Discussion
We showed in a large cohort of 2,703 COPD subjects that chronic bronchitics were younger, had a reduced 6-minute walk distance, had a greater exacerbation frequency, were more likely to have gastroesophageal reflux, allergic ocular and nasal symptoms, histories of asthma and bronchitis, and were more likely to be current smokers, Caucasian, and male compared to those without CB, thereby validating our prior clinical findings in a smaller cohort that was less well characterized from a radiographic standpoint [
2]. These findings were independent of the presence of active smoking. We also showed that the CB + group had a greater segmental wall area percent, Pi10, and Pi15 despite similar degrees of emphysema and gas trapping. Finally, we showed that the variables independently associated with CB were lung function, allergic rhinitis symptoms, history of acute bronchitis and asthma, airway wall thickness, exposure to dusts, gender, race, and current smoking in multivariate analysis. Using our prediction model, one can help identify those with the clinical phenotype of CB that is at higher risk for poor outcomes. To our knowledge, this is the first analysis that combines quantitative CT and clinical variables as predictors of CB in a large cohort of COPD subjects.
CB affects approximately 10 million individuals in the United States, and the majority are between 44 and 65 years of age [
16]. CB has been associated with numerous adverse clinical outcomes. Exacerbation frequency has been shown to be greater in patients with COPD and CB in several studies [
3,
17]. Seemungal et al. found that CB significantly increased the odds of having frequent exacerbations in a group of 70 patients [
17]. A cross-sectional analysis of 433 patients also similarly found an increased risk of exacerbation among individuals with CB [
3].
CB may increase all-cause mortality as well, independent of the level of airflow obstruction. Some but not all studies have shown CB to be an independent risk factor for death. In a study by Pelkonen et al., the multivariable hazard ratios for all-cause mortality in those with persistent CB was 1.64 (95% CI, 1.23–2.19) after adjustment for lung function [
9]. In a post hoc analysis of the National Emphysema Treatment Trial, severe CB, defined as chronic cough, phlegm, and chest trouble, was associated with a higher mortality and hospitalization rate in those treated with medical therapy alone [
18]. CB has also been shown to hasten the rate of lung function decline and reduce health related quality of life [
2,
19,
20].
Radiographic characterization of COPD has been performed extensively in the past, [
17,
18,
21] but few studies have related CT parameters to the clinical phenotype of CB. A small study of 42 COPD subjects showed that airway wall thickness was greater in those with CB compared to those without [
22]. We have shown that percent emphysema and percent gas trapping were no different between those with CB and those without in 1061 moderate to severe COPD subjects [
2]. We validate these prior findings on our study but add quantitative airway measurements in several compartments. Our findings of increased mean segmental wall area percent, Pi10, and Pi15 (“medium sized airways”) in chronic bronchitics is consistent with the notion that the clinical phenomenon of chronic bronchitis arises from mucus hypersecretion from larger more proximal airways, as opposed to small airway disease which is often difficult to detect clinically [
11,
23]. This is, however, hypothesis generating and would require further study for confirmation. Although the differences in WA% were small, the composite variable of wall thickness was significantly associated with CB.
One of the strongest predictors of CB in this cohort was current smoking. Smoking causes airway inflammation and oxidative stress which induces mucin gene expression [
1]. Active smokers have been shown in other studies to be at greater risk of CB. In a 30-year longitudinal study of 1,711 Finnish men, the cumulative incidence of CB was 42% in continuous smokers, 26% in ex-smokers, and 22% in never smokers [
9]. A recent metaanalysis found that among 101 studies, ever smoking and current smoking were associated with relative risks of 2.69 and 3.41, respectively, for CB [
24]. We showed that current smoking was associated with an odds ratio of 3.53 for CB.
