2012;9(4):417-425.
Excessive alcohol use in COPD has been associated with increased mortality; however, little is known about alcohol use in AATD-associated COPD. 538 individuals with AATD-associated COPD completed questionnaires at baseline and 330 also completed 2 years of follow-up questionnaires. Demographic and health information was collected, including information about alcohol use, ER visits for COPD, and hospitalizations for COPD. Problem alcohol use was characterized using the CAGE screening questionnaire and recent alcohol consumption. Demographic and clinical characteristics associated with problem drinking were identified using logistic regression. Problem drinking at baseline was examined as a predictor of ER visits and hospital admissions for COPD in the subsequent two years using logistic regression adjusting for demographic variables and baseline health status. 14% of the sample reported a history of problem drinking per the CAGE and 8% reported problem drinking in the past week. Problem drinking was associated with higher education and greater lifetime tobacco exposure. Recent alcohol consumption was a significant predictor of having an ER visit for COPD in the subsequent two years. Compared to individuals who reported problem drinking in the past week, individuals with no consumption (OR= 0.32, 95% CI= 0.10 to 0.97, p= .043) and individuals with low to moderate consumption (OR= 0.25, 95% CI= 0.08 to 0.77, p= .016) had significantly lower odds of an ER visit. Neither measure of problem drinking predicted hospital admission. Screening for recent excessive alcohol use in this population may identify individuals at risk for use of costly emergency health services.
doi:10.3109/15412555.2012.684414
PMCID: PMC3603142  PMID: 22651849
Alpha One Antitrypsin Deficiency (AATD); Alcohol Use; Emergency Room Use; Emergency Room Visits
8.  Gender Differences of Airway Dimensions in Anatomically Matched Sites on CT in Smokers 
COPD  2011;8(4):285-292.
Rationale and Objectives
There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers.
Materials and Methods
We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions.
Results
Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm2 for segmental bronchial lumen area, 10.4 vs 12.5 mm2 for subsegmental bronchi, 6.5 vs 7.7 mm2 for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness.
Conclusion
Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.
doi:10.3109/15412555.2011.586658
PMCID: PMC3703311  PMID: 21756032
Airway dimensions; CT scan; Gender differences; Smoker
9.  Automated Telecommunication to Obtain Longitudinal Follow-up in a Multicenter Cross-sectional COPD Study 
COPD  2012;9(5):466-472.
Background
It can be challenging to maintain longitudinal follow-up of subjects in clinical studies. COPDGene is a multicenter, observational study designed to identify genetic factors associated with COPD and to characterize COPD-related phenotypes. To obtain follow-up data on patient's vital status and outcomes, the COPDGene Longitudinal Follow-up (LFU) Program was developed to supplement its parent study.
Methods/Results
We used a telecommunication system that employed automated telephone contact or web-based questions to obtain longitudinal follow-up data in our subjects. A branching questionnaire asked about exacerbations, new therapies, smoking status, development of co-morbid conditions, and general health status. Study coordinators contacted subjects who did not respond to one of the automated methods. We enrolled 10,383 subjects in the COPDGene study. As of August 29, 2011, 7,959 subjects completed 19,955 surveys. On the first survey, 68.8% of subjects who completed their survey did so by electronic means, while 31.3% required coordinator phone follow-up. On each subsequent survey the number of subjects who completed their survey by electronic means increased, while the number of subjects who required coordinator follow-up decreased. Despite many of the patients in the cohort being chronically ill and elderly, there was broad acceptance of the system with over half the cohort using electronic response methods.
Conclusions
The COPDGene LFU Study demonstrated that telecommunications was an effective way to obtain longitudinal follow-up of subjects in a large multicenter study. Web-based and automated phone contacts are accepted by research subjects and could serve as a model for LFU in future studies.
doi:10.3109/15412555.2012.690010
PMCID: PMC3698488  PMID: 22676387
COPD; COPDGene; Emphysema; Longitudinal data collection; Exacerbations; Follow-up studies; Elderly
10.  Evaluation of Right Ventricular Remodeling Using Cardiac Magnetic Resonance Imaging in Co-Existent Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea 
COPD  2012;10(1):4-10.
