- Email: [email protected]
Obesity and symptoms of depression contribute independently to the poor asthma control of obesity
Accepted Manuscript Obesity and symptoms of depression contribute independently to the poor asthma control of obesity S.G. Kapadia , C. Wei , S.J. Bartlett , J. Lang , R.A. Wise , MD A.E. Dixon PII:
S0954-6111(14)00199-1
DOI:
10.1016/j.rmed.2014.05.012
Reference:
YRMED 4517
To appear in:
Respiratory Medicine
Received Date: 4 December 2013 Revised Date:
23 May 2014
Accepted Date: 26 May 2014
Please cite this article as: Kapadia S, Wei C, Bartlett S, Lang J, Wise R, Dixon A, Obesity and symptoms of depression contribute independently to the poor asthma control of obesity, Respiratory Medicine (2014), doi: 10.1016/j.rmed.2014.05.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Obesity and symptoms of depression contribute independently to the poor asthma control of obesity.
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University of Vermont College of Medicine, Burlington, Vermont Johns Hopkins University, Baltimore, MD 3 McGill University, Montreal, Canada 4 Nemours Children’s Hospital, Orlando, FL 2
Department of Medicine, University of Vermont and Fletcher Allen Health Care
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89 Beaumont Avenue,
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Burlington, VT 05405
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Corresponding Author: [email protected] Phone: (802) 656-8812 Fax: (802) 656-3526
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Keywords: obesity; asthma; depression
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Kapadia SG,1 Wei C,2 Bartlett SJ,3 Lang J, 4 Wise RA,2 MD & AE Dixon1 for the American Lung Association Asthma Clinical Research Centers5
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Credit Roster: American Lung Association Asthma Clinical Research Centers
The following persons participated in the TAPE study
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Baylor College of Medicine, Houston: N. A. Hanania (principal investigator), M. Sockrider (co-principal investigator), L. Giraldo (principal clinic coordinator), R. Valdez (coordinator);
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Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla, N.Y.: A. Dozor (principal investigator), N. Amin and Y. C. Kim (co-principal investigator), I. Gherson (principal clinic coordinator), M. Heydendael and M. Key (coordinators);
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Columbia University–New York University Consortium, New York: J. Reibman (principal investigator), E. DiMango (co-principal investigator), W. Hoerning (clinic coordinator at New York University), J. Sormillon (clinic coordinator at Columbia University); Duke University Medical Center, Durham, N.C.: L. Williams (principal investigator), J. Sundy (co-principal investigator), G. Dudek (principal clinic coordinator), R. Newton (coordinator);
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Emory University School of Medicine, Atlanta: W.G. Teague (principal investigator), S. Khatri (co-principal investigator), J. Costolnick, (principal clinic coordinator), J. Peabody, R. Patel, E Hunter (coordinators); Illinois Consortium, Chicago: L. Smith (principal investigator), J. Moy, E Naureckas, C.S. Olopade (co-principal investigators), J. Hixon (principal clinic coordinator), A. Brees, G. Rivera, S. Sietsema, V. Zagaja (coordinators);
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Indiana University, Asthma Clinical Research Center, Indianapolis: M. Busk (principal investigator), F. Leickly, C. Williams (co-principal investigators), S. Lynch (principal clinic coordinator); P. Puntenney (coordinator); Jefferson Medical College, Philadelphia: F. Leone (principal investigator), M. HayesHampton (principal clinic coordinator);
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Louisiana State University Health Sciences Center, Ernest N. Morial Asthma, Allergy, and Respiratory Disease Center, New Orleans: W.R. Summer (principal investigator), C. Glynn (principal clinic coordinator); National Jewish Medical and Research Center, Denver: S. Wenzel (principal investigator), P Silkoff (co-principal investigator), R. Gibbs (principal clinic coordinator), L. Lopez, C. Ruis, B. Schoen (coordinators); Nemours Children’s Clinic–University of Florida Consortium, Jacksonville: J. Lima 2
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(principal investigator), K. Blake (co-principal investigator), A. Santos (principal clinic coordinator), L. Duckworth, D. Schaeffer (coordinators); North Shore–Long Island Jewish Health System, New Hyde Park, 485 N.Y.: J. Karpel (principal investigator), R. Cohen (co-principal investigator), R. Ramdeo (principal clinic coordinator);
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Northern New England Consortium formerly Vermont Lung Center at the University of Vermont), Colchester, Vt.: C.G. Irvin (principal investigator), A.E. Dixon, D.A. Kaminsky, E. Kent, T. Lahiri, P. Shapiro (co-principal investigators), S. Lang (principal clinic coordinator), J. Allen, A. Coote, L.M. Doucette, K. Girard, J. Lynn, L. Moon, T. Viola (coordinators);
