ATS Abstracts 2010
COPDGene: The exacerbator phenotype
P.A. Bercz1, N. Marchetti2, G.B. Vance1, J.P. Gaughan3, B.J. Make4, G.J. Criner5, &. the COPDGene
Investigators6 1Temple University Hospital ‐ Philadelphia, PA/US, 2Temple University Hospital
Pulmonary Division/Parkison Pavillion ‐ Philadelphia, PA/US, 3Temple University ‐ Philadelphia, PA/US,
4Natl Jewish Health ‐ Denver, CO/US, 5Temple University Hospital Pulmonary & Critical Care Medicine
‐ Philadelphia, PA/US, 6The COPDGene Study ‐ Various/US
Background: Acute COPD exacerbations have a profound impact on patient quality of life, rate of lung function decline, degree of healthcare utilization and its cost, and overall prognosis. Predicting which patients develop AECOPD is challenging. We sought to identify factors which distinguish those prone to frequent AECOPD.
Methods: Data was drawn from COPD Gene, an on‐going, multi‐center study to establish a cross‐sectional cohort of smokers with and without COPD. Patients included had spirometry‐proven COPD (GOLD I‐IV, n=1182) and were subdivided into frequent exacerbators (≥2 exacerbations in the past 12 months, n=200), infrequent exacerbators (1 exacerbation in the past 12 months, n=217) and non‐exacerbator controls (n=765.) An exacerbation was defined as an event which prompted the patient to take an additional steroid or antibiotic, consult their physician, or be admitted to the hospital. Exacerbations which did not require any of the above therapies were excluded. Variables investigated included age, race, gender, BODE score and components, medical and social history, symptom history, and patients' perception of health status by survey instruments. Three‐way ANOVA was performed on the entire group and then repeated on subgroups by GOLD stage. Data are reported as means and SD or odds ratios and 95% confidence intervals.
Results: Regardless of GOLD stage, frequent exacerbators differed from non‐exacerbators by higher BODE scores (4.17±1.90 vs. 2.11±2.08, p<.0001), female gender (OR 1.99, CI 1.45‐2.73, p<.0001), higher MMRC dyspnea scale (2.94±1.19 vs. 1.59±1.43, p<.0001), higher SGRQ scores (53.01±19.13 vs. 29.55±20.58, p<.0001), history of asthma (OR 3.54, CI 2.53‐4.94, p<.0001), chronic cough (OR 2.40, CI 1.75‐3.29, p<.02), wheezing (OR 6.58, CI 4.05‐10.67, p<.0001), or sputum production (OR 2.37, CI 1.73‐3.26, p<.0001), and the presence of GERD (OR 1.87, CI 1.35‐2.59, p<.0002), CHF (OR 3.14, CI 1.63‐6.03, p<.001), and OSA (OR 1.92 CI 1.29‐2.85, p<.0011.) Frequent exacerbators were more commonly bronchodilator responsive and had higher MMRC and SGRQ scores than infrequent exacerbators. In early stages of COPD (GOLD I‐II), frequent exacerbators had lower 6MW distances (1131±376 vs. 1388±397, p<.0001), a difference which was not present in GOLD III‐IV. In later stages of COPD, frequent exacerbators were younger than non‐exacerbators (62.97±8.84 vs. 65.73±7.67, p<.0001).
Conclusion: Frequent exacerbators are more likely to be females with greater dyspnea, cough, sputum, wheeze, and GERD, CHF, or OSA. Distinct differences exist between those who tend to have exacerbations and those who do not, and these findings may help physicians tailor therapies towards minimizing exacerbations and their deleterious effects.
Cardiovascular Disease is associated with COPD severity and reduced functional capacity
Jennifer Black‐Shinn, Gregory L. Kinney, Anastasia Wise, Elizabeth Regan, Barry Make, Mori J. Krantz,
R. Graham Barr, James Murphy, Edwin Silverman, James Crapo, John E. Hokanson and the COPDGene
Investigators
Rationale: Smoking is a major risk factor for both cardiovascular disease (CVD) and COPD. In some studies more individuals with COPD die from CVD than respiratory causes and the risk of developing CVD appears to be independent of smoking burden. Although CVD is a common comorbid condition in COPD, the nature of this relationship and its influence on functional capacity is not well understood. We therefore examined the relationship between CVD and COPD disease severity and functional capacity in a the COPDGene cohort of smokers including subjects both with and without COPD.
Methods: The first 2,500 members of the COPDGene cohort were evaluated. The presence of CVD was determined from a medical history questionnaire administered by a trained staff member. Subjects were questioned about physician‐diagnosed CVD including; Transient Ischemic Attack, Angioplasty, Heart Attack, Congestive Heart Failure, Coronary Artery Disease, Peripheral Vascular Disease, or Coronary Artery Bypass Surgery.
Results: A total of 359 (14%) of the overall cohort had pre‐existing CVD. Those with CVD were older, more likely to be male, had greater smoking exposure, and were more likely to be hypercholesterolemic, and hypertensive (all p<0.0001). CVD was more common in subjects with COPD than those without COPD (18.4% versus 9.1 % respectively, p<0.0001). CVD was independently related to COPD (Odds Ratio=1.47, 95% CI=1.08‐2.01, p=0.01) after adjusting for demographics (age, sex, race), smoking history, and CVD risk factors (BMI, hypercholesterolemia, and hypertension). There was a statistically significant trend of increasing proportion of those with CVD with increasing GOLD stages: 12.0%; 18.9%, 18.2%, 24.2% (GOLD 1 - 4 respectively, p<0.0001).
Six‐minute walk distance was used as a measure of functional capacity. Those individuals with CVD and not COPD or those with COPD and not CVD had a shorter 6‐minute walk distance compared to those without either condition (1320±418 feet, p<0.05 and 1227±450 feet p<0.0001 versus 1516±397 feet respectively). Individuals with both CVD and COPD had the shortest 6‐minute walk distance (1109±424, p<0.001).
Conclusions: Patients with COPD are more likely to have CVD even after accounting for smoking history and CVD risk factors. The presence of both COPD and CVD is associated with markedly reduced functional capacity. Identification of CVD in those with COPD is an important consideration in determining functional capacity. In addition, CVD is associated with greater respiratory disease burden among patients with COPD.
Emphysema and Gas Trapping on Computed Tomography Are Predictive of Exercise Tolerance in the COPDGene® Cohort
R. Casaburi1, M. Rambod2, J. Porszasz2, R.G. Barr3, F.C. Sciurba4, B.J. Make5, C. Wilson6,
E. Hoffman7, E.A. Regan5, J. Murphy5, J. Crapo5, and the COPDGene Investigators8;
1Torrance, CA/US, 2Torrance/US, 3New York, NY/US, 4Pittsburgh,PA/US, 5Denver, CO/US,
6Denver/US, 7Iowa City/US, 8Various/US
Rationale: Exercise tolerance in COPD is only moderately well predicted by FEV1‐assessed airflow obstruction. We determined whether computerized tomography (CT) measures of emphysema and gas trapping are independent predictors of exercise tolerance in the COPDGene cohort.
Methods: COPDGene recruits non‐Hispanic Caucasian and African‐American current and ex‐smokers with a >10 pack‐year smoking history. Phenotyping measures include post‐bronchodilator FEV1 %predicted, 6‐minute walk distance (6MWD) and inspiratory and expiratory (at functional residual capacity) volumetric CT lung scans. %emphysema is percent of lung voxels below ‐950 Hounsfield Units on the inspiratory scan; %gas trapping is percent of lung voxels below ‐856 HU on the expiratory scan.
Results: Data of the first 2500 participants of the COPDGene cohort were analyzed. Participant age was 61±9 y; 51% were male; 74% were non‐Hispanic Caucasians, median pack‐year smoking history was 40, and body mass index (BMI) was 29±6 Kg/m2. Fifty‐one percent had spirometrically‐defined COPD by GOLD criteria with 8.2%, 21.3%, 13.7% and 7.7%, in GOLD stages I‐IV respectively. The %emphysema and %gas trapping estimates were available for 2480 and 2306 subjects, respectively. 6MWD fell approximately linearly by 11.4 ft for each % increase in emphysema and by 7.3 ft for each % increase in gas trapping (r=0.29 and 0.34 respectively; p<0.0001) (Figure). Multiple linear regression, including interaction terms, demonstrated that both %emphysema and %gas trapping improved the prediction of 6MWD over FEV1 %predicted (r=0.56, p<0.0001 and 0.57, p<0.0001; respectively, vs. r=0.50 for FEV1 %predicted alone). However, including both %emphysema and %gas trapping together did not improve linear model fit compared to gas trapping alone, suggesting that gas trapping was the stronger predictor. Including BMI in the regression revealed an inverse and independent association with 6MWD (p<0.0001).
Conclusions: CT measures of emphysema and gas trapping are predictors of exercise tolerance among current and ex‐smokers. We speculate that these measures predict a greater tendency for dynamic hyperinflation and/or an association with systemic processes (perhaps including peripheral muscle dysfunction) contributing to functional impairment.
A genome‐wide association study identifies FAM13A as a COPD susceptibility locus
Michael H. Cho1,2, Nadia Boutaoui1, Barbara J. Klanderman1, Jody S. Sylvia1, John P. Ziniti1,
Craig P. Hersh1,2, Dawn L. DeMeo1,2, Gary M. Hunninghake1,2, Augusto A. Litonjua1,2,
David Sparrow3, Christoph Lange4, Sungho Won4, James R. Murphy5, Terri H. Beaty6, Elizabeth A.