Untreated chronic obstructive pulmonary disease (COPD) co-existing with obstructive sleep apnea (OSA), also known as overlap syndrome, has higher cardiovascular mortality than COPD alone but its underlying mechanism remains unclear. We hypothesize that the presence of overlap syndrome is associated with more extensive right ventricular (RV) remodeling compared to patients with COPD alone. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome (n = 7), else classified as having COPD-only (n = 11). A cardiac MRI was performed to assess right and left cardiac chambers sizes, ventricular masses, and cine function. RV mass index (RVMI) was markedly higher in the overlap group than the COPD-only group (19 ± 6 versus 11 ± 6; p = 0.02). Overlap syndrome subjects had a reduced RV remodeling index (defined as the ratio between RVMI and RV end-diastolic volume index) compared to the COPD-only group (0.27 ± 0.06 versus 0.18 ± 0.08; p = 0.02). In the overlap syndrome subjects, the extent of RV remodeling was associated with severity of oxygen desaturation (R2 = 0.65, p = 0.03). Our pilot results suggest that untreated overlap syndrome may cause more extensive RV remodeling than COPD alone.
doi:10.3109/15412555.2012.719050
PMCID: PMC3679499  PMID: 23272670
Sleep disordered breathing; Overlap syndrome; Cardiac MRI; Lung
11.  Pulmonary Function is Associated with Distal Aortic Calcium, not Proximal Aortic Distensibility. MESA Lung Study 
COPD  2011;8(2):71-78.
Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.
The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors.
Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p=0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p=0.60). Percent emphysema was associated with neither measure.
FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
doi:10.3109/15412555.2011.558543
PMCID: PMC3629728  PMID: 21495835
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
12.  Difference in airflow obstruction between Hispanic and non-Hispanic white female smokers 
COPD  2008;5(5):274-281.
Rationale
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
Objective
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Methods
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Main findings
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Principal conclusions
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
doi:10.1080/15412550802363345
PMCID: PMC3616889  PMID: 18972275
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women
13.  Mesenchymal Cell Fate and Phenotypes in the Pathogenesis of Emphysema 
COPD  2009;6(3):201-210.
Emphysema is characterized by the destruction of alveolar parenchymal tissue and the concordant loss of lung epithelial cells, endothelial cells, and interstitial mesenchymal cells. Key features in the pathobiology of emphysema include inflammation, alveolar epithelial cell injury/apoptosis, and excessive activation of extracellular matrix (ECM) proteases. Mesenchymal cells are versatile connective tissue cells that are critical effectors of wound-repair. The excessive loss of connective tissue and the destruction of alveolar septae in emphysema suggest that the mesenchymal cell reparative response to epithelial injury is impaired. Yet, the mechanisms regulating mesenchymal cell (dys)function in emphysema remain poorly understood. We propose that mesenchymal cell fate, modulated by transforming growth factor beta-1 (TGF-β1) and the balance of ECM proteases and antiproteases, is a critical determinant of the emphysema phenotype. We examine emphysema in the context of wound-repair responses, with a focus on the regulation of mesenchymal cell fate and phenotype. We discuss the emerging evidence supporting that genetic factors, inflammation and environmental factors, including cigarette smoke itself, collectively impair mesenchymal cell survival and function, thus contributing to the pathogenesis of emphysema.
PMCID: PMC3524525  PMID: 19811376
Apoptosis; repair; fibroblast; myofibroblast; extracellular matrix; TGF-β1; Chronic Obstructive Pulmonary Disease: A Global Health Crisis
14.  Obesity and COPD: Associated Symptoms, Health-related Quality of Life, and Medication Use 
COPD  2011;8(4):275-284.
Background
There is little data about the combined effects of COPD and obesity. We compared dyspnea, health-related quality of life (HRQoL), exacerbations, and inhaled medication use among patients who are overweight and obese to those of normal weight with COPD.
