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1.  Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans 
Background
COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD.
Methods
We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW).
Results
Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms).
Conclusions
Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.
doi:10.15326/jcopdf.1.1.2014.0112
PMCID: PMC4329763
COPD; Comorbidities; Race
2.  Racial Differences in CT Phenotypes in COPD 
COPD  2013;10(1):20-27.
Background
Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD.
Methods
First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of % emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment.
Results
Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean % emphysema (13.1 % vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs.
Conclusions
AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs.
doi:10.3109/15412555.2012.727921
PMCID: PMC4321889  PMID: 23413893
Airway wall thickness; Air trapping; Chronic obstructive pulmonary disease; Emphysema; Quantitative CT; Race
3.  A score to predict short-term risk of COPD exacerbations (SCOPEX) 
Background
There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.
Methods
Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.
Results
The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).
Conclusion
SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.
doi:10.2147/COPD.S69589
PMCID: PMC4315304
chronic obstructive pulmonary disease; exacerbation; model; predictor; inhaled corticosteroids; bronchodilators
4.  A Simplified Score to Quantify Comorbidity in COPD 
PLoS ONE  2014;9(12):e114438.
Importance
Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.
Materials and Methods
Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.
Results
Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341).
Conclusions
Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
doi:10.1371/journal.pone.0114438
PMCID: PMC4267736  PMID: 25514500
5.  Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus 
BMC Pulmonary Medicine  2014;14(1):164.
Background
Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.
Methods
Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%).
Results
Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5–10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study.
Conclusions
Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa.
Trial registration
Clinicaltrials.gov identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-164) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2466-14-164
PMCID: PMC4216374  PMID: 25341556
Airway disease; CT scan; Diabetes mellitus; Emphysema; Spirometry
6.  Airway wall thickness is increased in COPD patients with bronchodilator responsiveness 
Respiratory Research  2014;15(1):84.
Rationale
Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR.
Methods
We analyzed subjects with GOLD 1–4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated.
Results
2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar.
Conclusion
BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD.
doi:10.1186/s12931-014-0084-3
PMCID: PMC4198908  PMID: 25248436
Bronchodilator responsiveness; Airway wall thickness; Chronic obstructive pulmonary disease; Airflow obstruction
7.  Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene 
Respiratory Research  2014;15(1):89.
Background
Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.
Methods
Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45–80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.
Results
The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.
Conclusions
PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.
Trial registration
Clinicaltrials.gov Identifier: NCT000608764.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-014-0089-y
PMCID: PMC4256936  PMID: 25096860
Spirometry; Restriction; Lung diseases; Smoking
8.  Implications of the GOLD 2011 Disease Severity Classification in the COPDGene Cohort 
Background
The 2011 Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) consensus report uses symptoms, exacerbation history and FEV1% to define four categories: A, low symptoms/low risk; B, high symptoms/low risk; C, low symptoms/high risk; and D, high symptoms/high risk where risk refers to exacerbations, hospitalization and death. Our objective was to determine (1) the influence of symptom instrument on category membership and (2) prospective exacerbation risk by category.
Methods
4,484 COPD subjects from COPDGene were analyzed. All subjects had smoking history ≥ 10 pack-years and FEV1/FVC<0·7. Categories were defined using the modified Medical Research Council Dyspnea [mMRC] (0–1 versus ≥ 2) and the Saint George’s Respiratory Questionnaire [SGRQ] (≥25 versus <25 as a surrogate for the COPD Assessment Test ≥ 10 versus <10) in addition to COPD exacerbations in the prior year (<2 versus ≥ 2), and FEV1% predicted (≥50 versus <50).
Findings
Category assignment using mMRC versus SGRQ were similar but not identical. Using the mMRC, category assignments were 34% A, 21% B, 8% C and 38% D and for SGRQ were 29% A, 25% B, 5% C and 41% D (kappa=0·77). Significant heterogeneity in exacerbation rates (exacerbations/person-year) were seen particularly within the D group, depending on the risk factor that determined category assignment (lung function (0·89), prior exacerbation history (1·34) or both (1·86), p<0·001.
Interpretations
The GOLD classification emphasizes the importance of symptoms and exacerbation risk in assessing COPD severity. The choice of symptom measure influences category assignment. The relative number of subjects with low symptoms and high risk for exacerbations (category C) is low. Differences in exacerbation rates for subjects in the highest risk category D were seen depending on whether risk was based on lung function, exacerbation history or both.
doi:10.1016/S2213-2600(12)70044-9
PMCID: PMC4105297  PMID: 24321803
9.  One-Year Safety and Efficacy Study of Arformoterol Tartrate in Patients With Moderate to Severe COPD 
Chest  2014;146(6):1531-1542.
