Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Running Head: Comorbidities Impact on Outcomes, African Americans

Funding support: NP is a postdoctoral research fellow supported by the institutional training grant at Johns Hopkins University, funded by the National Heart, Lung and Blood Institute(NHLBI) [T32HL007534]. The COPDGene® Study is funded by 2R01HL089897 (PI: James Crapo, MD) and 2R01HL089856 (PI: Edwin Silverman, MD). This work is also supported by the COPD Foundation, AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, Pfizer, Siemens and Sunovion Inc are ongoing supporters of the project through the COPDGene® Industry Advisory Board.

Date of acceptance: March 13, 2014.

Abbreviations: COPDGenetic Epidemiology study, COPD Gene®; African Americans, AA; non-Hispanic whites, NHWs; congestive heart failure, CHF; chronic kidney disease, CKD; obstructive sleep apnea, OSA; gastroesophageal reflux disease, GERD; coronary heart disease, CHD; Global Initiative for chronic Obstructive Lung Disease, GOLD; body mass index, BMI; 6-minute walk distance, 6MWD; St. George’s Respiratory Questionaire, SGRQ; modified Medical Research Council dyspnea questionnaire, MMRC; forced expiratory volume in 1 second, FEV1;odds ratio, OR; confidence level, CL; peripheral vascular disease, PVD; Evaluation of COPD Longitudinally to Indentify Predictive Surrogate Endpoints, ECLIPSE

Citation: Putcha N, Han MK, Martinez CH, et al. Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans. J COPD F. 2014; 1(1): 105-114. doi: http://doi.org/10.15326/jcopdf.1.1.2014.0112

Online Supplemental Material: Read Online Supplemental Material (74KB)

The prevalence of comorbidities is higher in COPD patients than the general population.1-8 Comorbidities, including congestive heart failure (CHF), chronic kidney disease (CKD), diabetes, and obstructive sleep apnea (OSA) have been linked to mortality in COPD.8-16 Specific comorbidities including gastroesophageal reflux disease (GERD),17 CHF, 10 diabetes,8,18 obesity,19,20 asthma21,22 and coronary heart disease (CHD)23,24 have also been associated with worse quality of life, exercise capacity, exacerbation risk and dyspnea. However, these findings have been shown for individual comorbidities, without regard to multimorbidity of the COPD population.

African-Americans (AAs) with COPD have an increased risk of mortality,25 and experience worse quality of life than non-Hispanic whites (NHWs).26 In general cohorts, AAs have also been shown to have increased prevalence 27 of and mortality27-35 from chronic conditions, such as cardiovascular disease, CKD, diabetes and stroke. However, it is unknown whether there are racial disparities in the impact of comorbidities on clinical outcomes in COPD.

There were 3 important hypotheses for this paper. First, we hypothesized that individuals with COPD would have higher risk for developing comorbidities compared to smokers without COPD after accounting for important confounding factors. Second, we hypothesized that comorbidities would play an important role in determining clinical outcomes in COPD, even after controlling for confounding variables and other comorbid conditions given that multiple comorbidities co-exist in individuals with COPD. Finally, we hypothesized there are racial differences between AAs and NHWs on the impact of comorbidities in COPD outcomes. To test these hypotheses, we conducted a comprehensive assessment of comorbidity in the Genetic Epidemiology of COPD (COPDGene®) study. Because it is a well-characterized population including a large number of AAs, the COPDGene® study provides an ideal opportunity to understand how comorbidities contribute to the clinical heterogeneity of COPD which has become increasingly recognized in recent COPD clinical research.

Methods

COPDGene® Study Design

The COPDGene® is an observational study in 21 American centers. The design and goals of this study have been previously described.36 The study recruited 10,192 current and former smokers (January 2008 through April 2011) with and without COPD to provide adequate power to detect genetic differences in the group. To be included, individuals had to be either NHW or AA between ages 45-80 years old with a minimum 10 pack-year smoking history. We analyzed cases of individuals falling within the Global Initiative for chronic Obstructive Lung Disease(GOLD) guidelines’ severity of airflow limitations levels 2-4 37(n=3690) and current or former smokers without COPD having normal spirometry (controls) (n=4388). The study was approved by institutional review boards at each center (e-Table 1in the online supplementary material) and all participants provided informed consent.