Methods
We performed secondary data analysis on 364 Veterans with COPD. We categorized subjects by body mass index (BMI). We assessed dyspnea using the Medical Research Council (MRC) dyspnea scale and HRQoL using the St. George's Respiratory Questionnaire. We identified treatment for an exacerbation and inhaled medication use in the past year. We used multiple logistic and linear regression models as appropriate, with adjustment for age, COPD severity, smoking status, and comorbidities.
Results
The majority of our population was male (n=355, 98%) and either overweight (n=115, 32%) or obese (n=138, 38%). Obese and overweight subjects had better lung function (obese: mean FEV1 55.4% ±19.9% predicted, overweight: mean FEV1 50.0% ±20.4% predicted) than normal weight subjects (mean FEV1 44.2% ±19.4% predicted), yet obese subjects reported increased dyspnea [adjusted OR of MRC score ≥2= 4.91 (95% CI 1.80, 13.39], poorer HRQoL, and were prescribed more inhaled medications than normal weight subjects. There was no difference in any outcome between overweight and normal weight patients.
Conclusions
Despite having less severe lung disease, obese patients reported increased dyspnea and poorer HRQoL than normal weight patients. The greater number of inhaled medications prescribed for obese patients may represent overuse. Obese patients with COPD likely need alternative strategies for symptom control in addition to those currently recommended.
doi:10.3109/15412555.2011.586660
PMCID: PMC3169653  PMID: 21809909
Obesity; COPD; health-related quality of life; symptoms; inhaled medications; exacerbations
15.  Activity Monitoring and Energy Expenditure in COPD Patients: A Validation Study 
COPD  2007;4(2):107-112.
There is increasing interest in the objective measurement of physical activity in chronic obstructive pulmonary disease (COPD) patients due to the close relationship between physical activity level, health, disability and mortality. We aimed to (a) determine the validity and reproducibility of an activity monitor that integrates accelerometry with multiple physiologic sensors in the determination of energy expenditure in COPD subjects and (b) to document the independent contribution of the additional physiologic sensors to accelerometry measures in improving true energy expenditure determination. Eight subjects (4 male, FEV1 56.4 ± 14.1%, RV 145.0 ± 75.7%) performed 2 separate 6-minute walk and 2 incremental shuttle walk exercise tests. Energy expenditure was calculated during each exercise test using the physiologic activity monitor and compared to a validated exhaled breath metabolic system. Test-retest reproducibility of physiologic activity monitor during the walking tests was comparable to an exhaled breath metabolic system. Physiologic sensor data significantly improved the explained variance in energy expenditure determination (r2= 0.88) compared to accelerometry data alone (r2 = 0.68). This physiologic activity monitor provides a valid and reproducible estimate of energy expenditure during slow to moderate paced walking in a laboratory setting and represents an objective method to assess activity in COPD subjects.
doi:10.1080/15412550701246658
PMCID: PMC3391963  PMID: 17530503
Energy Expenditure; COPD; Ambulatory Monitoring; Exercise Test; Activities Of Daily Living
16.  Antioxidant Diet Protects Against Emphysema, but Increases Mortality in Cigarette Smoke-Exposed Mice 
COPD  2011;8(5):362-368.