BACKGROUND:
Arformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD.
METHODS:
This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization.
RESULTS:
Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George’s Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05).
CONCLUSIONS:
Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo.
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov
doi:10.1378/chest.14-0117
PMCID: PMC4251615  PMID: 25451347
10.  Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study 
Respiratory Research  2014;15(1):52.
Background
Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways and a greater history of smoking, acute bronchitis, allergic rhinitis, and occupational exposures compared to those without CB.
Methods
We divided 2703 GOLD 1–4 subjects in the Genetic Epidemiology of COPD (COPDGene®) Study into two groups based on symptoms: chronic bronchitis (CB+, n = 663, 24.5%) and no chronic bronchitis (CB-, n = 2040, 75.5%). Subjects underwent extensive clinical characterization, and quantitative CT analysis to calculate mean wall area percent (WA%) of 6 segmental airways was performed using VIDA PW2 (http://www.vidadiagnostics.com). Square roots of the wall areas of bronchi with internal perimeters 10 mm and 15 mm (Pi10 and Pi15, respectively), % emphysema, %gas trapping, were calculated using 3D Slicer (http://www.slicer.org).
Results
There were no differences in % emphysema (11.4 ± 12.0 vs. 12.0 ± 12.6%, p = 0.347) or % gas trapping (35.3 ± 21.2 vs. 36.3 ± 20.6%, p = 0.272) between groups. Mean segmental WA% (63.0 ± 3.2 vs. 62.0 ± 3.1%, p < 0.0001), Pi10 (3.72 ± 0.15 vs. 3.69 ± 0.14 mm, p < 0.0001), and Pi15 (5.24 ± 0.22 vs. 5.17 ± 0.20, p < 0.0001) were greater in the CB + group. Greater percentages of gastroesophageal reflux, allergic rhinitis, histories of asthma and acute bronchitis, exposures to dusts and occupational exposures, and current smokers were seen in the CB + group. In multivariate binomial logistic regression, male gender, Caucasian race, a lower FEV1%, allergic rhinitis, history of acute bronchitis, current smoking, and increased airway wall thickness increased odds for having CB.
Conclusions
Histories of asthma, allergic rhinitis, acute bronchitis, current smoking, a lower FEV1%, Caucasian race, male gender, and increased airway wall thickness are associated with CB. These data provide clinical and radiologic correlations to the clinical phenotype of CB.
doi:10.1186/1465-9921-15-52
PMCID: PMC4067738  PMID: 24766722
Chronic bronchitis; Chronic obstructive pulmonary disease; Airway thickening; Asthma
11.  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
12.  Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis 
Nature genetics  2013;45(6):613-620.
We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.
doi:10.1038/ng.2609
PMCID: PMC3677861  PMID: 23583980
13.  Long-term Comparative Immunogenicity of Protein Conjugate and Free Polysaccharide Pneumococcal Vaccines in Chronic Obstructive Pulmonary Disease 
The Food and Drug Adminstration recently approved a diphtheria-conjugated pneumococcal polysaccharide vaccine for adults, although its long-term immunogenicity is unknown. We report that, in patients with moderate to severe chronic obstructive pulmonary disease, conjugate vaccination elicits a superior immune response to free-polysaccharide vaccine that persists for >2 years.
Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.
Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.
Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.
Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points.
Clinical Trials Registration: NCT00457977.
doi:10.1093/cid/cis513
PMCID: PMC3491850  PMID: 22652582
14.  Benefits of Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis 
Respiratory care  2011;56(6):783-789.
BACKGROUND
Information on the benefits of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF) is growing, but PR’s effects on certain important outcomes is lacking.
METHODS
We conducted a pilot study of PR in IPF and analyzed changes in functional capacity, fatigue, anxiety, depression, sleep, and health status from baseline to after completion of a standard, 6-week PR program.
RESULTS
Six-min walk distance improved a mean ± standard error 202 ± 135 feet (P = .01) from baseline. Fatigue Severity Scale score also improved significantly, declining an average 1.5 ± 0.5 points from baseline. There were trends toward improvement in anxiety, depression, and health status.
CONCLUSIONS
PR improves functional capacity and fatigue in patients with IPF. (ClinicalTrials.gov registration NCT00692796.)
doi:10.4187/respcare.00939
PMCID: PMC3753775  PMID: 21333082
pulmonary rehabilitation; idiopathic pulmonary fibrosis; IPF; outcomes; functional capacity; fatigue
15.  Relationship between Quantitative CT Metrics and Health Status and Bode in COPD 
Thorax  2012;67(5):399-406.