Comorbidity Assessment

Comorbidities were ascertained by self-report of physician diagnosis, except obesity which was based on each individual’s body mass index (BMI) (e-Table 2 in online supplementary material). We included comorbid chronic diseases and also risk factors for diseases, such as high cholesterol, obesity and hypertension.

Clinical Outcomes

Exercise capacity was measured using 6-minute walk distance (6MWD), expressed in feet using a standardized protocol.38 Quality of life was assessed using the St. George’s Respiratory Questionnaire (SGRQ)39 which measures disease impact specific to respiratory disease with higher numbers (range 0-100) representing worse quality of life (more impairment). Dyspnea was measured using the modified Medical Research Council (MMRC) dsypnea questionnaire scale40 with higher numbers (range 0-4) indicating worse dyspnea. All outcomes were assessed as part of the main COPDGene® study.

Statistical Analysis

All analyses were performed using Stata 12 statistical software.41 Using a test of proportions, we compared prevalence of comorbidities in cases vs. controls as well as between AAs and NHWs COPD cases. To determine differences in comorbidity prevalence between cases and controls, logistic regression models were fit with comorbidities as outcomes, case status as exposure of interest, and adjusted for age, gender, race, education level (less than high school, high school and some college, college or more) and pack-years of smoking history. An interaction term between race and COPD status was added to the logistic regression models to determine if race modified the impact of COPD status on the risk for specific comorbidities.

Among those within the GOLD 2-4 COPD levels, we assessed whether comorbidities were associated with clinical outcomes (6MWD, SGRQ, and MMRC). We performed adjusted multivariable regression models (linear or logistic regression models based upon the outcome of interest) including all covariates (age, gender, race, absolute post-bronchodilator forced expiratory volume in 1 second (FEV1), pack-years of smoking, education level and current smoking status) and all comorbidities simultaneously to assess which conditions are independently associated with the outcomes. We added interaction terms between comorbidities and race (both separately included in models as well) to determine if the impact of comorbidities upon patient-reported outcomes was modified by race. We also calculated variance inflation factors for the linear regression models in order to determine if significant collinearity existed between the individual comorbidities in the multivariable models.

Results

Comorbidity Prevalence in Cases and Controls

JCOPDF-2014-0112-Table1 Baseline demographics and clinical characteristics of the cohort in COPD cases (N=3,690) and controls (N=4,388) are displayed in Table 1 and have been previously described.42,43 COPD cases had worse lung function and more cumulative smoking history (but fewer current smokers) compared to controls. Most comorbidities were more prevalent in those with COPD, with the exception of obesity, which was less prevalent in COPD, and hay fever which was not statistically different between groups (e-Table 3 in the online supplementary material). COPD cases had a higher comorbidity burden compared to controls (3.3 conditions in cases vs. 2.4 in controls, p<0.001). JCOPDF-2014-0112-Figure1 After adjustment for confounders, risk for most comorbidities continued to be higher in COPD cases compared to controls (Figure 1). The highest risks were for CHF (odds ratio [OR] 3.36, 95% confidence level [CI] 2.37-4.49) and osteoporosis (OR 1.66, 95% CI 1.43-1.94). Individuals with COPD had a lower risk for high cholesterol (OR 0.84, 95% CI 0.75-0.93) and obesity (OR 0.87, 95% CI 0.79-0.97).

JCOPDF-2014-0112-Table2 Among participants with COPD, diabetes (17% vs. 12% prevalence in AA vs. NHW, p<0.001) and hypertension (56% vs. 49%, p<0.001) were more common in AAs (Table 2). However, after adjusting for confounders, there were no significant statistical interactions between race and case status in risk for individual comorbidities.