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The Ohio State University Medical Center/Columbus Children’s Hospital, Columbus: J. Mastronarde (principal investigator), K. McCoy (co-principal investigator), J. Drake (principal clinic coordinator), R. Compton, L. Raterman (coordinators);
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University of Alabama at Birmingham, Birmingham: L.B. Gerald (principal investigator), W.C. Bailey (co-principal investigator), S. Erwin (principal clinic coordinator), H. Young, A. Kelley, D. Laken, B. Martin (coordinators); University of Miami, Miami–University of South Florida, Tampa: A. Wanner (principal investigator), R. Lockey (principal investigator), E. Mendes (principal clinic coordinator for University of Miami), M. Grandstaff (principal clinic coordinator for University of South Florida), B Fimbel (coordinator);
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University of Minnesota, Minneapolis: M.N. Blumenthal (508 principal investigator), G. Brottman, J. Hagen (co-principal investigators), A. Decker, D. Lascewski, S. Kelleher (principal clinic coordinators), K. Bachman, M. Sneen (coordinators);
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University of Missouri, Kansas City School of Medicine, Kansas City: G. Salzman (principal investigator), D. Pyszczynski (co-principal investigator), P. Haney (principal clinic coordinator); St. Louis Asthma Clinical Research Center: Washington University, St. Louis University, and Clinical Research Center, St. Louis: M. Castro (principal investigator), L. Bacharier, K. Sumino (co-investigators), M.E. Scheipeter (principal clinic coordinator), J. Tarsi (coordinator);
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University of California San Diego: S Wasserman (principal investigator), J Ramsdell (co-principal investigator) Chairman’s Office, Respiratory Hospital, Winnipeg, Man., Canada: N. Anthonisen (research group chair); Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore: R. Wise (center director), J. Holbrook (deputy director), E. Brown (principal 3
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coordinator), M. Dale, M. Daniel, G. Leatherman, C. Levine, J. Jones, R. Masih, S Modak, D. Nowakowski, N. Prusakowski, D. Shade, E. Sugar;
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Data and Safety Monitoring Board: L. Hudson (chair), V. Chinchilli, P. Lanken, B. McWilliams, C. Rinaldo, D. Tashkin;
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Abstract
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control in this patient population are unclear. Symptoms of depression have been associated with
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poor asthma control, and increase with higher body mass index (BMI). The purpose of this study
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was to assess whether depressive symptoms underlie poor asthma control in obesity.
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Methods: We determined the relationship between BMI, psychological morbidity and asthma
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control at baseline in a well-characterized patient population participating in a clinical trial
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conducted by the American Lung Association-Asthma Clinical Research Centers.
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Obesity is a major risk factor for poorly controlled asthma, but the reasons for poor asthma
Results: Obese asthmatic participants had increased symptoms of depression (Center for
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Epidemiologic Studies Depression Scale score in lean 10·1±8·1, overweight 10·0±8·1, obese
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12·4±9·9; p=0·03), worse asthma control (Juniper Asthma Control Questionnaire score in lean
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1·43±0·68, overweight 1·52±0·71, obese 1·76±0·75; p<0·0001), and worse asthma quality of life
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(scores in lean 5·21±1·08, overweight 5·08±1·05, obese 4·64±1·09; p<0·0001). Asthmatics with
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obesity and those with symptoms of depression both had a higher risk of having poorly
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controlled asthma (adjusted odds ratio of 1·83 CI 1·23-3·52 for obesity, and 2·08 CI 1·23-3·52 for
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depression), but there was no interaction between the two.
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Conclusion: Obesity and symptoms of depression are independently associated with poor asthma
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control. As depression is increased in obese asthmatics it may be an important co-morbidity
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contributing to poor asthma control in this population, but factors other than depression also
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contribute to poor asthma control in obesity.