Oxidative stress plays an important role in cigarette smoke-induced lung inflammation and emphysema. We produced an enriched diet by adding freeze-dried fruits and vegetables and additional supplements to the 8604 Teklad Rodent Diet, a standard rodent diet. In this study, we examined the effects of the antioxidant-enriched diet on cigarette smoke-induced lung inflammation and emphysema. CH3/HeN mice were fed either a regular diet or an antioxidant diet. These mice were exposed to filtered air, a low concentration of cigarette smoke (total particulate matter: 100 mg/m3) or a high concentration of cigarette smoke (total particulate matter: 250mg/m3) for 6 hours/day, 5 days/week for total 16 weeks. Surprisingly, increased mortality (53%) was observed in the high concentration of cigarette smoke-exposed mice fed the antioxidant diet compared to the high concentration of cigarette smoke-exposed mice that were fed a regular diet (13%). The necropsy analysis revealed nasal passage obstruction due to mucous plugging in cigarette smoke-exposed mice on the antioxidant diet. However, the antioxidant diet significantly reduced neutrophilic inflammation and emphysema in the high concentration of cigarette smoke-exposed mice as compared to the regular diet /high concentration of cigarette smoke controls. The antioxidant capacity in the bronchoalveolar fluid or oxidative damage to the lung tissue was not affected by the antioxidant diet. Pro-MMP-2, MMP-2, and MMP-9 activity did not correlate with the protective effects of AOD on cigarette smoke-induced emphysema. These data suggest that the antioxidant diet reduced cigarette smoke -induced inflammation and emphysema, but increased mortality in the obligate nose-breathing mice.
doi:10.3109/15412555.2011.600361
PMCID: PMC3323122  PMID: 21834692
cigarette smoke; emphysema; oxidative stress; lung inflammation; adverse effects; lipid peroxidation; metalloproteinase
17.  Hypertension, Systemic Inflammation and Body Weight in Relation to Lung Function Impairment—An Epidemiological Study 
COPD  2009;6(4):250-255.
Recent reports on the simultaneous occurrence of systemic inflammation and airflow obstruction are usually based on a highly selective patient population, but their importance warrants further evaluation in the general population. The objectives were to study the interrelationship between airflow obstruction, smoking, hypertension, obesity and CRP as a marker of systemic inflammation in a randomly selected sample of the general Icelandic population (n = 939). This study comprised 758 randomly selected men and women 40 years and older living in Reykjavik, Iceland, and who were participating in the Burden of Obstructive Lung Disease (BOLD) study (81% response rate). In addition to the BOLD protocol, which included post-bronchodilator spirometry, they answered questions about general health and medication. Serum samples were taken for measurement of C-reactive protein (CRP). In the sample—245 individuals (33%) reported having hypertension. Subjects with hypertension were older, had a higher BMI and higher CRP levels. Subjects with hypertension had lower values of FEV1 than predicted (89.9 ± 18.5 vs. 94.5 ± 14.4%) (p < 0.001) and FVC (92.2 ± 15.1 vs. 95.3 ± 12.3%) (p = 0.002). These differences remained significant after adjusting for age, BMI, CRP and smoking. Hypertension and CRP levels above the median were both independently and additively associated with lower FEV1 and FVC. In addition a lower FVC% was also associated with a higher BMI (> 30 mg/m2). Use of betablocking antihypertensives was not related to lung function. Hypertension, BMI and systemic inflammation affect lung function independently of each other. All three variables have a negative effect on FVC, while hypertension and high CRP were independently associated with impaired FEV1.
PMCID: PMC3334274  PMID: 19811383
Airflow obstruction; hypertension; obesity; systemic inflammation; cytokines
18.  POLYMORPHISMS IN THE SUPEROXIDE DISMUTASE-3 GENE ARE ASSOCIATED WITH EMPHYSEMA IN COPD 
COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
doi:10.3109/15412555.2010.496821
PMCID: PMC2923920  PMID: 20673035
20.  Genetic Epidemiology of COPD (COPDGene) Study Design 
COPD  2010;7(1):32-43.
Background
COPDGeneis a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes.
Methods/Results
COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out.
Conclusions
COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
doi:10.3109/15412550903499522
PMCID: PMC2924193  PMID: 20214461
21.  Screening for Depression in Chronic Obstructive Pulmonary Disease 
COPD  2009;6(6):452-458.