Regan5, Barry J. Make5, John E. Hokanson7, James D. Crapo5, Xiangyang Kong8, Wayne H.
Anderson9, Ruth Tal‐Singer8, David A. Lomas10, Per Bakke11, Amund Gulsvik11, Sreekumar G.
Pillai9, Edwin K. Silverman1,2 1Channing Laboratory and 2Division of Pulmonary and Critical Care
Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School,
Boston, MA, USA; 3Veterans Administration Boston Healthcare System and Boston University Schools
of Public Health and Medicine, Boston, MA, USA; 4Harvard School of Public Health, Harvard University,
Boston, MA, USA; 5National Jewish Medical and Research Center, Denver, CO, USA; 6Johns Hopkins
School of Public Health, Baltimore, MD, USA; 7Colorado School of Public Health, University of Colorado
Denver, Aurora, CO, USA; GlaxoSmithKline Research and Development, 8King of Prussia, PA, and
9Research Triangle Park, NC, USA; 10Cambridge Institute for Medical Research, University of
Cambridge, Cambridge, UK; 11Haukeland University Hospital and Institute of Medicine, University of
Bergen, Bergen, Norway.
Introduction: While chronic obstructive pulmonary disease (COPD) is manifest primarily among current
and ex‐smokers, there is clear evidence of genetic susceptibility. Genome‐wide association studies are a powerful, unbiased method to discover novel risk loci. Recently, genome‐wide association studies have found associations between COPD and SNPs at the CHRNA3/CHRNA5 locus and near HHIP. We
hypothesized that a larger genome‐wide association study would reveal additional common COPD
susceptibility variants.
Methods: We combined genotyping data from three case‐control studies: 1) the previously reported Bergen, Norway, cohort; 2) the multicenter Evaluation of COPD Longitudinally to Identify PredictiveSurrogate End‐points (ECLIPSE) Study, and 3) cases from the National Emphysema Treatment Trial (NETT) and controls from the Normative Aging Study (NAS). All controls were current or former smokers with normal lung function, and all cases had moderate to very severe disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification). All subjects were genotyped using Illumina arrays, and a uniform set of quality control (QC) measures were applied to raw and processed genotyping data. A casecontrol analysis was performed in PLINK adjusting for age, pack‐years of smoking, and population stratification using principal components estimated using the EIGENSOFT package.
Results: A total of 499,578 markers that passed QC in all three cohorts was tested for association in 2940 cases and 1380 controls. We confirmed previous associations at the CHRNA3/CHRNA5 and HHIP loci; however, the most highly associated finding was with two SNPs in linkage disequilibrium (r2=0.85) in FAM13A (family with sequence similarity 13, member A) on chromosome 4 (rs1903003, p‐value=7.18 x 10‐ 8 and rs7671167, p‐value=8.6 x 10‐8). We replicated this association in an independent set of 498 cases and 500 controls from the COPDGene study (p‐value=0.025 and 0.017, respectively; giving a combined pvalue= 6.1x10‐9 and 4.8x10‐9). FAM13A appears to be involved in hypoxia response, and differences in respiratory epithelial cell expression have been noted during differentiation and in mild versus severe cystic fibrosis.
Conclusions: Variants in FAM13A appear to influence susceptibility to COPD. The specific variants
responsible for and the mechanism underlying this altered susceptibility are yet to be determined.
Early‐onset COPD is associated with maternal smoking and lung disease in the COPDGene Study
D L DeMeo1, L Zhang3, J Murphy3, M Foreman4, N Hansel5, B Make3, E K Silverman1 for the
COPDGene Investigators 1Channing Laboratory and Brigham & Women's Hospital, United States;
2U Michigan Hospital, United States; 3National Jewish Health, United States, 4Morehouse School
of Medicine, United States, and 5Johns Hopkins School of Medicine, United States. Background:
Severe, early‐onset (EO) COPD (before age 53) has been observed to be more prevalent in women.
Identifying factors that predispose to EOCOPD versus severe COPD at later ages may result in
targeted screening for individuals at higher risk for EOCOPD.
Methods: COPDGene is a study focused on identifying genes influencing COPD susceptibility in non‐Hispanic whites and African‐Americans (AA). This report analyzed epidemiologic data from the first 2500 white and AA subjects with complete verified data and with a history of greater than 10 pack‐years of smoking. To identify risk factors for EOCOPD, we focused on two definitions for cases with EOCOPD: 1) Self‐report of COPD diagnosis at age less than 53 and current FEV1 <40 % predicted (124 subjects) or 2) enrollment in COPDGene at age less than 53 and FEV1 <40 % predicted (35 subjects). Controls for each analysis included 208 subjects with "later‐onset" COPD (FEV1 <40% predicted) with both enrollment in COPDGene and self‐report of COPD diagnosis at age greater than 53 years.
Results: There were more women than men using either EOCOPD case definition (self‐report 54 % and enrollment‐age 71 %). In the group that self‐reported EOCOPD, cases had fewer pack‐years of smoking versus controls (50 vs. 61, p=0.0004), with the same amount of CT percent emphysema (26.1% vs. 26.8%, p=0.65) when compared to COPD controls. In this group, EOCOPD was associated with more frequent reporting a family history of a mother with COPD (p=0.0007), a mother with emphysema (p=0.002), a mother who smoked cigarettes (p=0.0006), and a mother who smoked cigarettes while pregnant (p=0.0001). Analysis which included cases with EOCOPD enrolled at age <53 was notable for subjects with fewer pack‐years of smoking (40 vs. 61, p<0.0001) and a lower amount of CT percent emphysema (20.8% vs. 26.8%, p=0.0.02) compared to COPD controls. In this EOCOPD group we also observed more frequent reporting of having a mother who smoked (p=0.009) and a mother who smoked while pregnant (p=0.001). Neither definition of EOCOPD had significant associations for reports of a paternal history of smoking or lung disease (all p>.1).
Conclusions: These preliminary observations from the COPDGene Study support the hypothesis that early‐onset COPD, particularly prevalent in women, may be influenced by maternal factors, including maternal susceptibility to lung disease and maternal smoking exposures. Future genetic studies should include specific attention to X chromosome and mitochondrial DNA interactions with cigarette smoking to address maternal genetic contributions to EOCOPD.
Consistency of Standard Airway Metrics and a Novel Metric, Airway Power, across CT Reconstruction Algorithms and Scanning Platforms
Raúl San José Estépar, James C Ross, Alejandro Díaz, Philip F. Judy, Carl‐Fredrik Westin, Ron Kikinis, Edwin K
Silverman,George R Washko for the COPDGene® investigators.
Department of Radiology, Pulmonary and Critical Care Division, Channing Laboratory, Brigham and
Women's Hospital, Boston, MA
Background: CT‐based quantification of airway disease is challenging due to the limited resolution of current scanning technologies as well as the systematic differences across reconstruction kernels between manufacturers. We have developed a new metric for airway quantification, airway power, that takes into account both airway size and airway composition. When the CT system is modeled as a linear system, airway power has the theoretical property of being accurate when measured from the CT signal using the full width at half maximum method to compute airway wall thickness. This property is based on the energy conservation principle.
Methods: The accuracy of airway power has been evaluated with a computer‐generated airway phantom with different reconstruction kernels (Fig 1A). The COPDGene phantom was used to evaluate the consistency of standard airway metrics, airway wall thickness, airway peak wall intensity, and airway power with respect to multiple scanner brands and reconstruction kernels. Each airway tube in the phantom was used as its own control and the relative difference error was computed between the measurements for each tube. The phantom was scanned with the COPDGene imaging protocol (two reconstructions) on three scanner brands: Philips Brilliance 40, Siemens Definition and GE LightSpeed.
Results: Mean absolute error between true airway power and airway power for different reconstruction kernels and wall thicknesses in a computer model was 0.67±1.2 mg/cm^3 (Fig.1A). The mean absolute relative difference across reconstruction kernels (standard and sharp) for all the combinations (Fig 1C) and for each scanner brand alone (Fig. 1B) was significantly smaller for airway power (1.86%±1.73) than airway wall thickness (11%±6.90) and wall attenuation (18.24%±11.66) (Fig 1C).
Conclusions: Airway wall power is a new metric for airway disease that combines airway size and density characteristics. This new metric is more consistent across scanning reconstruction protocols than standard metrics of airway disease and it has the property of being accurate.
Clinical Predictors of COPD Exacerbations in the COPDGene® Study
M. G. Foreman1, L. Zhang2, J. Murphy2, N. Hanania3, N. Hansel4, R. A. Wise4, G. Westney1, B.
Make2, E. K. Silverman5 for the COPDGene® Investigators. 1Morehouse School of Medicine,
Atlanta, GA;2National Jewish Health, Denver, CO;3Baylor College of Medicine, Houston, TX;4Johns
Hopkins University, Baltimore, MD;5Brigham and Women's Hospital, Boston, MA
Rationale: COPD exacerbations significantly increase medical expenditures, morbidity, and mortality.
We analyzed 2261 subjects with complete data from the first 2500 subjects in the Genetic Epidemiology of COPD: COPDGene® Study for COPD exacerbations.