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Introduction
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asthma control.1, 2 Depression and anxiety are likewise associated with poor asthma control, and
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the prevalence of depression and anxiety are dramatically increased in obesity. The underlying
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interaction between obesity, depression, and asthma is not well understood, yet may have critical
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implications for asthma control in the setting of obesity.
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Obesity is a significant risk factor for developing asthma and is associated with poor
Obesity is associated with decreased responsiveness to controller medication and poor
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asthma control.3 One study found that obese asthmatics are hospitalized at nearly five times the
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rate of lean asthmatics.4 Given the ever increasing prevalence of obesity,5 obesity is contributing
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to an epidemic of poorly controlled asthma.
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A number of studies suggest that anxiety and depression adversely affect asthma
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symptom severity and there is a significant correlation between severity of depressive symptoms
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and poor asthma control.6, 7 Depressed asthmatics also have an increased risk of asthma-related
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emergency department visits and poor adherence to asthma medication regimens.8
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Depression is a very common comorbidity associated with obesity.9 The strong
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association between high BMI and depressive symptoms is more pronounced in women, the
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demographic group with the highest rate of asthma related to obesity.3 This relationship is
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reversible as weight reduction surgery significantly reduces symptoms of anxiety and depression
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among obese asthmatics,10 this surgery also improves asthma control.11
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Considering that
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depression is increased in obesity, such psychological comorbidity may contribute significantly
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to the poor asthma control characteristic of obese asthmatics.
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The purpose of this study was first to determine if depression and obesity were associated
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with poor asthma control, and then to determine if depression could explain poor asthma control
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in obesity. We evaluated the relationship of both markers of depression and measures of asthma
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control with obesity, hypothesizing that a significant interaction between obesity and depression
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would contribute to worse asthma control among obese asthmatics. This study was completed in
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a well characterized, patient population participating in a clinical trial of the placebo response in
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asthma.
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Methods
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multicenter clinical trial designed to assess the placebo effect in asthma performed by the
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American Lung Association Asthma Clinical Research Centers. Details of the main study and
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eligibility criteria have been published elsewhere, and are summarized below.12 The study was
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approved by the Institutional Review Boards at all participating centers, and all participants
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signed informed consent.
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Data on obesity and symptoms of depression were derived from participants in a
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Males and females at least 15 years of age who had been diagnosed with asthma by a
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physician, regularly used any prescribed asthma medication in the last 12 months, and had a
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post-bronchodilator forced expiratory volume (FEV1) ≥ 75% predicted were included in the trial.
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Participants had inadequate control of asthma symptoms indicated by one of the following:
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short-acting β2 agonist use two or more times per week for relief of asthma symptoms, nocturnal
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awakenings once or more per week due to asthma symptoms, or a Juniper Asthma Control
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Questionnaire (ACQ) score of ≥ 1·5 at their enrollment visit.
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Participants were excluded if they had a significant smoking history (≥ 10 pack years or
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active smoking in the past 6 months), or had used montelukast or other leukotriene antagonists
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within the past 14 days. Participants were also excluded if they reported a history of
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hospitalization, emergency department visits, or prednisone use for asthma within the past 3
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months, past respiratory failure secondary to asthma, or prior adverse reaction to montelukast. At
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baseline, participants were extensively evaluated for their asthma characteristics with the Juniper
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Asthma Control Questionnaire,13 and the Juniper Asthma Quality of Life Questionnaire.14
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Spirometry was performed according to ATS guidelines.15
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measured by the Center for Epidemiological Studies Depression Score (CES-D).16,
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Participants’ asthma knowledge and sense of asthma self-efficacy were measured by the
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Knowledge, Attitude, and Self-efficacy Asthma Questionnaire (KASE-AQ).18
Symptoms of depression were
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Statistical Approach
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Descriptive statistics were used to summarize baseline characteristics of the study subjects, divided into three categories according to body mass index (BMI): lean (BMI 18·5-24·9
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kg/m2), overweight (BMI 25-29·9 kg/m2), and obese (BMI ≥ 30 kg/m2). Continuous variables
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were compared using analysis of variance, with log transformations for non-parametric variables,
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and proportions were compared using χ2 analysis. Post-hoc comparison of groups was performed
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using the Bonferroni procedure.