Depression and chronic obstructive pulmonary disease (COPD) are major causes of disability. Identifying COPD patients at risk for depression would facilitate the alleviation of an important comorbidity conferring additional risk for poor outcomes. The purpose of this study was to determine the utility of a brief screening measure, the 15-item Geriatric Depression Scale (GDS-15), in detecting the mood disorders in persons with COPD. This is a cross-sectional study of 188 persons with COPD, stratified by age (65 and older versus less than 65) and COPD severity using Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging. Screening cut-points were empirically derived using threshold selection methods and receiver operating characteristic (ROC) curves were estimated. The GDS-15 was used as a screening measure and diagnoses of Major Depressive Disorder (MDD) or other mood disorders were determined using a “gold standard” standardized structured clinical interview. Of the 188 persons with COPD, 25% met criteria for any mood disorder and 11% met criteria for MDD. Optimal threshold estimations suggested a GDS cut score of 5, which yielded adequate sensitivity and specificity in detecting MDD (81% and 87%, respectively) and correctly classified 86% of participants. To detect the presence of any mood disorder, a cut score of 4 was suggested yielding sensitivity and specificity of 67% and 82%, respectively; correctly classifying 79%. These results suggest that mood disorders are relatively common among persons with COPD. The GDS-15 is a useful screening measure to identify patients at risk for depression.
doi:10.3109/15412550903341463
PMCID: PMC2981409  PMID: 19938969
Chronic Obstructive Pulmonary Disease; Depression; Screening; Validity
22.  Family Relationship Quality is Associated with Psychological Distress, Dyspnea, and Quality of Life in COPD 
COPD  2009;6(5):359-368.
Family relationship quality predicts medical outcomes in various health conditions, including stroke, end stage renal disease, and heart failure. Family relationships also influence the onset and course of depression and anxiety disorders. Family may be particularly important in COPD given the high prevalence of depression and anxiety in COPD patients and the association of depression and anxiety with important clinical features of COPD such as dyspnea. The objective of this study was to test three hypotheses in a sample of individuals with COPD: 1) unsupportive family relationships are associated with psychological distress; 2) psychological distress is associated with dyspnea and impairment in health-related quality of life; and 3) unsupportive family relationships are indirectly associated with dyspnea and health-related quality of life via psychological distress. Cross-sectional data were collected via self-report questionnaires completed by 526 individuals with COPD. Structural equation modeling was used to test the hypotheses. All three hypotheses were supported. Unsupportive family relationships were associated with psychological distress, psychological distress was associated with dyspnea and impairment in health-related quality of life, and unsupportive family relationships were indirectly associated with dyspnea and health-related quality of life via psychological distress. If subsequent longitudinal investigations demonstrate that unsupportive family relationships do indeed lead to psychological distress among individuals with COPD, then interventions to improve family relationships of patients with COPD could lead to reductions in psychological distress and, ultimately, to improvements in dyspnea and quality of life.
PMCID: PMC2805093  PMID: 19863365
Pulmonary disease; chronic obstructive; Psychological distress; Health status; Family; Interpersonal relations
23.  Quantitative airway assessment on computed tomography in patients with α1-antitrypsin deficiency 
COPD  2009;6(6):468-477.
Background
The relationship between quantitative airway measurements on computed tomography (CT) and airflow limitation in individuals with severe α1-antitrypsin deficiency (AATD) is undefined.
Objectives
To clarify the relationship between CT-based airway indices and airflow limitation in AATD.
Methods
52 patients with AATD underwent chest CT and pre-bronchodilator spirometry at three institutions. In the right upper (RUL) and lower (RLL) lobes, wall area percent (WA%) and luminal area (Ai) were measured in the third, fourth, and fifth generations of the bronchi. The severity of emphysema was also calculated in each lobe and expressed as low attenuation area percent (LAA%). Correlations between obtained measurements and FEV1% predicted (FEV1%P) were evaluated by the Spearman rank correlation test.
Results
In RUL, WA% of all generations was significantly correlated with FEV1%P (3rd,R=−0.33, p=0.02; 4th,R=−0.39, p=0.004; 5th,R=−0.57, p<0.001; respectively). Ai also showed significant correlations (3rd,R=0.32, p=0.02; 4th,R=0.34, p=0.01; 5th,R=0.56, p<0.001; respectively). Measured correlation coefficients improved when the airway progressed distally from the third to fifth generations. LAA% also correlated with FEV1%P (R=−0.51, p<0.001). In RLL, WA% showed weak correlations with FEV1%P in all generations (3rd,R=−0.34, p=0.01; 4th,R=−0.30, p=0.03; 5th,R=−0.31, p=0.03; respectively). Only Ai from the fifth generation significantly correlated with FEV1%P in this lobe (R=0.34, p=0.01). LAA% strongly correlated with FEV1%P (R=−0.71, p<0.001).