Impact of Comorbidities on Clinical Outcomes

6MWD

After adjusting for all other comorbidities in addition to potential confounders (Figure 2a), CHF (99.6 fewer feet walked, 95% CI -150.5,-48.7), obesity (91.1 fewer feet walked, 95% CI -115.7, -66.4) and OSA (73.8 fewer feet walked, 95% CI -104.2, -43.3) had the strongest independent associations with exercise capacity. Peripheral vascular disease (PVD), CHD, diabetes, osteoporosis and osteoarthritis were also significantly associated with shorter distance walked in 6 minutes. Addition of height to the above models did not appreciably change our results. For models including all comorbidities simultaneously, checking the variance inflation factors indicated that collinearity was not a significant issue.

SGRQ

After adjusting for all comorbidities simultaneously, 9 conditions were independently associated with higher SGRQ (Figure 2b), most remarkably OSA (higher SGRQ score by 6.6 points; 95% CI 4.9-8.3), stroke (4.7; 95% CI 2.2-7.2) and GERD (4.1; 95%CI 2.8-5.5).

Dyspnea

After controlling for all comorbidities, (Figure 2c) 8 conditions including OSA (OR for worse dyspnea 1.62, 95% CI 1.38-1.92), CHF (OR 1.42; 95% CI 1.08-1.88), and stroke (OR 1.45; 95% CI 1.12-1.88) were independently associated with worse dyspnea.

JCOPDF-2014-0112-Figure2a JCOPDF-2014-0112-Figure2b JCOPDF-2014-0112-Figure2c

Racial Differences in Impact of Comorbidities on Clinical Outcomes in COPD

Despite having younger age, less smoking history, better lung function and fewer comorbidities, AAs had worse dyspnea, exercise capacity and health status in unadjusted calculations (Table 3).

JCOPDF-2014-0112-Table3 JCOPDF-2014-0112-Table4

There were racial disparities in the impact of comorbidities on outcomes (Table 4). Osteoarthritis and GERD had a greater impact on AAs than NHWs. The presence of GERD was associated with 109.1 (95% CI-170.4, -47.9) fewer feet walked in six minutes, 9.1 (95% CI 5.5, 12.7) points higher on the SGRQ scale, and OR 1.93 (95% CI 1.40, 2.66) for worse dyspnea score in AAs compared to 38.5 (95% CI -65.1, -12.0) fewer feet walked, 5.8 (95% CI 4.4, 7.2) points higher on the SGRQ and OR 1.49 (95% CI 1.29, 1.72) for worse dyspnea in NHWs. Osteoarthritis was associated with 132.6 (95% CI -202.8, -62.3) fewer feet walked in 6 minutes, 6.7 (95%CI 2.5, 10.8) points higher on the SGRQ scale and OR 2.05 (95% CI 1.43, 2.96) for worse dyspnea score in AAs compared to 64.2 (95% CI -94.2, -34.2) fewer feet walked, 4.5 (95% CI 2.9, 6.1) points higher on the SGRQ and OR 1.37 (95% CI 1.16, 1.61) for worse dyspnea in NHWs. Only obesity was less detrimental in AAs compared to NHWs in its contribution to decreased exercise capacity. The cardiovascular risk factors of hypertension and high cholesterol also had worse effects on quality of life and dyspnea among AAs as compared to NHWs. Sensitivity analyses were performed including use of inhaled corticosteroids in all of the above models, with minimal change in our results (data not shown).

Discussion

Using the large multi-center COPDGene® study, we confirmed that most comorbidities are significantly more prevalent among individuals with COPD than in controls. Further, among individuals with COPD, most comorbidities were independently and strongly associated with lower exercise capacity, worse respiratory-specific quality of life and dyspnea. Importantly, several common comorbidities, particularly GERD and osteoarthritis, had a greater impact on clinical outcomes in AAs with COPD than in NHWs.