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We determined the risk of poor asthma control associated with obesity (defined as a BMI
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≥ 30) compared to non-obese (defined as those with a BMI < 30) and depression (defined as a
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CES-D score ≥ 16 compared to those with a score < 16). We performed multiple logistic
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regression including sex, age, race, education, income and employment status in the final model.
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We evaluated the relationship between asthma control and symptoms of depression, using an
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interaction term for obesity (BMI > 30 kg/m2) and significant symptoms of depression (defined
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as a CES-D score ≥ 16). Analyses were performed with STATA 10·0 (College Station, Texas).
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Role of Funding Source
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The study sponsors had no role in study design, data collection, data analysis, data interpretation
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or decision to submit manuscript. The corresponding author had full access to all the data, and
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the final responsibility for the decision to submit for publication.
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Results
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demographic characteristics are summarized in Table 1. The mean age of participants was 32
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years in the lean group, overweight and obese asthmatic participants were significantly older.
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Most participants were female, constituting nearly 82% of the obese group. There was a higher
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proportion of African American participants in the obese category. Obese asthmatics reported
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completing less education than leaner participants, though there was no overall difference in
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reported income. Employment status differed among the BMI categories, with a higher
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proportion of students in the lean category.
Participant characteristics
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A total of 601 unique participants were enrolled in the primary study. Participant
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Asthma characteristics
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and overweight asthmatics reported significantly later-onset asthma than lean asthmatics. Obese
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asthmatics tended to report more frequent use of oral prednisone for asthma. Obese participants
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had worse asthma control as assessed by the Juniper Asthma Control Questionnaire (ACQ) and
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worse asthma-related quality of life as assessed by the Asthma Quality of Life Questionnaire
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(AQLQ) compared with both lean and overweight asthmatics.
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Data on asthma characteristics in the distinct BMI groups are reported in Table 2. Obese
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Data on pulmonary function are also provided in Table 2, and differed among
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participants. Obese asthmatics had significantly lower FEV1 and FVC than lean asthmatics, and
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obese and overweight asthmatics had greater change in FVC in response to bronchodilator than
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lean asthmatics.
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Psychological morbidity
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Epidemiologic Studies Depression Scale (CES-D) and more frequently surpassed the reported
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thresholds for mild depressive symptoms (a score of 16 and above)
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depression (a score of 23 and above) (Table 3).17 Obese asthmatics also reported significantly
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lower self-efficacy related to asthma compared with lean and obese asthmatics, and both obese
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and overweight asthmatics had lower asthma knowledge, as assessed by the Knowledge,
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Attitude, and Self-Efficacy Asthma Questionnaire (KASE-AQ).
Obese asthmatics had higher depression scores as assessed by the Center for
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as well as probable
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Combined effect of depression and obesity
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controlled asthma, as defined by a score of 1·5 or greater on the Juniper Asthma Control Score
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(311 out of 605 participants had a score of 1·5 or greater when depression symptoms were
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assessed at the second study visit) (Table 4).
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Both obesity and having symptoms of depression increased the risk of having poorly
When both obesity and depression were considered in the same model, there was little
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change in the odds of having poorly controlled asthma, and the interaction between obesity and
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asthma was not significant (p = 0·58), suggesting that obesity and depression contribute
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independently to poor asthma control. Depressed patients had worse asthma control in all BMI
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groups, suggesting that the contribution of depression to poor asthma control was not unique to
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obesity (Table 5).
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Discussion
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specific quality of life, and suffer a greater burden of symptoms of depression than leaner
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asthmatics. Obesity and symptoms of depression are both independently related to poor asthma
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control, without a significant interaction between the two comorbidities. This suggests that
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depression should be considered in managing obese patients with poor asthma control as the
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prevalence of depression increases with BMI, but that poor asthma control in obesity is also
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related to factors other than depression. This study has important clinical implications with
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regard to understanding the physical and mental underpinnings of poor asthma control among
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obese asthmatics.
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This study demonstrates that obese asthmatics have poor asthma control, worse asthma-
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The present study provides further evidence of the relationship between obesity and poor
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asthma control as well as worse asthma-related quality of life. Obesity is not only a risk factor
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for incident asthma, but is also associated with worse control characterized by increased
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symptoms, more frequent use of rescue bronchodilator medications, increased risk of
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hospitalizations for asthma, and missed work days.2, 7, 19 Obesity is a significant cause of poorly
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controlled asthma due to many factors such as altered lung mechanics, altered responses to
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medications, elevated airway oxidative stress, effects of adipokines and cytokines, and other co-
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morbidities which occur in obesity such depression and obstructive sleep apnea.3 We have
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previously reported that symptoms of obstructive sleep apnea are associated with worse asthma
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control,20 but few studies have investigated the role of psychological morbidity in the poor
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asthma control of obesity.