Methods: Severe exacerbations were defined as self‐reported emergency department visits or hospitalizations for lung problems in the past year. Exacerbation frequency captured the number of exacerbations or changes in therapy in the past year, limited to 6 episodes. Stepwise selection was used to construct logistic regression models that included the following predictors: age, gender, race, age at onset of smoking, pack‐years, current smoking, BODE index, history of asthma or pneumonia, FEV1 % predicted, environmental tobacco exposure, or history of working in a dusty occupation. A proportional odds model was used for exacerbation frequency.
Results: In the 1711 non‐Hispanic white and 550 non‐Hispanic African American (AA) subjects, 13% experienced severe exacerbations. Exacerbation frequency increased as COPD severity increased (p <
0.0001). AA were more likely to report a history of asthma (p = 0.0002), paternal (p = 0.02) and maternal asthma (p = 0.006). White subjects were more likely to report a history of pneumonia (p <
0.001), paternal (p = 0.007) and maternal COPD (p < 0.0001). The models are reported in Tables 1 and 2.
Conclusions: In these preliminary analyses, AA race was associated with a higher odds ratio for exacerbations, exacerbation frequency, history of and family history of asthma. Common predictors of
exacerbations in both racial groups were a low FEV1 percent predicted, higher BODE index, history of
pneumonia, and a history of asthma. These findings suggest that the Dutch hypothesis may be highly
relevant in the pathogenesis of COPD exacerbations, underscoring the importance of research into
common mechanisms between asthma and COPD.
Quantitative computed tomography of emphysema in smokers without airflow obstruction: a novel COPD phenotype?
Adam L. Friedlander1,2, Gregory L. Kinney3, John E. Hokanson3, James Murphy2, David A. Lynch2,
Barry Make2, James Crapo2 and the COPDGene® Investigators
1Divison of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver
2Department of Medicine, National Jewish Health, Denver, CO 3Colorado School of Public Health,
Department of Epidemiology, University of Colorado Denver
Rationale: The current classification of smoking‐related lung disease fails to take into account the heterogeneity of chronic obstruction pulmonary disease (COPD), which remains defined by airflow limitation independent of emphysema or chronic bronchitis. Advances in computed tomography (CT) has allowed for the quantification of emphysema. However, it is not known if this radiographic feature is clinically important. The initial step in answering this question is to determine the significance of emphysema in smokers without COPD.
Methods: The COPDGene® study enrolled non‐Hispanic white and African American subjects with a smoking history of at least 10 pack‐years. Data from the first 2500 subjects, including volumetric CT to measure the percent of emphysema [% of lung attenuation area (LAA) < ‐950 HU], was analyzed. 876 subjects were identified without COPD, and were divided into 4 groups based upon quartiles of %LAA < ‐950 HU using a grouped scanner‐specific ranking, which accounts for differences between models. Nonparametric and chi‐square testing was used to compare characteristics between groups, and multiple logistic regression was utilized to control for the effects of several variables on emphysema severity.
Results: There is a skewed distribution of emphysema among smoking controls, with a mean %LAA < ‐950 HU of 2.81% (range, 0.02% - 24.99%; SD, 3.10%). Comparing the bottom to the top quartile, increasing emphysema is associated with older age (55.6 years vs. 60.7 years, p<0.0001) and lower BMI (29.5 vs. 27.9, p=0.0113). Controls with emphysema are more likely to be white (57% vs. 83%, p<0.001), male (28% vs. 66%, p<0.001) and former smokers (37% vs. 65%, p<0.001). There is no difference in tobacco exposure measured in pack‐years (p=0.29). Emphysema severity is not associated with co‐morbid medical conditions, symptoms or exacerbations. Surprisingly, lower emphysema severity is significantly associated with poorer functional capacity (mean distance on 6‐minute walk test 1412 ft. vs. 1587 ft., p<0.0001) and increased dyspnea (mean MMRC dyspnea index 0.9 vs. 0.6, p=0.0293). These differences are not seen in regression analysis controlling for age, gender, race, smoking status and lung function.
Conclusions: Severity of emphysema in smokers without airflow obstruction is associated with age, race, gender and smoking status, independent of cumulative smoke exposure. Current smokers are less likely to have significant emphysema, suggesting that the development of emphysema may be associated with smoking cessation. However, smokers with significant emphysema do not have more medical problems, symptoms or exacerbations. This suggests that significant emphysema in smokers without airflow limitation simply reflects the natural history of prior tobacco exposure and is not clinically relevant.
Acute Exacerbations of COPD in COPDGene®
MeiLan Han, Doug Everett, Elizabeth Regan, Jim Murphy, Fernando Martinez, Ed Silverman,
Barry Makeand the COPDGene® Investigators
Background: COPDGene® is one of the largest studies to investigate underlying genetic factors in COPD resulting in comprehensive characterization of over 2,000 smokers to date, including detailed information regarding patient reported acute exacerbations of COPD (AECOPD) in the prior year. Using the ATS‐DLD‐78 Respiratory Questionnaire, we report the frequency and severity of exacerbations stratified by age, gender and disease severity.
Methods: 1,281 non‐hispanic white and African American COPD subjects were analyzed from the COPDGene cohort. All subjects included had a smoking history of at least 10 pack‐years and a post‐bronchodilator FEV1/FVC ratio of < 0.7. The total number of AECOPD were determined by the total number of episodes in which the individual had a "flare‐up of chest trouble in the last 12 months" that required either additional antibiotic and/or steroid medication kept at home, an additional antibiotic and/or steroid prescribed by a physician, or led to hospital admission. Severe exacerbations were defined as AECOPD requiring a hospitalization. Negative binomial regression analysis was used to model exacerbation frequency.
Results: 599 women and 682 men were included in the dataset with average age 63.9 and 63.8 respectively. 444 (35%) individuals reported at least 1 exacerbation. 250 (19.5%) individuals reported at least 1 or more severe exacerbations. Significantly more total exacerbations were seen in women (0.86/year) versus men (0.53/year), p<0.0001 (Figure 1). Total exacerbation frequency also increased by GOLD stage, p<0.0001 (Figure 2). Gold I subjects (n=219) experienced an average of 0.16 exacerbations / year, GOLD II (n=533) an average of 0.56 exacerbations / year, GOLD III (n=339) an average of 0.96 exacerbations / year, GOLD IV 1.17 exacerbations / year. No significant relationship between age and total exacerbation frequency was seen, p=0.11.
Conclusions: AECOPD are common and increase in frequency with disease severity. On average, women also report a greater number of exacerbations. By itself, age is not an independent predictor of exacerbation frequency. Future studies of the COPDGene cohort will allow us to better define the relationships between exacerbation frequency and other clinical and radiographic predictors.
Radiographic Predictors of Exacerbation Frequency: A Preliminary Analysis of COPDGene®
MeiLan Han, Victor Kim, George Washko, Gerard Criner, James Murphy, John Hokanson, Eric Hoffman,
David Lynch, Fernando Martinez, Ed Silverman, Barry Make and the COPDGene® Investigators
Background: The clinical importance of acute exacerbations of COPD are increasingly being
recognized. As yet we do not fully understand what factors influence exacerbation frequency.
We hypothesized that radiographic measures from quantitative CT would correlate with
exacerbation frequency.
Methods: 1,281 non‐hispanic white and African American subjects with COPD were analyzed from the COPDGene dataset. All subjects had a smoking history of at least 10 pack‐years and a post‐bronchodilator FEV1/FVC ratio of < 0.7. Emphysema percent was determined using 3D Slicer software from quantified CT; wall area percent (WA%) was measured at the right upper lobe apical segment using VIDA software. Data on exacerbation frequency in the prior year was collected at baseline utilizing a series of questions aimed at identifying an increase in symptoms that was treated with an antibiotic, steroid or both. Negative binomial regression was used to model the data.
Results: 444/1,281 (35%) individuals reported at least 1 exacerbation. The breakdown of exacerbation frequency is illustrated in Figure 1. In a multivariate model, for a given FEV1% predicted, a 10% increase in emphysema is associated with a 0.89 fold decrease in the number of exacerbations (p=0.02). For a given level of emphysema, a 10% increase in FEV1% predicted results in a 0.72 fold decrease in the number of exacerbations (p<0.0001). Female gender was associated with a 1.38 fold increase in the number of exacerbations (p=0.003). WA% was not significant in the full model, but if FEV1% predicted was removed from the model, a 10% increase in WA% was associated with a 1.42 fold increase in number of exacerbations (p=0.01).
Conclusions: Quantitative CT provides unique COPD phenotyping information. Radiographic quantification of emphysema is associated with lower exacerbation frequency when whereas airway thickness is associated with greater exacerbation frequency.
Characteristics of Elderly COPD Patients in the COPDGene® Cohort
NA Hanania1, MG Foreman2 , A Sharafkhaneh1, RA Wise3, L Zhang4, DL DeMeo5, B Make4 for the
COPD Gene Investigators 1Baylor College of Medicine, Houston, TX; 2Morehouse School of Medicine,
Atlanta, GA; 3Johns Hopkins University, Baltimore, MD 4National Jewish Health, Denver, CO; 5Channing
Laboratory, Brigham & Women's Hospital, Boston, MA
Rationale: Although the number of elderly patients with COPD is projected to grow significantly, little is
known about the impact of age on COPD. We analyzed data of subjects in the COPDGene cohort to determine if elderly subjects with COPD had a greater burden of disease than younger subjects. Methods: COPDGene enrolled non‐Hispanic smokers between the ages of 45 and 80 years with and
without COPD. We compared indices of disease severity (lung function, percent of emphysema and gas
trapping, exacerbations), and prevalence of co‐morbidities in elderly COPD (age ≥ 65) compared to
younger COPD subjects and smokers without COPD. Data from 1281 subjects with COPD and 980
smokers without COPD were used for these analyses.