Our results support those of previous studies showing an increased comorbidity burden among individuals with COPD compared to general populations.2-4,8,44 Though in some cases these studies did control for confounding,3,4,44 there has not yet been a comprehensive accounting of comorbidity risk in individuals with COPD while also accounting for confounders. A recently published study displayed not only a higher prevalence of comorbidity in patients with COPD to compared smoking controls, it also demonstrated that the risk for comorbidity is higher in smokers with and without COPD compared to nonsmoking controls.45 One study described clusters of comorbidities in individuals with COPD to define clinical subgroups with regards to inflammation and outcomes.46 Our approach differs in that we attempt to understand the contribution of each comorbidity within the framework of coexisting conditions. Specifically, we found that risk for cardiovascular conditions is substantially increased in individuals with COPD compared to controls after adjustment for smoking. These findings challenge us to understand the mechanism for this increased risk, particularly for cardiovascular conditions, among individuals with COPD. Some have hypothesized that systemic inflammation leading to or resulting from COPD puts the individual at heightened risk for cardiovascular disease.47 The finding that a subgroup with COPD and higher levels of inflammatory biomarkers have a higher risk for heart disease and diabetes46,48lends some weight to this theory. Other explanations include increased susceptibility or increased exposure to the toxic effects of smoke in COPD.49

A majority of comorbidities studied were independently associated with worse exercise capacity, respiratory-specific quality of life, and dyspnea. Though a study from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort did not show a significant association between cardiovascular disease and exercise capacity50 other studies have shown associations of cardiovascular diseases8,10,23,24 and diabetes 8,18 with exercise capacity, poor quality of life, exacerbation risk, dyspnea and mortality. Our findings extend those of previous studies in that we were able to control for the presence of other conditions, confirming the independence of these associations in some cases. Our results show that CHF, OSA and obesity were strongly linked to worse exercise capacity. Given that the results are based on associations noted in this observational study, we cannot conclude causality, and it is possible that individuals have worse cardiovascular disease as a result of poor exercise capacity. Regardless, such a finding is important in its suggestion that programs for improving exercise capacity such as pulmonary rehabilitation could be particularly beneficial in patients with concomitant cardiovascular disease. Finally, the finding that OSA is strongly associated with poor exercise capacity, quality of life and worse dyspnea in individuals with COPD challenges us to better understand this overlap syndrome and suggests that more aggressive diagnosis and treatment of this disease could improve clinical outcomes in COPD. One could speculate that the mechanism for the impact of OSA, particularly untreated or undertreated OSA, on clinical outcomes in COPD would be through worsening of pulmonary vascular disease, which would in turn impact clinical endpoints such as exercise capacity and dyspnea.

We found that most comorbidities were less prevalent in AA COPD cases compared with NHWs, but when present, these comorbidities were associated with higher risk for worse outcomes among AAs with COPD. Among cases, both GERD and osteoarthritis were associated with a higher risk for worse clinical outcomes in all measured domains in AAs compared to NHWs. In addition, other comorbidities such as osteoporosis (for quality of life), high cholesterol and hypertension (both for quality of life and dyspnea) also had greater impact on health outcomes in AAs compared to NHWs. The etiology for GERD and osteoarthritis being important comorbidities which impact AAs more than NHWs is unclear, however it is possible that AAs are more susceptible to dietary influences or exercise habits which predispose individuals to developing these diseases and subsequent poor health outcomes. Previous investigations have also suggested that other clinical factors, such as exacerbations and total percent emphysema measured on quantitative CT, are more strongly linked to poor health outcomes, such as quality of life and exercise capacity, among AAs as compared to NHWs. 26,50 In addition, cardiovascular disease and CKD have been associated with heightened mortality risk for AAs in general population studies,28-35,52,53 supporting our findings that chronic diseases may have disparate health impacts on AAs. Though it is possible that the differences found by race could be related to confounding factors such as access to care and medication use, the comprehensive data available on our study population allowed us to control for these important parameters in our analyses. It is also possible that certain conditions are associated with worse clinical outcomes in AAs because of a higher severity of illness in AAs compared to NHWs, given that data on severity of illness for comorbidities was not available in this study.