Although the primary risk factor for CB is smoking, it should be noted that CB has been described in up to 22% of never smokers, [
9] suggesting that other risk factors may exist. Other potential risk factors include inhalational exposures to biomass fuels, dusts, and chemical fumes [
25,
26]. A survey of South African adults found occupational exposure to be a risk factor for CB in men (OR 2.6; 95% CI 1.7–4.0) and domestic fuel exposure to be a risk factor for CB in women (OR, 1.9; 95% CI 1.4–2.6) [
27]. In a recent analysis of 5,858 smokers or ex-smokers without COPD, patients with CB were more likely to have been exposed to fumes at work (76.4 vs. 60.9%, P < 0.001) or to have worked more than 1 year at a dusty job (76 vs. 57%, P < 0.001) [
28]. We found that subjects with CB had a 1.4-fold and 1.3-fold increased risk for exposure to dusts and occupational exposures, respectively. Although occupational exposures were not statistically significant in the multivariate predictive model, we present some evidence of their association in univariate analysis, providing more evidence of a causal association.
Another potential risk factor for CB is the presence of gastroesophageal reflux disease (GERD), possibly by pulmonary aspiration of refluxed gastric contents producing acid-induced injury and infection or neurally mediated reflex bronchoconstriction secondary to irritation of esophageal mucosa [
29]. There is increasing evidence that not only is GERD a significant comorbidity but also that it is a risk factor for COPD related outcomes. For example, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study identified GERD as a risk factor for COPD exacerbations in longitudinal follow-up [
30]. In the Azithromycin for Prevention of Exacerbations of COPD (MACRO) trial, GERD was associated with an increased risk of COPD exacerbations [
31]. In our study, we demonstrated that GERD was more common in those with CB and that GERD conferred a slightly increased odds ratio of having CB in multivariate analysis that almost reached statistical significance.
Other risk factors identified in our study include a history of acute bronchitis, and allergic nasal symptoms. Repeated bouts of acute bronchitis has been considered a risk factor for the development of CB, [
32] possibly by the development of persistent inflammation and mucus hypersecretion after multiple episodes of infectious bronchitis. Mucus hypersecretion is a signature pathologic feature of asthma, and asthma’s association with allergic rhinitis is strong. The association between chronic bronchitis and allergic nasal symptoms suggests a link between upper and lower airway inflammation that has commonly been described in asthma. This raises the possibility of a common pathophysiology between CB and asthma, which deserves further attention.
The influence of gender on CB continues to be a matter of debate. Many studies have found that CB affects men more than women, [
2,
33,
34] but in the 2009 National Center for Health Statistics report, 67.8% of patients with CB were women [
35]. The reasons for the higher prevalence of CB in women compared with men is unclear, but may be due to hormonal influences, sex differences in symptom reporting, and sex diagnostic bias. Our study showed that men were more likely to be affected by CB and that gender was an independent predictor of CB in multivariate analysis.
Despite the clinical and CT findings in this robust cohort of unselected COPD subjects, there are several limitations that are worthy of mention. First, the assessment of medical history and exposures was by self-report, potentially leading to recall bias. The outcome of interest itself is somewhat subjective as well (chronic cough and phlegm). Although the identified clinical and computed tomographic factors were used in a prediction model, one could argue that some of predictors of interest are caused by chronic bronchitis, not the result of it (eg, airway wall thickness). In addition, it is unclear why the FVC is lower in chronic bronchitics in univariate analysis but higher in multivariate analysis; this phenomenon is most likely due to the confounding factors of differences in FEV1, race, and gender. However, the predictors of interest were chosen because of the more likely causal relationship of CB. Nonetheless, our analysis offers a comprehensive characterization of chronic bronchitis in COPD as well as a prediction model for CB using several clinical and computed tomographic parameters.
Acknowlegements
We acknowledge and thank the COPDGene Core Teams:
Administrative Core: James D. Crapo, MD (PI); Edwin K. Silverman, MD, PhD (PI); Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Stephanie Bratschie, MPH; Rochelle Lantz; Sandra Melanson, MSW, LCSW; Lori Stepp.
Executive Committee: Terri Beaty, PhD; Russell P. Bowler, MD, PhD; James D. Crapo, MD; Jeffrey L. Curtis, MD; Douglas Everett, PhD; MeiLan K. Han, MD, MS; John E. Hokanson, MPH, PhD; David Lynch, MB; Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Edwin K. Silverman, MD, PhD; E. Rand Sutherland, MD.