Results: 49.8% of COPD subjects and 23.5% of control subjects were ≥ 65 years of age. Mean percent
predicted FEV1 (SD) in young and elderly COPD subjects were not significantly different (57.2% (23.2)
and 55.4% (23.8), respectively). Elderly COPD subjects had significantly higher percent gas trapping and emphysema on CT scan imaging than young subjects (43.6% vs. 34.4% and 16.2% vs. 11.6%, p<0001, respectively,). In addition, elderly COPD subjects had significantly lower 6 minute walk distance (6MW) and resting oxygen saturation than young COPD patients (p< 0.05). However, young subjects with COPD had more dyspnea (MRC scale), poorer quality of life (SGRQ activity, symptom, impact and total scores), and reported higher incidence of severe exacerbations than elderly COPD subjects even after controlling for disease severity and smoking intensity (for all comparisons, p< 0.001). Elderly COPD subjects had significantly worse quality of life, lower 6MW distance and more dyspnea than elderly smokers without COPD (p < 0.0001). Furthermore, they reported significantly higher physician‐diagnosed co‐morbidities (coronary artery disease, hypertension, osteoporosis, peripheral vascular disease) than younger subjects with COPD and higher physician‐diagnosed CHF than elderly smokers without COPD (p < 0.05).
Conclusions: Elderly subjects with COPD have worse gas trapping, emphysema, exercise tolerance,
resting oxygenation and more co‐morbidities than younger subjects with COPD. However, younger
subjects with COPD experience more symptoms, severe exacerbations and have poorer quality of life.
We speculate that age and disease duration may influence the perception of symptoms and ability to
cope with COPD in the elderly with COPD but this requires further investigation.
Racial differences in emphysema and air trapping in subjects with COPD. Results from the COPDGene Study.
NN Hansel1, MG Foreman2, L Zhang3, G Washko4, E. Hoffman5, R.G. Barr6, E.J.R. Van Beek5, E.
A. Kazerooni7, RA Wise1, J Hokanson3, B Make3 for the COPDGene® Investigators. 1Johns Hopkins
University, Baltimore, MD; 2Morehouse School of Medicine, Atlanta, GA; 3National Jewish Health,
Denver, CO, 4Brigham and Women's Hospital, Boston, MA, 5University of Iowa, Iowa City, IA
6Columbia University, NY, NY, 7University of Michigan, Ann Arbor, MI
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is more common in Caucasian
populations than African Americans, mainly due to historical trends in smoking. However, some studies
suggest that African Americans may be more susceptible to the effects of cigarette smoke. We investigate whether racial differences exist between the amount of emphysema and air trapping, as
measured by quantitative CT scans.
METHODS: The first 1,281 subjects of the COPDGene Study with COPD (Gold Stage 1‐4) and 10 packyears or more of cigarette smoking with verified data including quantitative CT (QCT) scans formed the study group. Total % emphysema (lung voxels below ‐950HU in TLC scan) and total % air trapping (lung voxels below ‐850HU in expiratory scans) were calculated using SLICER software (www.slicer.org). Analysis of Variance (ANOVA) models were used for racial difference analysis. Multi‐variate linear regression models were used where race, age, gender, pack‐years, age at initiation of smoking, BMI, asthma and years of dust exposure were included as potential confounders. Interaction between race and other covariates were also analyzed. Backward selection methods were used to develop the final model.
RESULTS: In bivariate analyses, African Americans (n=233) had lower mean % emphysema (11.1 % vs. 14.5%, p<0.001) and less air trapping (35.7% vs. 39.6%, p=0.01) compared to Caucasians. After adjusting for confounders, there were no significant racial differences in CT measurements. Lower BMI, male gender and no current smoking were associated with higher % emphysema (less inflammation could present as increased emphysema by QCT). In addition, ever working in a dusty environment was more strongly associated with emphysema among Caucasians (interaction p=0.03) as compared to African Americans. Lower BMI, male gender, no current smoking, asthma, age and pack‐years were associated with higher % air trapping.
CONCLUSIONS: African Americans have similar mean % emphysema and air trapping as compared to
Caucasians. These results would suggest that African Americans are not more susceptible to the development of smoking‐induced emphysema.
The Overlap of COPD and Asthma in the COPDGene Study
M. Hardin1, E.K. Silverman1, R.G. Barr2, N.N. Hansel3, J. Schroeder4, B.J. Make5, C.P. Hersh1,
&. the COPDGene Investigators6; 1Boston, MA/US, 2New York, NY/US, 3Baltimore, MD/US,
4Denver/US, 5Denver, CO/US, 6Various/US
Rationale: The Dutch hypothesis proposes a common origin to both asthma and COPD. Individuals with both diagnoses may have features of both diseases and provide clues to shared genetic traits. We hypothesized that these individuals represent a clinically relevant subgroup and experience more respiratory symptoms and healthcare utilization despite less CT evidence of emphysema and decreased smoking history.
Methods: The COPDGene study enrolled non‐Hispanic white and African American subjects with and without COPD. Subjects had a smoking history of at least 10 pack‐years. This analysis was limited to COPD cases with GOLD stage 2 or higher. Asthma was defined as a self‐reported history of physician‐diagnosed asthma before the age of 40. Subjects meeting this definition of asthma and COPD were compared to COPD subjects without an asthma history.
Results: 890 subjects with COPD were identified. 136 (15%) reported a history of asthma. African Americans and those who were younger at enrollment were more likely to report a history of asthma. Subjects with asthma and COPD had significantly fewer pack years of smoking (55 vs. 43, p<0.0001). During the year prior to enrollment, these subjects reported more frequent exacerbations of respiratory disease (1.8 vs. 0.64, p<0.0001) as well as more frequent severe exacerbations requiring either physician visits or hospital stay (0.4 vs. 0.2, p<0.001) and a lower quality of life as measured by St George's Respiratory Questionnaire (45 vs. 39, p=0.0005). Exacerbation frequency and SGRQ remained significant after adjusting for age, sex and race. BODE and MMRC dyspnea score were not significantly different (p=0.1). There was no difference in FEV1 % predicted, exercise capacity, quantitative bronchodilator response, or CT evidence of emphysema or gas‐trapping.
Familial Risk of COPD is Not Due to Childhood Environmental Tobacco Smoke Exposure: the COPDGene Study
C.P. Hersh1, J. Hokanson2, D.A. Lynch3, G.R. Washko1, J. Crapo3, E.K. Silverman1, &. the COPDGene
Investigators4; 1Boston, MA/US, 2Aurora/US, 3Denver, CO/US, 4Various/US
Background: Multiple studies have shown that family history is a risk factor for chronic obstructive pulmonary disease (COPD). This may be due to genetic susceptibility, shared smoking behaviors, or exposure of the child's developing lung to environmental tobacco smoke (ETS).
Methods: We compared 991 COPD cases (GOLD stage 2 or greater) to 936 control smokers with normal spirometry from the COPDGene Study. Family history of COPD and ETS exposure before age 18 were determined by questionnaire. Socioeconomic status (SES) was defined based on educational achievement. The percent of emphysema on inspiratory chest CT scan (% of lung < ‐950 HU) and gas trapping on expiratory CT (% of lung < ‐856 HU) were measured using 3D‐SLICER software.
Results: 37% of subjects reported a family history of COPD, and 82% reported childhood ETS exposure. In univariate analyses, family history (p<0.0001), education level (p<0.0001), and childhood ETS exposure (p=0.04) were each associated with COPD affection status. In a logistic regression model, adjusted for age, sex, race, and pack‐years of smoking, family history (OR 1.69, p<0.0001) and education level (OR 0.48 for some college vs. no college, p<0.0001) remained significant predictors of COPD, but childhood ETS exposure was no longer significant (OR 1.19, p=0.27). In the population, 17.4% of COPD was attributable to family history. Family history of COPD, but not childhood ETS exposure, was significantly associated with both CT emphysema and gas trapping among subjects with COPD.
Conclusions: Family history is a strong risk factor for COPD, but the effect was not explained by childhood ETS exposure. Familial risk of COPD may be due to genetic factors or due to shared smoking behaviors in family members, which also may have a genetic contribution.
CT Metrics of Restriction and Emphysema in Smokers with Preclinical Interstitial Lung Disease
Gary M Hunninghake, George R Washko, Isis Fernandez, Tsuneo Yamashiro, James C Ross, Raúl San José
Estépar, David A Lynch, Frank C Sciurba, John M Brehm, Alejandro Diaz, Edwin K Silverman, Hiroto Hatabu,
and Ivan O Rosas for the COPDGene® Investigators.Pulmonary and Critical Care Division, Department
of Radiology and Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Channing
Laboratory, Boston MA
Background: Smoking has been associated with chest computed tomographic (CT) evidence of preclinical interstitial lung disease (ILD), but the degree to which these radiographic changes are associated with reduced total lung capacity and emphysema is not known.