Our study is subject to some limitations. The data are cross-sectional, thus inferences about causality are limited. Comorbid conditions were defined by self-report of physician diagnosis (“Have you ever been told by a physician that you have...”), without regards to severity of the disease or treatment status. Validity of self-report for defining chronic diseases appears to vary based upon characteristics of the study population, the disease in question, and whether the disease is prevalent or incident. Self-report for diseases such as diabetes or osteoarthritis54-56 is likely more valid than that of CHD or stroke,56-58 though this validity is much more variable in the case of malignancy.57-59 Comparing the prevalence of comorbid conditions in our study to another population in which conditions were identified with objective data such as laboratory values, anthropometrics and validated instruments,46 we find that with some comorbidities such as hypertension the prevalence is comparable (51% in our study, 48% in the Vanfleteren, et al, study), while in other comorbidities the prevalence is disparate, as in osteoporosis (17% in our study, 31% in the VanFleteren. et al study). Comparing to Divo, et al,9 which also used medication and objective data to confirm the presence of conditions when available, our study showed a lower prevalence of congestive heart failure (5% vs. 15.7%) and coronary heart disease (17% vs. 30.2%) but a comparable prevalence of gastric ulcers (10% vs.11.5%). Though some of these differences in prevalence could potentially be attributed to the difference between self-report and objective measures of comorbidity, it is also possible that different prevalence of disease exists between European and American populations. In this study, individuals with active cancer undergoing treatment or with suspected lung cancer were excluded, a possible reason for the insignificant findings for the association of cancer with outcomes. Further, the group with cancer reported cancers of bladder, breast, colon or prostate, representing a heterogeneous spectrum of disease burden. Additionally, COPDGene® did not gather data on the presence of depression or anxiety (shown in previous studies to be prevalent with COPD 8 and when present, associated with poor outcomes, 50nor was data available on anemia in the population. We also did not have data on the severity of comorbidities or the current treatment status of conditions, which would potentially impact the association with outcomes. Finally, we used education level as a surrogate measure for socioeconomic status. This has been shown to be an appropriate and relevant measure of socioeconomic status in previous studies.60,61

In conclusion, this study shows a high prevalence of comorbidities and a large impact of these conditions on functional status in individuals with COPD. In particular, certain comorbidities were more predictive of poor functional status in African-Americans compared to non-Hispanic whites. Currently, it is unknown if targeting therapies for specific comorbidities will improve functional status in COPD. A better understanding of how comorbidities contribute to the heterogeneity of COPD is important. Ultimately, developing such an understanding can determine whether screening for and treating comorbidities can improve quality of life, symptoms and exercise capacity of patients with COPD.

Acknowledgements:

NP takes responsibility for the content of the manuscript, including data and analysis. NP, MKH, CPH, RW, EAR and NNH provided substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. MGF, ARA, RC, MHC, NAH, CPH, GLK, BJM, RMS, SML, BMT, AAW, SPB, THB, RPB, JLC, DE, JEH, DAL, ERS, EKS, JDC, JWR contributed to conception and design and, interpretation of data. All authors contributed to revising the manuscript critically for important intellectual content and provided final approval of the version to be published.

Declaration of Interest:

All authors declare that they have no special interests related to or impacting the work included in this manuscript with the following exceptions: RC, BMT, RAW, CPH, BJM, EKS, MKH report monies paid to them for consultancy; RC, RAW, BJM and EKS report monies paid to their institutions; RC, BJM, EKS and MKS report monies paid for lectures; BMT, RAW, BJM, and MKH report being on advisory boards; BJM and MKH report royalties paid to them for previous work, and BJM reports paid educational presentations as well as paid manuscript preparation.

Role of Sponsors:

The funding organizations/sources did not influence or guide the development of this research and manuscript.

1. Holguin F, Folch E, Redd S, et al. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest. 2005; 128(4):2005-2011. doi: http://dx.doi.org/10.1378/chest.128.4.2005.

2. Schnell KM, Weiss CO, Lee T, et al. The prevalence of clinically-relevant comorbid conditions in patients with COPD: a cross-sectional study using data from NHANES 1999-2008. BMC Pulm Med. 2012;12:26.doi: http://dx.doi.org/10.1186/1471-2466-12-26.

3. Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008; 32(4):962-969. doi: http://dx.doi.org/10.1183/09031936.00012408

4. García-Olmos L, Alberquilla A, Ayala V, et al. Comorbidity in patients with chronic obstructive pulmonary disease in family practice: a cross sectional study. BMC Fam Pract. 2013;14:11. doi: http://dx.doi.org/10.1186/1471-2296-14-11.