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Asthmatics are more likely to suffer from anxiety and depression than the general
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population, irrespective of BMI.21 Data from the 2002 World Health Survey collected by the
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World Health Organization across 54 countries suggested that depression was significantly
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associated with asthma in 65% of countries.22 There may be a causal link between depression
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and asthma; in a longitudinal 20 year follow up CARDIA study by Brunner et al, elevated
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depressive symptoms were associated with a 1.26 increased risk of developing incident asthma
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(independent of BMI).23 Depression in asthmatics has been associated with poor asthma
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control,21, 24 with one study reporting that comorbid depression was associated with greater health
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care utilization and 51% higher health care costs.25 Depression may contribute to poor asthma
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control through a number of pathways. Asthmatics with psychological comorbidity may perceive
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a greater intensity of breathlessness.21 Asthmatics with depressive symptoms may also develop
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cholinergic-mediated airway constriction in the event of psychological stress.26,
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may also affect medication adherence: high levels of depressive symptoms are associated with an
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11-fold increase in odds of poor adherence (measured electronically) to inhaled corticosteroid
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therapy after hospitalization for an asthma exacerbation.27 It is also possible that poor asthma
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control contributes to the development of depression. In the current study we found that over
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20% of the study population reached the threshold for mild depression on the validated CES-D
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questionnaire, which is in line with previous reports on the prevalence of depression in asthma.8,6
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Asthmatic participants with symptoms of depression were approximately twice as likely to have
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poor asthma control as those without symptoms of depression. Our data provide further evidence
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that symptoms of depression are associated with poor asthma control and worse asthma quality
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of life.
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Depression
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Many studies suggest there is a significant relationship between depression and obesity.
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Meta-analyses of cohort studies suggest a significant association between obesity and
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depression;9,
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participants reported a significant association between depression and obesity, particularly
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among females (OR, 1·26; 95% CI, 1·17-1·36).9 Our current study demonstrates that obese
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asthmatics had significantly higher scores on the CES-D questionnaire and a higher prevalence
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of depression. Many factors may contribute to the increased risk of depression with obesity.
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Obesity and depression share common risk factors such as low socioeconomic status and
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insufficient physical activity.29 Psychological distress may be worsened by obesity because of
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social stigmatization which produces low self-worth and self-esteem, a negative body image,
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guilt, and peer isolation.9,
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psychological distress elevates circulating cortisol levels which may contribute to abdominal
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obesity. Depression and obesity likely share common risk factors and may in part share a
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common pathophysiology, whether these factors interact with each other to produce the worse
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asthma control characteristic of obesity is not known.
one meta-analysis of 17 community based studies encompassing 204,507
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Hypothalamic-pituitary-adrenal axis dysfunction from
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A few studies have addressed the potential for a concurrent interaction between obesity
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and depression in mediating poor asthma outcomes. Data collected from the 2006 European
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National Health and Wellness Survey of 37,476 adults demonstrated that less educated, obese,
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and depressed asthmatics experience significantly poorer asthma control.30 Acosta-Perez et al
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examined the effects of obesity and depressive/anxiety disorders co-occurring in a community
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sample of Puerto Rican youth 10 to 19 years of age diagnosed with asthma: depression/anxiety
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was three times more common in the obese, but asthma exacerbations were associated with an
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increased prevalence of psychological comorbidity among the non-obese youth only.31 A recent
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single center Canadian study reported that depression appeared to explain poor asthma control in
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obese asthmatics, this differs from our own findings; these differing results are likely related to
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differences in the two study patient populations (our own being a multi-center study with a
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younger more diverse U.S. patient population).32 Our current study demonstrates a clinically
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meaningful effect of obesity and depression independently contributing to significantly poorer
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asthma control. The presence of depression contributed to poor asthma control in all BMI
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groups. Contrary to our hypothesis, there was no significant interaction between obesity and
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depression, suggesting that the mechanisms linking depression and asthma are the same in lean
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patients as they are in obese patients, though obese patients have a higher prevalence of
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depression. Awareness of the finding that depression contributes to poor asthma control is likely
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critical in the management of both lean and obese patients with asthma.