Methods: We assessed 2414 (96%) of the first 2525 CT scans in smokers from the COPDGene study for the presence of radiographic changes consistent with ILD by a consensus panel. Logistic regression was used for the multivariable association analyses.
Results: Of the 2414 CT scans evaluated 189 (8%) had preclinical ILD, while 877 (36%) were indeterminate. Preclinical ILD was associated with a reduced CT estimated total lung capacity (TLC) in models adjusting for age, gender, race, pack years of smoking, current smoking status, and body mass index (BMI), and COPD status ([‐]0.436 Liters, 95% confidence interval [CI] [‐]0.276 ‐[‐]0.596, P=1x10‐7). A restrictive lung deficit (TLC < 80% of predicted) was present in (n=41 [22%]) of the preclinical ILD subjects and associated with preclinical ILD (odds ratio [OR] 2.4, 95% CI 1.4‐3.9, P=8x10‐4). Additionally, preclinical ILD was associated with a 43% relative reduction in emphysema on CT although the absolute reduction in emphysema was small ([‐]3%, 95% CI [‐]2‐[‐]4%, P=7x10‐6). Subjects with preclinical ILD were 52 % less likely to have COPD (> Gold Stage 2) (OR 0.48, 95% CI 0.33‐0.70, P=1x10‐4).
Conclusions: Smokers with CT radiographic changes consistent with ILD have strong evidence for reduced TLC and less emphysema. The degree to which lung volumes are reduced in smokers with preclinical ILD suggests clinical follow‐up of these subjects may be warranted.
ATS/ERS and GOLD classifications correlated to high resolution CT scan densities in the COPDGene study
RL Jensen, RO Crapo, J Crapo, J Hardie, P Enright, J Hokanson, D Lynch and the COPDGene investigators.
University of Utah, Salt Lake City, Utah and National Jewish Medical Center, Denver Colorado,
University of Bergen, Bergen Norway, University of Tucson, Tucson Arizona.
Introduction: Spirometry and high resolution cat scan (HRCT) total lung densities were obtained using a standard protocol at full inspiration and expiration during the COPDGene study. 2,329 subjects had HRCT, GOLD and ATS/ERS data. Classification of obstruction was done using both the ATS/ERS 2004 "Interpretative Strategies" and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Differences exist between the two classifications and investigated disagreement of GOLD classifications from ATS/ERS.
Methods: First the HRCT percent total lung density that fell below ‐950 HU at full inspiration (defined as % Emphysema) , were independently compared to the "Normal" and "Obstructed" patients from each classification method (ATS/ERS and GOLD). The mean % Emphysema was determined for Normal and each level of obstruction defined in ATS/ERS and separately in the GOLD. ANOVA was performed across the classification groups to analyze differences in % Emphysema. Tabulation tables were created for GOLD ‐1 to 4 and ATS/ERS (0 to 6). Disagreement in classification between ATS/ERS and GOLD were analyzed.
Results: ANOVA post hoc analysis shows significant differences between ATS/ERS Normal and all other ATS/ERS categories. GOLD 0 (Normal) showed no significant difference from GOLD 0 (Normal Variant). Table 1 shows 28% disagreement between ATS/ERS Normal and the GOLD classifications in the same patients. ATS/ERS classifications 2,3 and 4 are only associated with GOLD 2. Mean % Emphysema for ATS/ERS Normal was 2.96% vs. 2.77% for GOLD Normal and for ATS/ERS Very Severe was 26.90 vs. 28.87% for GOLD 4. Mean % Emphysema for GOLD ‐1 (Normal Variant) was lower than for GOLD 0 (1.8 vs. 2.77% respectively).
Conclusions: In 28% of patients with ATS/ERS classification for Normal the GOLD classification using identical spirometry disagree. Mean ATS/ERS %Emphysema changes little between Normal Variant and Moderate. GOLD -1 shows smaller mean % Emphysema than GOLD 0 and ATS/ERS Normal.
The Nicotine Dependence and Radiographic Features in Currently Smoking COPD Subjects from the COPDGene study
D.K. KIM1, C.P. Hersh1, G.R. Washko1, J. Hokanson2, D.A. Lynch3, J. Newell3, J. Murphy3,
J. Crapo3, E.K. Silverman1, &. the COPDGene Investigators4; 1Boston, MA/US, 2Aurora/US,3Denver, CO/US,
4Various/US
Background: Smoking is the most important environmental risk factor for developing COPD. Nicotine dependence is an important determinant of smoking behavior. The relationship between the severity of nicotine addiction and radiographic phenotypes of COPD has not been widely studied.
Materials and Methods: This study recruited COPD cases across the GOLD stages and smoking controls with normal lung function between 45 and 80 years of age. All subjects reported at least 10 pack years of smoking. Clinical variables including Fagerstrom nicotine tolerance (FNT) score were obtained by questionnaire. For CT phenotyping, volumetric CT acquisitions to measure the percent of emphysema (% of lung < ‐ 950 HU) and air trapping on expiratory CT (% of lung < ‐856 HU) were obtained. Only current smokers whose FNT score was available were included in final analysis.
Results: 858 subjects (396 cases with COPD and 462 controls) were included. 461 of the subjects (53.7%) were male. 277 cases (32.3%), 355 cases (41.4%), and 226 cases (26.3%) showed mild, moderate, and severe nicotine dependence, respectively. In the severely nicotine dependent group, mean age was lower and age started smoking was younger than in the mildly addicted group. While mean value of FEV1% was not different among the groups, severely dependent cases showed higher SGRQ scores and reported symptoms of chronic bronchitis more frequently. The percent of emphysema on CT was negatively correlated with the FNT score in control group (Pearson coefficient; ‐0.181, p<.0001) as well as in COPD group (Pearson coefficient; ‐0.233, p<.0001). In multivariate analysis of emphysema severity in COPD cases, lower FNT score, male gender, lower body mass index (BMI), lower FEV1, recruitment in Denver, and measurement with Siemens sensation‐64 CT scanner were independent risk factors. In smoking controls, lower FNT score, male gender, white race, lower FEV1, and measurement with Siemens sensation‐64 CT scanner were risk factors for increasing emphysema severity. In terms of air trapping on CT, lower FNT score, age, male gender, lower BMI and lower FEV1 were independent risk factors in the COPD group, while age, male gender, and lower BMI were predictors for air trapping in the control group.
Conclusion: Surprisingly, nicotine dependence measured with FNT score was a negative predictor for emphysema on CT in COPD patients and in control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution; further investigation of the clinical significance of this finding will be necessary.
The clinical and radiographic determinants affecting resting hypoxemia in the COPDGene Study
D.K. KIM1, G.R. Washko1, D.A. Lynch2, J. Crapo2, E.K. Silverman1, C.P. Hersh1, &. the
COPDGene Investigators3; 1Boston, MA/US, 2Denver, CO/US, 3Various/US
Background: Resting hypoxemia is a major complication of advanced Chronic Obstructive Pulmonary Disease (COPD), and it contributes to dyspnea, poor quality of life and eventually mortality in COPD. The aims of this study are to find clinical and radiographic risk factors affecting resting hypoxemia.
Materials and Methods: COPDGene recruited 2500 smokers between ages of 45 and 80 years with and without COPD across the GOLD stages. Volumetric CT acquisitions to measure the percent of emphysema (% of lung < ‐950 HU) and air trapping on expiratory CT (% of lung < ‐856 HU) were obtained. Lung volumes were also estimated using 3D‐SLICER software. Hypoxemia was defined when the resting oxygen saturation (SpO2) was less than or equal to 88%. In this analysis, only COPD subjects in GOLD Stage II or greater were included.
Results: Eighty‐two out of 987 COPD cases (8.30%) showed resting hypoxemia, with mean SpO2 85.1 ± 2.5%. The mean SpO2 of non‐hypoxemic patients was 95.2±2.4%. In univariate analysis, the patients recruited in Denver comprised most of the hypoxemic group (81.7% vs. 16.8%, p<.0001). Women were overrepresented (59.8% vs. 48.4%, p=0.049) and currently smoking patients were less frequent among the hypoxemic patients including those in Denver. The mean FEV1(% predicted), FVC(% predicted), and FEV1/FVC ratio were significantly lower in hypoxemic patients. The percent of emphysema and air trapping were higher in the hypoxemic group including those in Denver, while functional residual capacity (FRC) value was not significantly different. In logistic regression analysis, age (OR 1.08, p=0.045) female sex (OR 3.68, p=0.001), higher BMI (OR 1.10, p= 0.011), and decreasing FEV1% (OR 1.04, p<.0001) were risk factors for hypoxemia in Denver subjects only, while female gender, higher BMI, and decreasing FEV1% were independent risk factors for hypoxemia in all subjects including those in Denver. In linear regression analysis for resting SpO2 as a quantitative outcome, age, female gender, higher BMI, and lower FEV1% were independent risk factors for decreasing SpO2 in Denver subjects only, while age, white race, higher BMI, and lower FEV1% were independent risk factors for decreasing SpO2 in all subjects including those in Denver.
Conclusion: This study confirmed the effects of altitude and reduced FEV1 on hypoxemia in COPD patients while the severity of radiographic emphysema was not independently associated with the presence of hypoxemia.