5. Ekstrom MP, Wagner P, Strom KE. Trends in cause-specific mortality in oxygen-dependent Chronic Obstructive Pulmonary Disease. Am J Respr Crit Care Med. 2011; 183(8): 1032-1036. doi: http://dx.doi.org/10.1164/rccm.201010-1704OC.

6. Lin PJ, Shaya FT, Scharf SM. Economic implications of comorbid conditions among Medicaid beneficiaries with COPD. Respir Med. 2010;104(5):697-704. doi: http://dx.doi.org/10.1016/j.rmed.2009.11.009.

7. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65(11):956-962. doi: http://dx.doi.org/10.1136/thx.2009.128082.

8. Miller J, Edwards LD, Agustí A, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med. 2013 ;107(9):1376-1384.doi: http://dx.doi.org/10.1016/j.rmed.2013.05.001.

9. Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(2):155-161.doi: http://dx.doi.org/10.1164/rccm.201201-0034OC.

10. Mentz RJ, Schulte PJ, Fleg JL et al. Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: Findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION). Am Heart J. 2013;165(2):193-199. doi: http://dx.doi.org/10.1016/j.ahj.2012.10.029.

11. Marin JM, Soriano JB, Carrizo SJ et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182(3):325-31.doi: http://dx.doi.org/10.1164/rccm.200912-1869OC.

12. Antonelli Incalzi R, Fuso L, De Rosa M, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 1997;10(12):2794-2800. doi: http://dx.doi.org/10.1183/09031936.97.10122794.

13. Patil SP, Krishnan JA, Lechtzin N, Diette GB. In-hospital mortality following acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med. 2003;163(10):1180-1186.doi: http://dx.doi.org/10.1001/archinte.163.10.1180.

14. Almagro P, Cabrera FJ, Diez J, et al; Working Group on COPD , Spanish Society of Internal Medicine. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest. 2012;142(5):1126-1133.doi: http://dx.doi.org/10.1378/chest.11-2413

15. Burgel PR, Paillasseur JL, Peene B, et al.Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS One. 2012;7(12):e51048.doi: http://dx.doi.org/10.1371/journal.pone.0051048.

16. de Lucas-Ramos P, Izquierdo-Alonso JL, Rodriguez-Gonzalez Moro JM, Frances JF, Lozano PV, Bellón-Cano JM; CONSISTE study group. Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case-control study (CONSISTE study). Int J Chron Obstruct Pulmon Dis. 2012;7:679-686.

17. Casanova C, Baudet JS, del Valle Velasco M et al. Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J. 2004 ;23(6):841-5. doi: http://dx.doi.org/10.1183/09031936.04.00107004.

18. Jimenez-Garcia R, de Miguel-Díez J, Rejas-Gutierrez J, et al. Health, treatment and health care resources consumption profile among Spanish adults with diabetes and chronic obstructive pulmonary disease. Prim Care Diabetes. 2009; 3(3):141-148. doi: http://dx.doi.org/10.1016/j.pcd.2009.06.005.

19. Cecere LM, Littman AJ, Slatore CG, et al. Obesity and COPD: associated symptoms, health-related quality of life, and medication use. COPD. 2011;8(4):275-84. doi: http://dx.doi.org/10.3109/15412555.2011.586660.

20. Ramachandran K, McCusker C, Connors M, Zuwallack R, Lahiri B. The influence of obesity on pulmonary rehabilitation outcomes in patients with COPD. Chron Respir Dis. 2008;5(4):205-209.doi: http://dx.doi.org/10.1177/1479972308096711.

21. Hardin M, Silverman EK, Barr RG. et al. The clinical features of the overlap between COPD and asthma. Respir Res. 2011;12:127. doi: http://dx.doi.org/10.1186/1465-9921-12-127.

22. Kauppi P, Kupiainen H, Lindqvist A,et al. Overlap syndrome of asthma and COPD predicts low quality of life. J Asthma. 2011;48(3):279-285.doi: http://dx.doi.org/10.3109/02770903.2011.555576.

23. Patel AR, Donaldson GC, Mackay A, et al. The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD. Chest 2012;141(4):851-857.doi: http://dx.doi.org/10.1378/chest.11-0853.