Background
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
Methods
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
Results
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Conclusion
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
doi:10.1136/thoraxjnl-2011-201185
PMCID: PMC3719874  PMID: 22514236
Imaging; COPD; emphysema
16.  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
17.  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
18.  The development of a patient-reported outcome measure for assessing nighttime symptoms of chronic obstructive pulmonary disease 
Background
The assessment of symptoms of chronic obstructive pulmonary disease (COPD) is important for monitoring and managing the disease and for evaluating outcomes of interventions. COPD patients experience symptoms during the day and night, and symptoms experienced at night often disturb sleep. The aim of this paper is to describe methods used to develop a patient-reported outcome (PRO) instrument for evaluating nighttime symptoms of COPD, and to document evidence for the content validity of the instrument.
Methods
Literature review and clinician interviews were conducted to inform discussion guides to explore patients’ nighttime COPD symptom experience. Data from focus groups with COPD patients was used to develop a conceptual framework and the content of a new PRO instrument. Patient understanding of the new instrument was assessed via cognitive interviews with COPD patients.
Results
The literature review confirmed that there is no instrument with evidence of content validity currently available to assess nighttime symptoms of COPD. Additionally, the literature review and clinician interviews suggested the need to understand patients’ experience of specific symptoms in order to evaluate nighttime symptoms of COPD. Analyses of patient focus group data (N = 27) supported saturation of concepts and aided in development of a conceptual framework. Items were generated using patients’ terminology to collect data on concepts in the framework including the occurrence and severity of COPD symptoms, use of rescue medication at night, and nocturnal awakening. Response options were chosen to reflect concepts that were salient to patients. Subsequent cognitive interviewing with ten COPD patients demonstrated that the items, response options, recall period, and instructions were understandable, relevant, and interpreted as intended.
Conclusions
A new PRO instrument, the Nighttime Symptoms of COPD Instrument (NiSCI), was developed with documented evidence of content validity. The NiSCI is ready for empirical testing, including item reduction and evaluation of psychometric properties.
doi:10.1186/1477-7525-11-104
PMCID: PMC3701508  PMID: 23799883
COPD; Symptoms; PRO; Nighttime; Awakening
19.  Pulmonary Arterial Enlargement and Acute Exacerbations of COPD 
The New England journal of medicine  2012;367(10):913-921.
BACKGROUND
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations.
METHODS
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
RESULTS
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
CONCLUSIONS
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.)
doi:10.1056/NEJMoa1203830
PMCID: PMC3690810  PMID: 22938715
20.  Pulmonary rehabilitation in idiopathic pulmonary fibrosis: A call for continued investigation☆ 
Respiratory medicine  2008;102(12):1675-1680.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that afflicts patients with relentlessly progressive shortness of breath [Joint Statement of the American Thoracic Society and the European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161:646–641]. Despite nearly 30 years of intense investigation, effective therapy for IPF remains elusive; median survival rates have stubbornly remained less than five years from the time of diagnosis [Bjoraker JA, Ryu JH, Edwin MK, Meyers J, Tazelaar H, Schroeder D, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199–2032, Flaherty KR, Thwaite E, Kazerooni EA, Gross B, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143–483], and no medical therapy has been proved to be in any way effective for the treatment of this disease. Without medications that help IPF patients live longer, an important question to ask is whether there are interventions that might allow these people to live better—to be more active; to experience less dyspnea, less depression, less anxiety; to possess a greater sense of control over their disease; and to have better quality of life. Pulmonary rehabilitation helps to accomplish many of these goals in patients with chronic obstructive pulmonary disease, and emerging data suggest that it may do the same for patients with IPF.
doi:10.1016/j.rmed.2008.08.014
PMCID: PMC3673288  PMID: 18848771
Pulmonary fibrosis; Pulmonary rehabilitation; Dyspnea
21.  Religious and Spiritual Coping and Quality of Life Among Patients With Emphysema in the National Emphysema Treatment Trial 
Respiratory care  2011;56(10):1514-1521.
BACKGROUND
Although prior research indicates that religious and spiritual coping is associated with positive health outcomes, few studies have examined religious and spiritual coping among patients with emphysema.
OBJECTIVE
To describe the utilization of religious and spiritual coping and its relationship to quality of life among patients with emphysema, in a 2-year longitudinal follow-up study.
METHODS
Forty patients with emphysema (mean age 63.5 ± 6.0 y, 8 women) who participated in the National Emphysema Treatment Trial were matched on age, sex, race, and education with 40 healthy individuals recruited from the community. We conducted baseline assessment of overall coping strategies, psychological functioning, quality of life, pulmonary function, and exercise capacity, and we assessed overall coping strategies and religious and spiritual coping at 2-year follow-up.