Use of supplemental oxygen therapy in the COPDGene Study
D.K. KIM1, G.R. Washko1, D.A. Lynch2, J. Crapo2, E.K. Silverman1, C.P. Hersh1, &. the
COPDGene Investigators3; 1Boston, MA/US, 2Denver, CO/US, 3Various/US
Background: Resting hypoxemia is a major complication of advanced Chronic Obstructive Pulmonary Disease (COPD), and long term oxygen therapy is known to improve survival in hypoxemic COPD patients. The aim of this study is to find clinical and radiographic factors influencing the pattern of oxygen use in COPDGene patients.
Materials and Methods:
Among the first 2500 COPDGene subjects, only COPD subjects in GOLD Stage II or more were included in this analysis. Volumetric chest CT scans were used to measure the percent of emphysema (% of lung < ‐950 HU), air trapping on expiratory CT (% of lung < ‐856 HU), and lung volumes using 3DSLICER software. Resting oxygen saturation (SpO2) was measured and the use of oxygen therapy was determined by questionnaire. Hypoxemia was defined by SpO2 less than or equal to 88%. Adequate treatment with oxygen was defined only when the patients with resting hypoxemia used the oxygen continuously. Both hypoxemic and non‐hypoxemic patients were assessed for the adequacy of oxygen use.
Results: Nine hundred and eighty out of 987 COPD cases had available data for the use of oxygen therapy. Twenty‐one out of 82 hypoxemic patients (25.6%) were not treated adequately with continuous supplemental oxygen. 240 out of 898 non‐hypoxemic patients (26.7%) were using oxygen therapy. In multivariate analysis, enrollment in Denver and higher score of St. George's Respiratory Questionnaire (SGRQ) were independent predictors for adequate use of oxygen in the hypoxemic group. In nonhypoxemic patients, lower SpO2, age, female gender, African American race, enrollment in Denver, higher level of education, higher BMI, lower FEV1pred%, and higher score of SGRQ were associated with the use of oxygen. Radiographic parameters including percent of emphysema and percent of air trapping on chest CT were not predictors of the adequate use of oxygen in hypoxemic and nonhypoxemic groups
Conclusion: We found that a substantial percentage of COPD patients without resting hypoxemia were using long term oxygen therapy. The appropriate use of oxygen therapy was affected by quality of life measured by SGRQ, independent of resting SpO2 and FEV1, in hypoxemic and non‐hypoxemic COPD patients. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup.
Chronic Bronchitic Symptoms are Associated with Worse Symptoms and Greater Exacerbation Frequency in COPD
V. Kim, MD1, M.K. Han, MD2, G.B. Vance, RN1, B.J. Make, MD3, J.D. Newell, MD3, D. Stinson3, G.J.
Criner, MD1 and the COPDGene® Investigators 1Temple University School of Medicine, Philadelphia,
PA; 2University of Michigan School of Medicine, Ann Arbor, MI; 3National Jewish Health, Denver, CO
Background: Chronic cough and sputum production are significant symptoms in COPD, and have been related to an accelerated decline in lung function and increased risk of respiratory infection. However, the clinical and radiographic characteristics of COPD patients with chronic bronchitic symptoms have not been well characterized.
Methods: The COPDGene® study enrolled non‐hispanic white and African American subjects with a smoking history of at least 10 pack‐years. We included subjects with COPD of GOLD 2 disease and higher in our analysis. We divided patients into two groups based on of the presence or absence of chronic bronchitis ‐ chronic cough and phlegm production for 3 months or more per year.
Results: 910 patients were identified out of the first 2500 enrolled. There were 272 subjects with chronic bronchitis (CB+) and 638 subjects without chronic bronchitis (CB‐). Lung function was similar between groups (FEV1 49.1% pred vs 47.8% pred, p=0.31). Patients in the CB+ group were younger (62.4 years vs 64.6 years, p=0.0002), smoked more (58 vs 51 pack years, p=0.0002), were less likely to be African American (15% vs 21%, p=0.03), and tended to be male (56% vs 50% p=0.056) compared to the CB‐ group. The CB+ group had higher SGRQ scores (51.1 vs 35.4, p<0.0001), MMRC scores (2.59 vs 2.09, p<0.0001), BODE scores (3.40 vs 3.02, p=0.0088), and number of exacerbations (1.15 vs 0.62 per patient per year, p<0.0001), and was more likely to report hospitalizations or ER visits for exacerbations (26% vs 20%, p=0.023) compared to the CB‐ group. There was less emphysema in the CB+ group (13.8% vs 15.9%, p=0.022), and a higher TLC (6213mL vs 5874mL, p=0.035) and FRC (4171mL vs 3863mL, p=0.027) compared to the CBgroup.
Conclusions: A history of chronic bronchitic symptoms in COPD is associated with worse symptoms and can identify a higher risk group for exacerbations, hospitalizations, and poor outcome. This group may derive more benefit from targeted therapy to decrease phlegm production.
Severity of Emphysema is Associated with Bronchodilator Reversibility in COPD
V. Kim, MD1, R. Casaburi, MD2, G.B. Vance, RN1, A.L. Friedlander, MD3, C.P. Hersh, MD4, D. Stinson3,
J.D. Newell, MD3, J.P. Gaughan, PhD1, G.J. Criner, MD1, B.J. Make, MD3 and the COPDGene®
Investigators. 1Temple University School of Medicine, Philadelphia, PA; 2Rehabilitation Clinical
Trials Center, Los Angeles Biomedical Research Institute at Harbor‐UCLA Medical Center, Torrance,
CA; 3National Jewish Health, Denver, CO; 4Brigham and Women's Hospital, Boston, MA
Background: COPD has classically been associated with irreversible or poorly reversible airflow obstruction. However, many COPD patients demonstrate bronchodilator reversibility (BDR) on lung function testing. The clinical and radiographic characteristics that differentiate COPD patients with BDR
from those without BDR have not been well described.
Methods: We analyzed patients with GOLD 2 to 4 disease in the COPDGene® study. Percent emphysema and gas trapping were quantified using 3D Slicer (Boston, MA). We divided patients into two groups based on emphysema >20% (Emph) or <20% (No Emph). BDR was assessed in two ways: 1) as the difference in FEV1 pre and post bronchodilator divided by the predicted FEV1 (BDR by PredFEV1), and 2) as a change in FEV1 >12% (BDR by %Change).
Results: There were 627 patients in the No Emph group and 298 in the Emph group. The Emph group had lower BDR by PredFEV1 (2.57% vs 3.90%, p<0.0001), but no difference in BDR by %Change was detected between the two groups. The Emph group also had worse lung function (FEV1 35.1% pred vs 54.8% pred, p<0.0001, FVC 70.2% pred vs 78.9% pred, p<0.0001), greater %gas trapping (63.1% vs 32.4%, p<0.0001), were older (65.6 years vs 63.0 years, p<0.0001), had a lower mean BMI (25.1 kg/m2 vs 29.2 kg/m2, p<0.0001), and were more likely to be Caucasian (87% vs 79%, p=0.0008) compared to the No Emph group. When adjusted for %gas trapping, age, lung function, BMI, and race, emphysema >20% was still a significant negative predictor of BDR by PredFEV1 (regression coefficient ‐0.48, p=0.03). When analyzed as continuous variables, %emphysema and %gas trapping in the entire cohort had weak inverse correlations with BDR by PredFEV1 (r2=0.021, p=<0.001, and r2=0.013, p=0.0007, respectively) and FEV1% had a weak positive correlation with BDR by PredFEV1 (r2=0.057, p<0.0001). None of these variables were related to BDR by %Change. When these three variables were combined, they were all still significant predictors of BDR by PredFEV1 (r2=0.075, p<0.0001).
Conclusions: More severe emphysema is weakly associated with less BDR when related to predicted FEV1 but not conventional measures of BDR. Reversible airflow obstruction in COPD patients, therefore, may be more closely related to airway pathology. Further study is needed to relate clinical and radiographic phenotype to BDR in COPD. In addition, change in FEV1 expressed as a percentage of the predicted FEV1 is another measure of BDR that deserves further attention.
Gender differences in airway dimensions on CT in smokers with COPD
Y.I. KIM1, A.L. Friedlander2, K. Butterfield3, B.J. Make4, G.R. Washko5, R. San Jose Estepar6, N.A.
Hanania7, D.A. Lynch8, J. Schroeder3, J. Newell8, C. Wilson3, E.K. Silverman9, J. Hokanson10, R.P.
Bowler8, &. the COPDGene Investigators11 1National Jewish Health & Chonnam National University
Hospital ‐ Denver, CO/US, 2University of Colorado Denver ‐ Denver, CO/US, 3National Jewish Health ‐
Denver/US, 4Natl Jewish Health ‐ Denver, CO/US, 5Brigham & Womens Hosp Div of Pul and Critical
Care Medicine ‐ Boston, MA/US, 6Brigham & Womens Hospital Department of Radiology ‐ Boston,
MA/US, 7Baylor College of Medicine ‐ Houston, TX/US, 8National Jewish Health ‐ Denver, CO/US,
9Channing Laboratory / Brigham & Women's Hospital ‐ Boston, MA/US, 10Colorado School of Public
Health ‐ Aurora/US, 11The COPDGene Study ‐ Various/US
Background: There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. We used two different programs (3D SLICER and VIDA) to analyze high resolution CT images in two distinct populations of smokers to assess gender differences in airway dimensions.