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This study does have some limitations. The patient population was recruited for a clinical
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trial and so may not reflect the general asthma population, although ethnic and economic
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diversity in the population was strong. This was a cross-sectional study, and so we cannot draw
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any conclusions about the direction of the association between asthma and depression.
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This study shows that depression likely contributes to poor asthma control in obese
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patients, as obese patients have a higher prevalence of depression than lean asthmatics, and
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depression is associated with poor asthma control. However, obesity also contributes to poor
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asthma control independent of depression; understanding poor asthma control in obesity requires
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research into the pathophysiology of airway disease in obesity. This study suggests that
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interventions to address psychological comorbidity should be studied in obese asthmatics, and
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that improving asthma control in obese asthmatics will require a holistic approach to improve
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asthma outcomes.
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Funding: Supported by the American Lung Association, and NIH grants R01HL073494 and P30 RR031158-01
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References
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1. Ronmark E, Andersson C, Nystrom L, Forsberg B, Jarvholm B, Lundback B. Obesity increases the risk of incident asthma among adults. The European respiratory journal 2005; 25(2): 282-8. 2. Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype? Journal of applied physiology 2010; 108(3): 729-34. 3. Dixon AE, Holguin F, Sood A, et al. An official American Thoracic Society Workshop report: obesity and asthma. Proceedings of the American Thoracic Society 2010; 7(5): 325-35. 4. Mosen DM, Schatz M, Magid DJ, Camargo CA, Jr. The relationship between obesity and asthma severity and control in adults. The Journal of allergy and clinical immunology 2008; 122(3): 507-11 e6. 5. Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377(9765): 557-67. 6. Wilson DH, Appleton SL, Taylor AW, et al. Depression and obesity in adults with asthma: multiple comorbidities and management issues. The Medical journal of Australia 2010; 192(7): 381-3. 7. Lavoie KL, Bacon SL, Labrecque M, Cartier A, Ditto B. Higher BMI is associated with worse asthma control and quality of life but not asthma severity. Respiratory medicine 2006; 100(4): 648-57. 8. Cazzola M, Segreti A, Calzetta L, Rogliani P. Comorbidities of asthma: current knowledge and future research needs. Current opinion in pulmonary medicine 2013; 19(1): 36-41. 9. de Wit L, Luppino F, van Straten A, Penninx B, Zitman F, Cuijpers P. Depression and obesity: a meta-analysis of community-based studies. Psychiatry research 2010; 178(2): 230-5. 10. Andersen JR, Aasprang A, Bergsholm P, Sletteskog N, Vage V, Natvig GK. Anxiety and depression in association with morbid obesity: changes with improved physical health after duodenal switch. Health and quality of life outcomes 2010; 8: 52. 11. Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. The Journal of allergy and clinical immunology 2011; 128(3): 508-15 e1-2. 12. Wise RA, Bartlett SJ, Brown ED, et al. Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers. The Journal of allergy and clinical immunology 2009; 124(3): 436-44, 44e1-8. 13. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. The European respiratory journal 1999; 14(4): 902-7. 14. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. The American review of respiratory disease 1993; 147(4): 832-8. 15. Standardization of Spirometry, 1994 Update. American Thoracic Society. American journal of respiratory and critical care medicine 1995; 152(3): 1107-36. 16. Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. American journal of epidemiology 1977; 106(3): 203-14. 17. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1977; 1: 6. 18. Wigal JK, Stout C, Brandon M, et al. The Knowledge, Attitude, and Self-Efficacy Asthma Questionnaire. Chest 1993; 104(4): 1144-8. 19. Grammer LC, Weiss KB, Pedicano JB, et al. Obesity and asthma morbidity in a community-based adult cohort in a large urban area: the Chicago Initiative to Raise Asthma Health Equity (CHIRAH). The Journal of asthma : official journal of the Association for the Care of Asthma 2010; 47(5): 491-5.