RESULTS
Ninety percent of the patients with emphysema considered themselves at least slightly religious and spiritual. The patients reported using both negative religious coping (eg, questioning God) and positive religious coping (eg, prayer) more than the healthy control subjects at follow-up. However, greater use of religious and spiritual coping was associated with poorer illness-related quality of life.
CONCLUSIONS
Patients with emphysema appear to use various coping strategies in responding to their illness. Future research should investigate if patients using religious and spiritual coping would benefit from interventions to address emotional distress and reduced quality of life.
doi:10.4187/respcare.01105
PMCID: PMC3630474  PMID: 21513606
emphysema; pulmonary rehabilitations; coping; depression; anxiety; quality of life; religiosity; spirituality; National Emphysema Treatment Trial
22.  Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD 
Respiratory Research  2013;14(1):42.
Background
Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.
Methods
Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.
Results
In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.
Conclusions
Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
doi:10.1186/1465-9921-14-42
PMCID: PMC3627637  PMID: 23566024
Emphysema; Chest CT scan; Small airways; Lung function tests; Smoking
23.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13 
Human Molecular Genetics  2011;21(4):947-957.
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
doi:10.1093/hmg/ddr524
PMCID: PMC3298111  PMID: 22080838
24.  LUNG DEFLATION AND OXYGEN PULSE IN COPD: RESULTS FROM THE NETT RANDOMIZED TRIAL 
Respiratory medicine  2011;106(1):109-119.
Background
In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume.
Methods
In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O2 pulse=VO2/HR) at baseline and 6 months. Medical and surgical patients were divided into “deflators” and “non-deflators” based on change in RV/TLC from baseline (ΔRV/TLC). We defined deflation as the ΔRV/TLC experienced by 75% of surgical patients. We examined changes in O2 pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs.
Results
In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O2 pulse (median ΔRV/TLC −18.0% vs. −9.3%, p=0.0003; median ΔO2 pulse 13.6% vs. 1.8%, p=0.12). Surgical deflators also improved iso-work O2 pulse (0.53 mL/beat, p=0.04 at 20 watts). In the validation cohort, surgical deflators experienced a greater improvement in peak O2 pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O2 pulse at rest and during unloaded pedaling (0.32 mL/beat, p<0.0001 and 0.47 mL/beat, p<0.0001, respectively) corresponded with significant reductions in HR and improvements in VO2. On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O2 pulse (OR 1.88, 95% CI 1.30–2.72, p=0.0008).
Conclusion
In COPD, decreased hyperinflation through lung volume reduction is associated with improved O2 pulse.
doi:10.1016/j.rmed.2011.07.012
PMCID: PMC3233645  PMID: 21843930
cardiac function; hyperinflation; lung volume reduction surgery; oxygen pulse
25.  Sequential Cognitive Skills in Emphysema Patients Following Lung Volume Reduction Surgery: A Two Year Longitudinal Study 
PURPOSE
This study compared visuomotor speed and cognitive flexibility in emphysema patients treated either with standard multidisciplinary medical therapy (MT) or lung volume reduction surgery (LVRS), followed over a 2-year period.
METHODS
MT patients (n=544) and 542 LVRS patients completed the Trail Making Test (TMT) Parts A and B prior to randomization (baseline). Testing was repeated at 1 and 2 years.
RESULTS
There were no differences on scores for TMT Part A and B between the LVRS and MT groups at baseline or at years 1 and 2. No significant difference between MT and LVRS was noted in terms of overall change in TMT Part A and B over 2 years. The MT group had a significant improvement on TMT-Part A at each followup time compared to baseline (P<.03) but the LVRS group did not. Both the MT and LVRS groups had a significant decline in performance (increase in time to completion) on TMT-Part B when comparing year 1 to baseline (P<.0001).
CONCLUSION
Emphysema patients who received LVRS or MT as treatment performed similarly on measures of visuomotor speed and flexibility at baseline and 1 and 2 year followup. Both groups showed improvement on visuomotor speed during the first year yet overall cognitive flexibility declined. By the second year neither group had any significant change from baseline. These findings suggest that improvement on visuomotor speed and flexibility, observed in a previous 6-month study of LVRS subjects, was not sustained at 1 and 2 year followup.
doi:10.1097/HCR.0b013e3182343bc8
PMCID: PMC3221608  PMID: 22089885
Lung volume reduction surgery; Medical therapy; Sequential skills

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