Methods: Eighty‐five [men/women, n=46/39] smokers that had spirometry and high resolution CT (HRCT) scans were recruited from an outpatient pulmonary clinic in National Jewish Health (NJH). 3D SLICER [http://www.slicer.org] was used to analyze HRCT scans to determine regional airway thickness and percentage of wall area (WA%; defined as [total area (Ao)‐luminal area (Ai)]/total area x 100) using the phase congruency method from 5 sites: trachea; right upper apical segmental and subsegmental bronchi (RB1 4th and 5th generation); right posterior basal segmental and subsegmental bronchi (respectively RB10 4th and 5th generation). Univariate and multivariate analysis was performed to determine predictors of WA% adjusted for age, sex, BMI, smoking status and FEV1% predicted. To validate these findings, we used HRCT analysis using VIDA from 897 subjects [men/women, n=443/454] of COPDGene cohort of smokers.
Results: Using 3D Slicer, women had greater WA% in all measured airways than men in NJH cohort (men vs women in trachea: 36.8% vs 40.3%, p < 0.001; RB1 4th, 58.3% vs 61.8%, p = 0.024; RB1 5th, 65.2% vs 70.0%, p = 0.001; RB10 4th, 55.9% vs 60.2%, p = 0.002; RB10 5th, 60.7% vs 64.2%, p = 0.042). In COPDGene subjects, women had thicker WA% in trachea, 5th and 6th generation bronchi than men. The internal radii, directly measured wall thickness, and square root of a hypothetical airway of internal perimeter of 10 mm (SQRTWA@pi10) of women's airways were smaller in both cohorts. In multivariate regression analysis, gender was a significant predictor of WA% especially in trachea, 5th and 6th generation bronchi.
Conclusions: Using two different measurement techniques in two independent populations, we found that women smokers had relatively thicker airways than men in trachea and segmental bronchi when using WA% as a measure of wall thickness. The larger WA% in women likely reflects smaller diameters in matched airways in women, since the directly measured wall thickness and the SQRTWA@pi10 were both smaller in women. The higher WA% and smaller airway lumen in matched airways in women may in part explain gender differences in the presentation of COPD.
History of Cardiovascular Disease is Associated with Serious COPD Exacerbations
Gregory L Kinney, Jennifer Black‐Shinn, Adam L Friedlander, Barry Make, Elizabeth Regan, R. Graham Barr,
James Murphy, Edward Silverman, James Crapo, John E. Hokanson, for the COPDGene Investigators
RATIONALE: Cardiovascular disease (CVD) is among the most important comorbid conditions of
chronic obstructive pulmonary disease (COPD) and is a leading cause of death among COPD
patients. Whether this relationship is due to a biological link or shared risk factors is unclear.
Exacerbations associated with COPD may necessitate treatment or hospitalization. This study
explores the association of CVD and acute exacerbations of COPD (AECOPD) requiring
hospitalization.
METHODS: The COPDGene® has recruited 2500 smokers between ages 45 and 80 years with and without COPD. 1,170 individuals with COPD (GOLD stage 1 through 4) were assessed at the time of enrollment for CVD (Transient Ischemic Attack, Angioplasty, Heart Attack, Congestive Heart Failure, Coronary Artery Disease, Peripheral Vascular Disease, or Coronary Artery Bypass Surgery) and exacerbations in the previous 12 months. Questionnaires were administered by an interviewer, history of CVD events were recorded as yes/no and the severity of up to 6 AECOPD episodes was assessed on a scale ranging from "required no special treatment" to "admitted to hospital." Exacerbations resulting in hospital admission were classified by summing each instance of hospitalization to a maximum of 6. Post‐bronchodilator spirometry was performed using a standard protocol to assess FVC, FEV1 and FEV1/FVC. Ordinal logistical regression (OLR) was performed using SAS 9.2 to determine the association between CVD and AECOPD requiring hospitalization.
RESULTS: Of, 1,170 participants with COPD, 134 (11%) had at least one AECOPD requiring hospitalization during the previous year. These participants were more likely to have a history of CVD events (28% vs 17%, p=0.002), be female (56% vs 47%, p=0.05), be younger (62.8 vs 64.5, p=0.03), report no current smoking (18% vs 37%, p <0.0001), and have lower FEV1% predicted (40.0 vs 57.7, p<.0001). There was no difference in pack‐years of smoking. AECOPD requiring hospitalization were negatively associated with FEV1% predicted (<0.0001), no current smoking (p<0.0001), and age (p=0.02), but not with gender or pack‐years. OLR showed that a history of CVD was associated with an increased odds of AECOPD requiring hospitalization (OR 2.1, 95% C.I. 1.4‐3.3, p=0.001) for each increasing number of hospitalizations controlling for age (p<0.0001 for younger age), sex (p=0.07), FEV1% predicted (p<0.0001), no current smoking (p<0.0001) and pack‐years (p=0.46).
CONCLUSION: A history of CVD was associated with an increased number of AECOPD requiring hospitalization in the last year in COPD patients. Though CVD events and AECOPD requiring hospitalizations commonly overlap, clinical prevention and optimization of treatment of CVD in patients with COPD may be important in limiting hospitalizations due to exacerbations.
Disparities in COPD Diagnosis and Treatment are Determined by Region, Race, Gender and Education.
A.J. Mamary1, J.P. Gaughan1, J. Murphy2, G.B. Vance3, G.J. Criner4, &. the COPDGene Investigators5
1Temple University ‐ Philadelphia, PA/US, 2National Jewish Hospital ‐ Denver, CO/US, 3Temple University
Hospital ‐ Philadelphia, PA/US, 4Temple University School of Medicine ‐ Philadelphia, PA/US, 5The
COPDGene Study ‐ Various/US
Rationale: COPDGene provides a rich dataset of patients with varied severity of illness, geographic residence, race, gender and socioeconomic class and provides insight into the current state of medical care for COPD patients.
Hypothesis: To determine the influence of geographic region of residence, race, gender and education level according to disease severity on optimized COPD medical treatment as defined by GOLD guidelines.
Methods: COPDGene is an ongoing, nationwide, 18‐center, prospective study of current and former smokers. Data from the first 2,500 subjects were analyzed. Subjects were white(non‐hispanic) and black ≥45 years of age with at least 10 pack years of cigarette smoking. Characterization included spirometry, demographics, point of enrollment and self‐reported COPD diagnosis and treatment. We evaluated geographic region of residence (enrolling center), race, gender, education level and the patterns of COPD treatment and diagnosis adjusted for severity of airflow obstruction (GOLD stage). COPDGene Data were analyzed by multiple logistic regression using JMP® software.
Results: N=2,500 (F=1,204,B=660, BF=303) age (years±SD) 61±9.3, Gold Stages ‐1(restricted) n=174; 0 n=950;1 n=193; 2 n=486; 3 n=320; 4 n=174; no spirometry n=181. Appropriate diagnosis of COPD and frequency of prescription of all classes of medical therapies varied significatly between the 18 centers of enrollment when adjusted for GOLD stage(p≤0.05). Subjects characterized by COPDGene with GOLD stage 3 or 4 COPD were previously prescribed tiotropium 62%, ICS+LABA 60%, ICS 33% and LABA 20%. Subjects diagnosed with GOLD stage 2 COPD were previously prescribed tiotropium 72%, ICS+LABA 80%, ICS 18%, LABA 12%.
Summary: Prior to study enrollment, female subjects were more often diagnosed with COPD, prescribed ICSs, combination ICS+LABA, nebulizer machines, oxygen, SABAs, tiotropium and were less often active smokers than similarly obstucted men. Black subjects were less often diagnosed with COPD or emphysema, less frequently prescribed tiotropium, more often oral steroids and more likely to be active smokers than similarly obstructed white subjects.
Conclusion: Region of residence, race, gender and education level are associated with disparities in COPD diagnosis and treatment. Inhaled corticosteroids, LABAs, and tiotropium are under prescribed in moderate and severe COPD.
Subjects in the COPDGene® study exposed to gas, smoke, chemical vapors, and fumes at work have worse lung function, a greater amount of emphysema on CT imaging, and more exacerbations.
N. Marchetti1, J.P. Gaughan2, G.B. Vance1, B.J. Make3, and G.J.Criner1 Pulmonary and Critical Care
Medicine Temple University School of Medicine1, Biostatistics department Temple University School
of Medicine2, Pulmonary and Critical Care Medicine National Jewish Health3
Rationale: The main risk factor for developing COPD is smoking but occupational exposure (OE) to gas, smoke, chemical vapors, and fumes contributes to this risk. Although COPD related to OE and smoking maybe more severe and have a different clinical course, no study has addressed whether OE will alter the radiographic phenotype of COPD or whether these individuals are at increased risk for exacerbations.
Methods: COPDGene® is an ongoing multicenter prospective study of current and former smokers that undergo genetic analysis as well as clinical and radiographic phenotype assessment. Subjects for this analysis were chosen from the COPDGene® study if they answered yes or no to the following question: "Have you ever been exposed to gas, smoke, chemical vapors or fumes at your work?" Those who did not answer or were uncertain were excluded. Percent emphysema was defined as %lung <‐ 950HU at full inspiration, and percent gas trapping was defined by % lung <‐856HU at
full expiration on CT imaging. CT analysis was done using 3D slicer software. Spirometry, 6 minute walk distance (6MWD), exacerbation frequency, MMRC dyspnea scale, SGRQ quality of life index, and BODE were compared between groups. All data is presented as mean ± SD. Analysis of covariance was used to control for pack years of smoking when comparing the two groups.