24. Sundh J, Ställberg B, Lisspers K, Montgomery SM, Janson C. Co-morbidity, body mass index and quality of life in COPD using the Clinical COPD Questionnaire. COPD. 2011;8(3):173-181.doi: http://dx.doi.org/10.3109/15412555.2011.560130.

25. Dransfield MT, Bailey WC. COPD: racial disparities in susceptibility, treatment, and outcomes. Clin Chest Med. 2006;27(3):463-471,vii. doi: http://dx.doi.org/10.1016/j.ccm.2006.04.005.

26. Han MK, Curran-Everett D, Dransfield MT, et al. Racial differences in quality of life in patients with COPD. Chest. 2011;140(5):1169-1176 doi: http://dx.doi.org/10.1378/chest.10-2869.

27. McGee D, Cooper R, Liao Y, et al. Patterns of comorbidity and mortality risk in blacks and whites. Ann Epidemiol. 1996;6(5):381-385. http://dx.doi.org/10.1016/S1047-2797(96)00058-0

28. Williams JE, Massing M, Rosamond W, et al. Racial disparities in CHD mortality from 1968-1992 in the state economic areas surrounding the ARIC study communities. Ann Epidemiol. 1999;9(8):472–480.doi: http://dx.doi.org/10.1016/S1047-2797(99)00029-0.

29. Barnett E, Halverson J. Local increases in coronary heart disease mortality among blacks and whites in the United States, 1985-1995. Am J Public Health. 2001; 91(9):1499–1506.doi: http://dx.doi.org/10.2105/AJPH.91.9.1499.

30. Agodoa L. African American Study of Kidney Disease and Hypertension (aaSK)—Clinical trial update. Ethn Dis. 1998; 8(2):249–253.

31. Liao D, Cooper L, Cai J, et al. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: The ARIC Study. Neuroepidemiology .1997;16(3):149–162.

32. Gillum RF. Secular trends in stroke mortality in African Americans: The role of urbanization, diabetes and obesity. Neuroepidemiology .1997;16(4):180–184.doi: http://dx.doi.org/10.1159/000109685.

33. Klag MJ, Whelton PK, Randall BL, et al. End-stage renal disease in African-American and white men. 16-Year MRFIT findings. JAMA. 1997;277(16):1293–1298. doi: http://dx.doi.org/10.1001/jama.1997.03540400043029.

34. Gaines K, Burke G. Ethnic differences in stroke: Black-white differences in the United States population. SECORDS Investigators. Southeastern Consortium on Racial Differences in Stroke. Neuroepidemiology. 1995; 14(5):209–239. doi: http://dx.doi.org/10.1159/000109798.

35. Ayala C, Greenlund KJ, Croft JB, et al. Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995-1998. Am J Epidemiol. 2001;154(11):1057–1063.doi: http://dx.doi.org/10.1093/aje/154.11.1057.

36. Regan EA, Hokanson JE, Murphy JR, et al. Genetic epidemiology of COPD (COPDGene®) study design. COPD. 2010;7(1):32-43. doi: http://dx.doi.org/10.3109/15412550903499522.

37. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. doi: http://dx.doi.org/10.1164/rccm.201204-0596PP.

38. Butland RJ, Pang J, Gross ER. et al. Two, six, and 12 minute walking tests in respiratory disease. Br Med J (Clin Res Ed).1982;284(6329):1607–1608. doi: http://dx.doi.org/10.1136/bmj.284.6329.1607.

39. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med. 1991;85(supplB):25-31;discussion 33-37.

40. Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999;54(7):581-586. doi: http://dx.doi.org/10.1136/thx.54.7.581.

41. StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.

42. Castaldi PJ, Cho MH, Litonjua AA, et al. The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. Am J Respir Cell Mol Biol. 2011;45(6):1147-1153. doi: http://dx.doi.org/10.1165/rcmb.2011-0055OC.

43. Bhatt SP, Sieren JC, Dransfield MT,et al; for the COPDGene Investigators. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction. Thorax. In press.