Conclusions
Quantitative airway measurements are significantly correlated with airflow limitation in AATD, particularly in the distal airways of RUL. Emphysema of the lower lung is the predominant component; however, airway disease also has a significant impact on airflow limitation in AATD.
doi:10.3109/15412550903341521
PMCID: PMC2945281  PMID: 19938971
24.  Current perspectives on role of chromatin modifications and deacetylases in lung inflammation of COPD 
COPD  2009;6(4):291-297.
Chromatin modifications and epigenetic regulation are critical for sustained and abnormal inflammatory response seen in lungs of patients with chronic obstructive pulmonary disease (COPD) because the activities of enzymes that regulate these epigenetic modifications are altered in response to cigarette smoke. Cigarette smoke induces chromatin modifications and epigenetic changes by causing post-translational modifications of histone acetyltransferases, and histone/non-histone deacetylases (HDACs), such as HDAC2 and sirtuin 1 (SIRT1), which leads to chromatin remodeling. In this review, we discussed the current knowledge on cigarette smoke/oxidants-mediated post-translational modifications of deacetylases (HDAC2 and SIRT1), disruption of HDAC2/SIRT1-RelA/p65 corepressor complex associated with acetylation of RelA/p65, and chromatin modifications (histone H3 phospho-acetylation) leading to sustained pro-inflammatory gene transcription. Knowledge on molecular mechanisms of epigenetic changes in abnormal lung inflammation will help in understanding the pathophysiology of COPD which may lead to the development of novel epigenetic therapies in the near future.
PMCID: PMC2760053  PMID: 19811389
COPD; oxidants; epigenetics; HDAC; SIRT1; cigarette smoke
25.  Alveolar Macrophage Recruitment and Activation by Chronic Second Hand Smoke Exposure in Mice 
COPD  2009;6(2):86-94.
Background
Approximately 15% of cases of COPD occur in non-smokers. Among the potential risk factors for COPD in non-smokers is second hand smoke (SHS) exposure. However, the Surgeon General reported in 2006 that the evidence linking second hand smoke and COPD is insufficient to infer a causal relationship, largely because current evidence does not establish a biological link.
Objectives
The goal of this study was to determine whether SHS exposure can induce alveolar macrophage recruitment and expression of activation markers that we have previously demonstrated in human smokers and in mouse models of emphysema. To achieve these goals, we studied mice exposed to an ambient mixture of predominantly [89%] sidestream smoke at increasing doses over 3 months.
Results
We found that second hand smoke exposure induced a dose-dependent increase in alveolar macrophage recruitment (mean ± sd; 224,511 ± 52,330 vs 166,152 ± 47,989 macrophages/ml of bronchoalveolar lavage in smoke-exposed vs air-exposed controls at 3 months, p=0.003). We also found increased expression of several markers of alveolar macrophage activation (PLA2g7, dkfzp434l142, Trem-2, and pirin, all p<0.01 at 3 months) and increased lavage levels of two inflammatory mediators associated with COPD (CCL2 [MCP-1], 58 ± 12 vs. 43 ± 22 pg/ml, p=0.03; and TNFα, 138 ± 43 vs 88 ± 78 pg/ml, p=0.04 at 3 months).
Conclusions
These findings indicate that second smoke exposure can cause macrophage recruitment and activation, providing a biological link between second hand smoke exposure and the development of inflammatory processes linked to COPD.
doi:10.1080/15412550902751738
PMCID: PMC2873864  PMID: 19378221
macrophage; tobacco; cigarette smoke; inflammation; cytokine

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