External Advisory Committee: Eugene R. Bleecker, MD; Harvey O. Coxson, PhD; Ronald G. Crystal, MD; James C. Hogg, MD; Michael A. Province, PhD; Stephen I. Rennard, MD; Duncan C. Thomas, PhD.
NHLBI: Thomas Croxton, MD, PhD; Weiniu Gan, PhD; Lisa Postow, PhD.
COPD Foundation: John W. Walsh; Randel Plant; Delia Prieto.
Data Coordinating Center: Douglas Everett, PhD; Andre Williams, PhD; Ruthie Knowles; Carla Wilson, MS.
Epidemiology Core: John Hokanson, MPH, PhD; Jennifer Black-Shinn, MPH; Gregory Kinney, MPH.
Genetic Analysis Core: Terri Beaty, PhD; Peter J. Castaldi, MD, MSc; Michael Cho, MD; Dawn L. DeMeo, MD, MPH; Marilyn G. Foreman, MD, MS; Nadia N. Hansel, MD, MPH; Megan E. Hardin, MD; Craig Hersh, MD, MPH; Jacqueline Hetmanski, MS; John E. Hokanson, MPH, PhD; Nan Laird, PhD; Christoph Lange, PhD; Sharon M. Lutz, MPH, PhD; Manuel Mattheisen, MD; Merry-Lynn McDonald, MSc, PhD; Margaret M. Parker, MHS; Elizabeth A. Regan, MD, PhD; Stephanie Santorico, PhD; Edwin K. Silverman, MD, PhD; Emily S. Wan, MD; Jin Zhou, PhD.
Genotyping Cores: Genome-Wide Core: Terri Beaty, PhD; Candidate Genotyping Core: Craig P. Hersh, MD, MPH; Edwin K. Silverman, MD, PhD.
Imaging Core: David Lynch, MB; Mustafa Al Qaisi, MD; Jaleh Akhavan; Christian W. Cox, MD; Harvey O. Coxson, PhD; Deanna Cusick; Jennifer G. Dy, PhD; Shoshana Ginsburg, MS; Eric A. Hoffman, PhD; Philip F. Judy, PhD; Alex Kluiber; Alexander McKenzie; John D. Newell, Jr., MD; John J. Reilly, Jr., MD; James Ross, MSc; Raul San Jose Estepar, PhD; Joyce D. Schroeder, MD; Jered Sieren; Arkadiusz Sitek, PhD; Douglas Stinson; Edwin van Beek, MD, PhD, MEd; George R. Washko, MD; Jordan Zach.
PFT QA Core: Robert Jensen, PhD; E. Rand Sutherland, MD.
Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD: Samantha Bragan; Stacey Cayetano.
We further wish to acknowledge the COPDGene Investigators from the participating Clinical Centers:
Ann Arbor VA: Jeffrey Curtis, MD, Ella Kazerooni, MD.
Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS, Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD, Mustafa Atik, MD, Hasan Al-Azzawi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD.
Brigham and Women’s Hospital, Boston, MA: Dawn DeMeo, MD, MPH, Craig Hersh, MD, MPH, George Washko, MD, Francine Jacobson, MD, MPH, Hiroto Hatabu, MD, PhD, Peter Clarke, MD, Ritu Gill, MD, Andetta Hunsaker, MD, Beatrice Trotman-Dickenson, MBBS, Rachna Madan, MD.
Columbia University, New York, NY: R. Graham Barr, MD, Dr PH, Byron Thomashow, MD, John Austin, MD, Belinda D’Souza, MD.
Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD, Lacey Washington, MD, H Page McAdams, MD.
Fallon Clinic, Worcester, MA: Richard Rosiello, MD, Timothy Bresnahan, MD, Joseph Bradley, MD, Sharon Kuong, MD, Steven Meller, MD, Suzanne Roland, MD.
Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH, Joseph Tashjian, MD.
Johns Hopkins University, Baltimore, MD: Robert Wise, MD, Nadia Hansel, MD, MPH, Robert Brown, MD, Gregory Diette, MD, Karen Horton, MD.
Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD, Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD, Matt Budoff, MD, Mehdi Rambod, MD.
Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD, Charles Trinh, MD, Hirani Kamal, MD, Roham Darvishi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD.
Minneapolis VA: Dennis Niewoehner, MD, Quentin Anderson, MD, Kathryn Rice, MD, Audrey Caine, MD.
Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS, Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD.
National Jewish Health, Denver, CO: Russell Bowler, MD, PhD, David Lynch, MB, Joyce Schroeder, MD, Valerie Hale, MD, John Armstrong, II, MD, Debra Dyer, MD, Jonathan Chung, MD, Christian Cox, MD.
Temple University, Philadelphia, PA: Gerard Criner, MD, Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD, Chandra Dass, MD, Libby Cone, MD.
University of Alabama, Birmingham, AL: William Bailey, MD, Mark Dransfield, MD, Michael Wells, MD, Surya Bhatt, MD, Hrudaya Nath, MD, Satinder Singh, MD.
University of California, San Diego, CA: Joe Ramsdell, MD, Paul Friedman, MD.
University of Iowa, Iowa City, IA: Alejandro Cornellas, MD, John Newell, Jr., MD, Edwin JR van Beek, MD, PhD.
University of Michigan, Ann Arbor, MI: Fernando Martinez, MD, MeiLan Han, MD, Ella Kazerooni, MD.
University of Minnesota, Minneapolis, MN: Christine Wendt, MD, Tadashi Allen, MD.
University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD, Joel Weissfeld, MD, MPH, Carl Fuhrman, MD, Jessica Bon, MD, Danielle Hooper, MD.
University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD, Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD, Amy Mumbower, MD, Ariel Kruger, MD, Carlos Restrepo, MD, Michael Lane, MD.
Competing interests
This study was supported by the NHLBI R01 HL089856 and R01 HL08989.
VK is supported by NHLBI K23HL094696-03.
VK has participated in clinical trials sponsored by Boehringer Ingelheim, Glaxo-Smith-Kline, and Roche pharmaceuticals. AD, JC, and CHM report no conflicts. APC has been a consultant for VIDA diagnostics. Also, APC has participated in clinical trials sponsored by Boehringer Ingelheim, Glaxo-Smith-Kline, and Astra-Zeneca, and Forest. MKH has participated in advisory boards for Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Genentech, Novartis, and Medimmune; participated on speaker’s bureaus for Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Forest, Grifols therapeutics, and the National Association for Continuing Education, and WebMD; has consulted for Novartis, Ikaria and United Biosource Corporation; and has received royalties from UpToDate and ePocrates. GW has received grants from the NHLBI to perform quantitative image analysis and have been a paid consultant for MedImmune and Spiration, and his spouse is an employee of Merck Research Laboratories. Over the last three years, BJM has participated in advisory boards, speaker bureaus, consultations and multi-center clinical trials with funding from the National Heart Lung and Blood Institute, Abbott, Astellas, AstraZeneca, Boerhinger-Ingelheim, Coviden, Dey, Forest, GlaxoSmithKline, Merck, MedImmune, NABI, Novartis, Pfizer, Respironics, Sepracor, Sequal and Talecris. EKS received grant support from GlaxoSmithKline for studies of COPD genetics, and he received honoraria and consulting fees from AstraZeneca, Merck, and GlaxoSmithKline. DAL’s institution and laboratory receives research support from the National Heart Lung and Blood Institute, Siemens, Inc, Perceptive Imaging, Inc, and Centocor, Inc, Inc. Dr Lynch is a consultant to Perceptive Imaging, Inc, Boehringer Ingelheim, Inc, Genentech, Inc, Gilead, Inc, Veracyte, Inc and Intermune, Inc. GJC has served on Advisory Committees for Boehringer Ingelheim, CSA, Amirall and Holaira. All of these sums are less than $2,500. GJC has received research grants from: Boehringer Ingelheim, AstraZeneca, MedImmune, Pearl, Actelion, Glaxo-Smith-Kline, Forest, Aeris, Therapeutics, Pulmonx and PneumRx. All research grant monies are deposited and controlled by Temple University.