44. Lahousse L, Vernooij MW, Darweesh SK, et al. Chronic obstructive pulmonary disease and cerebral microbleeds: The Rotterdam Study. Am J Respir Crit Care Med. 2013; 188(7):783-787.doi: http://dx.doi.org/10.1164/rccm.201303-0455OC.

45. Van Remoortel H, Hornikx M, Langer D, et al. Risk factors and comorbidities in the preclinical stages of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(1):30-38.

46. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. doi: http://dx.doi.org/10.1164/rccm.201209-1665OC.

47. Sin DD, Anthonisen NR, Soriano JB et al. Mortality in COPD: role of comorbidities. Eur Resp J. 2006;28(6):1245-1257.doi: http://dx.doi.org/10.1183/09031936.00133805.

48. Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982-8. doi: http://dx.doi.org/10.1164/rccm.201206-1113OC

49. Hwang J, Rajendrasozhan S, Yao H, et al. FoxO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J Immunol. 2011;187(2):987–998. doi: http://dx.doi.org/10.4049/jimmunol.1001861.

50. Spruit MA, Watkins ML, Edwards LD, et al. Determinants of poor 6-min walking distance in patients with COPD: the ECLIPSE cohort. Respir Med. 2010;104(6):849-857.doi: http://dx.doi.org/10.1016/j.rmed.2009.12.007.

51. Hansel NN, Washko GR, Foreman MG, et al. Racial differences in CT phenotypes in COPD. COPD. 2013;10(1):20-27. doi: http://dx.doi.org/10.3109/15412555.2012.727921.

52. Ellis C, Grubaugh AL, Egede LE. Factors associated with SF-12 physical and mental health quality of life scores in adults with stroke. J Stroke Cerebrovasc Dis. 2013;22(4):309-317.doi: http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2011.09.007.

53. Ibrahim SA, Burant CJ, Siminoff LA, Stoller EP, Kwoh CK. Self-assessed global quality of life: a comparison between African-American and white older patients with arthritis. J Clin Epidemiol. 2002 ;55(5):512-517. doi: http://dx.doi.org/10.1016/S0895-4356(01)00501-7.

54. Oksanen T, Kivimäki M, Pentti J, Virtanen M, Klaukka T, Vahtera J. Self-report as an indicator of incident disease. Ann Epidemiol. 2010;20(7):547-554. doi: http://dx.doi.org/10.1016/j.annepidem.2010.03.017.

55. Midthjell K, Holmen J, Bjørndal A, et al. Is questionnaire information valid in the study of a chronic disease such as diabetes? The Nord-Trøndelag diabetes study. J Epidemiol Community Health. 1992;46(5):537-542. doi: http://dx.doi.org/10.1136/jech.46.5.537

56. Beckett M, Weinstein M, Goldman N, et al. Do health interview surveys yield reliable data on chronic illness among older respondents? Am J Epidemiol. 2000;151(3):315-323. doi: http://dx.doi.org/10.1093/oxfordjournals.aje.a010208.

57. Paganini-Hill A, Chao A. Accuracy of recall of hip fracture, heart attack, and cancer: a comparison of postal survey data and medical records. Am J Epidemiol. 1993;138(2):101-106.

58. Colditz GA, Martin P, Stampfer MJ, et al. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol .1986;123(5):894-900.

59. Desai MM, Bruce ML, Desai RA, Druss BG. Validity of self-reported cancer history: a comparison of health interview data and cancer registry records. Am J Epidemiol. 2001;153(3):299-306.doi: http://dx.doi.org/10.1093/aje/153.3.299

60. Prescott E, Vestbo J. Socioeconomic status and chronic obstructive pulmonary disease. Thorax. 1999;54(8):737-741.doi: http://dx.doi.org/10.1136/thx.54.8.737.

61. Liberatos P, Link BG, Kelsey JL. The measurement of social class in epidemiology. Epidemiol Rev. 1988;10:87-121.

Posted in: Original Research, Issue 1 | Volume 1

Bookmark the Permalink

Images

  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans
  • Comorbidities of COPD Have a Major Impact on Clinical Outcomes, Particularly in African Americans

Share This Article

E-mail this article to a friend