Results: Of 2500 subjects enrolled in COPDGene® with available data 1,175 had OE while 1,137 did not. The FEV1/FVC ratio and FEV1 %predicted were significantly lower in the group with OE (66±16% vs 62±18%; p<0.001 and 77±26% vs 72±28%; p=0.002). There was no difference in 6MWD or resting SpO2 between the groups. Subjects with OE had more emphysema present and % gas trapping on HRCT imaging (7.6±10.7% vs 9.3±11.4%, p=0.047 and 24.0±20.6% vs 27.6±21.7%, p=0.007). Exacerbation frequency was greater in the OE group (0.34±0.92 #/year vs 0.56±1.2 #/year, p<0.001). Subjects with OE had significantly greater MMRC dyspnea scores and worse quality of life by SGRQ (1.2±1.4 vs 1.6±1.5, p<0.001 and 23.4±21 vs 30.7±23.7, p<0.001).
Conclusions: Subjects with OE to gas, smoke, chemical vapors, and fumes have more airflow obstruction, more symptoms, worse quality of life, and more exacerbations. Additionally they have more emphysema and gas trapping on HRCT than those without OE.
COPD patients on oral steroids may share phenotypic characteristics with asthma and have more severe disease
I. Permut1, A. Satti1, V. Kim2, B.J. Make3, J. Newell4, R.M. Steiner5, C. Wilson6, J. Murphy7, G.J.
Criner8, &. the COPDGene Investigators9 1Temple University ‐ Philadelphia, PA/US, 2Temple
University Hospital ‐ Philadelphia, PA/US, 3Natl Jewish Health ‐ Denver, CO/US, 4National Jewish
Health ‐ Denver, CO/US, 5Temple University ‐ Philadelphia/US, 6National Jewish Health ‐ Denver/US,
7National Jewish Hospital ‐ Denver, CO/US, 8Temple University School of Medicine ‐ Philadelphia,
PA/US, 9COPDGene ‐ Various/US
Background: Chronic oral steroids are not recommended in COPD but are sometimes used to manage select patients with refractory symptoms.
Hypothesis: We speculated that COPD patients taking chronic oral steroids may have a different clinical phenotype with more severe airflow obstruction, exhibit bronchodilator responsiveness on spirometric testing, have frequent and severe AECOPDs and have a lesser degree of emphysema and thereby more severe airways disease on CT scan characterization.
Methods: 1479 non‐hispanic White and African American subjects were analyzed from the COPDGene dataset. Subjects were characterized by oral corticosteroid use, clinical data (diagnosis of asthma, pack years, family history of asthma, history of acute exacerbations), spirometry data pre and post bronchodilator (FEV1/FVC ratio, FEV1 % predicted, GOLD stage, bronchodilator responsiveness), and radiographic data (%emphysema).
Results: The cohort on chronic oral steroids (5.4%) were on more inhaled medications than those not on steroids (short and long acting beta agonists, inhaled corticosteroids, nebulized medications, tiotroprium, and theophylline (p=0.03)). Dyspnea scores were greater for the chronic oral steroid group on both the MMRC and SGRQ questionnaires (p<0.0001). O2 use was greater for the chronic oral steroid group during rest and 6MWT (p<0.0001). The oral steroid group had higher BODE scores and GOLD stages, and lower FEV1, 6MWT distance (p<0.0001). The oral steroid cohort was more likely to carry a prior diagnosis of asthma (p=0.04) and trended to more bronchoreversibility (p=0.06). Additionally, the oral steroid group experienced more frequent and severe exacerbations and hospitalizations (p<0.0001).
Conclusions: COPD patients that require chronic oral corticosteroids have a different clinical, physiological and radiological phenotype than those who do not with a more frequent history of prior asthma and a trend towards increased bronchoreversibility. This group also represents a sicker cohort of patients with more severe COPD, more frequent exacerbations, increased oxygen use, and increased dyspnea.
Osteoporosis predicts function in COPD
E.A. Regan1, J. Hokanson2, B.J. Make3, J. Murphy4, R. Casaburi5, J. Bon6, E.K. Silverman7,
M. Foreman8, M.T. Dransfield9, R.P. Bowler1, G. McLennan10, J.W. Ramsdell11, J. Crapo4
1National Jewish Health ‐ Denver, CO/US, 2Unversity of Colorado Denver ‐ Denver/US, 3Natl Jewish
Health ‐ Denver, CO/US, 4National Jewish Hospital ‐ Denver, CO/US, 5Los Angeles Biomedical Rsch
Inst Harbor UCLA BRI ‐ Torrance, CA/US, 6University of Pittsburgh ‐ Pittsburgh/US, 7Channing
Laboratory / Brigham & Women's Hospital ‐ Boston, MA/US, 8Morehouse School of Medicine ‐
Atlanta/US, 9University of Alabama Birmingham & Birmingham VA Med Ctr 422 THT ‐ Birmingham,
AL/US, 10University of Iowa ‐ Iowa City/US, 11University of California San Diego ‐ San Diego/US
Background: Low bone mineral density (BMD) or osteoporosis is a common systemic manifestation of COPD that increases the risk of insufficiency fractures. We probed the COPDGene cohort, consisting of current and ex‐smokers with and without spirometric evidence of COPD, to investigate the characteristic of subjects with physician diagnosed osteoporosis or previous insufficiency fractures.
Methods: 2500 participants in COPDGene who had complete data were analyzed. Bone density measurements are not part of the data collection in COPDGene but we constructed a dichotomous variable for osteoporosis that reflected a "yes" response to any one of the following questions: 1. physician‐diagnosis of osteoporosis, 2. vertebral fracture or 3. hip fracture. Subjects with and without osteoporosis were compared for functional measures (Six minute walk distance, MMRC Dyspnea score, BODE index); and quality of life measures ‐ St George Respiratory Questionnaire ‐SGRQ, and SF‐1 ("In general how would you describe your health?" ‐ Excellent, Very Good, Good, Fair, Poor)
Results: 274 (10.9%) participants reported osteoporosis by physician diagnosis, 122 had known vertebral fractures and 50 had previous hip fractures. 15.3% in the cohort overall had osteoporosis and it increased in higher GOLD stages to 25% in GOLD 4. Using logistic regression we found that age, race, gender, BMI, history of rheumatoid and osteoarthritis and COPD case‐control status were all significant predictors of osteoporosis in the cohort. Steroid use and pack years of smoking were not significant in the model. To assess the relationship between osteoporosis and the functional measures of: 6 minute walk distance, MMRC dyspnea score, BODE index, and the quality of life measures of SGRQ and SF‐1, we used multiple regression models to adjust for the covariates ‐ age, gender, race, BMI, % predicted FEV1, pack years, use of oral and inhaled steroids, and occurrence of exacerbations. Osteoporosis remained a significant predictor after adjustment for the covariates in all of the outcomes except the BODE index.
Discussion: Osteoporosis and its consequences appear to negatively impact patients with COPD, and is associated with greater dyspnea, higher BODE index, reduced walking tolerance and lower health related quality of life as measured by SGRQ and SF1. Our ascertainment of osteoporosis by patient report is likely less sensitive than measuring bone density. Despite this limitation, we find that smokers with osteoporosis have more impairment than those without. Identifying and treating osteoporosis in patients with COPD may improve quality of life and reduce disease symptoms.
COPDGene Phantom: Quality Control of Quantitative Lung Imaging in a Multi‐center Trial.
Jered Sieren, Keith Gunderson, David Lynch, John Newell, Philip Judy and Eric A. Hoffman
Purpose: In order to standardize quantitative lung CT for the COPDGene Study, a custom designed, commercially available (Phantom Labs, Greenwich, NY) phantom has been developed to evaluate differences among CT manufacturers and models in lung related image metrics including CT attenuation and spatial (airway) resolution. We report here the attenuation findings.
Methods: The COPDGene Phantom (CTP657) consists of an outer water equivalent ring. The center structure consists of a simulated lung parenchyma density (approximately ‐859HU) which contains a variety of internal holes with and without associated walls of lung‐related dimensions. Other structures inside the phantom consist of water (HU 0) and acrylic. All twenty of the COPDGene sites were provided with a phantom for monthly testing of their individual site scanners. All phantoms were first scanned on a single benchmark scanner (Siemens Sensation 64). Data were sent to the University of Iowa for analysis via custom built software that automatically segmented and measured the phantom components.
Results: The range of the phantom density values all assessed by the Siemens 64 was 0, 2 and 5HU for air, water and lung respectively. Results included data for 10 different models of scanners, and revealed inconsistencies in scanner performances. Across scanner types, air attenuation ranged from (‐1013HU to ‐993HU), water attenuation ranged from (‐12HU to 5HU), lung equivalent attenuation ranged from (‐861 to ‐848), and high contrast attenuation ranged from (108HU to 132HU). In general, CT scanners of a given manufacturer and model performed consistently at different sites. Across 3 months, scanner measures remained consistent with their baseline.
Conclusion: Quantitative CT used to assess lung density as an index of emphysema must account for differences in manufacturer and model differences to accurately measure attenuation. Further analysis will be necessary to determine whether the COPDGene phantom accurately accounts for all of the variability across scanners, including issues such as the handling of beam hardening and scatter by the various reconstruction algorithms.