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20. Dixon AE, Clerisme-Beaty EM, Sugar EA, et al. Effects of obstructive sleep apnea and gastroesophageal reflux disease on asthma control in obesity. The Journal of asthma : official journal of the Association for the Care of Asthma 2011; 48(7): 707-13. 21. Thomas M, Bruton A, Moffat M, Cleland J. Asthma and psychological dysfunction. Primary care respiratory journal : journal of the General Practice Airways Group 2011; 20(3): 250-6. 22. Wong KO, Hunter Rowe B, Douwes J, Senthilselvan A. Asthma and wheezing are associated with depression and anxiety in adults: an analysis from 54 countries. Pulmonary medicine 2013; 2013: 929028. 23. Brunner WM, Schreiner PJ, Sood A, Jacobs DR, Jr. Depression and Risk of Incident Asthma in Adults. The CARDIA Study. American journal of respiratory and critical care medicine 2014; 189(9): 104451. 24. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respiratory medicine 2005; 99(10): 1249-57. 25. Richardson LP, Russo JE, Lozano P, McCauley E, Katon W. The effect of comorbid anxiety and depressive disorders on health care utilization and costs among adolescents with asthma. General hospital psychiatry 2008; 30(5): 398-406. 26. Miller BD, Wood BL. Influence of specific emotional states on autonomic reactivity and pulmonary function in asthmatic children. Journal of the American Academy of Child and Adolescent Psychiatry 1997; 36(5): 669-77. 27. Nadel JA, Barnes PJ. Autonomic regulation of the airways. Annual review of medicine 1984; 35: 451-67. 28. Dockray S, Susman EJ, Dorn LD. Depression, cortisol reactivity, and obesity in childhood and adolescence. The Journal of adolescent health : official publication of the Society for Adolescent Medicine 2009; 45(4): 344-50. 29. Faith MS, Butryn M, Wadden TA, Fabricatore A, Nguyen AM, Heymsfield SB. Evidence for prospective associations among depression and obesity in population-based studies. Obesity reviews : an official journal of the International Association for the Study of Obesity 2011; 12(5): e438-53. 30. Demoly P, Paggiaro P, Plaza V, et al. Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK. European respiratory review : an official journal of the European Respiratory Society 2009; 18(112): 105-12. 31. Acosta-Perez E, Canino G, Ramirez R, Prelip M, Martin M, Ortega AN. Do Puerto Rican youth with asthma and obesity have higher odds for mental health disorders? Psychosomatics 2012; 53(2): 162-71. 32. Boudreau M, Bacon SL, Ouellet K, Jacob A, Lavoie KL. Mediator effect of depressive symptoms on the association between body mass index and asthma control in adult asthmatics. Chest 2014 (in press).
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Table 1: Baseline characteristics of participants Lean
Overweight
Obese
205 (34%)
164 (27%)
232 (39%)
32.4±13.3
40.5±14.9*
41.1±12.6*
<0.0001
22.3 (20.9-23.7)
27.2 (26.0 – 28.3)
35.0 (32.6-41.1)
< 0.001
140 (68)
106 (63)
191 (82)
White
144 (69)
104 (64)
114 (49)
Black
45 (22)
54 (32)
102 (44)
Hispanic
6 (3)
1 (1)
1 (0)
Other
10 (6)
5 (3)
n (%)
p value
Age (years) 2
BMI (kg/m ) Women
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Demographic characteristics
Highest level of Education (%) 19 (9)
High school
20 (10)
Some college
81 (39)
Bachelor’s degree
48 (23)
Some post-graduate
15 (7)
Post-graduate degree
22(11)
Employment status (%) 64 (30)
Student
16 (8)
Full time Part time Retired Disabled Household Income (%) < $20,000
45 (20)
62 (37)
117(50)
38 (23)
27 (12)
10 (6)
11 (5)
21 (13)
13 (6)
19 (12)
16 (7)
15 (9)
30 (13)
94 (57)
114 (49)
25 (12)
16 (9)
29 (13)
6 (3)
12 (7)
12(5)
3 (1)
3 (2)
19 (8)
5 (2)
5 (3)
12 (5)
48 (23)
21 (13)
59 (25)
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Other
19(8)
22 (13)
86 (42)
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Not working
11 (7)
57 (28)
52 (31)
74 (32)
$50,000 - $75,000
24 (12)
21 (13)
23 (10)
> $75,000
23 (11)
23 (14)
20 (9)
Declined to answer
37 (18)
36 (22)
42 (18)
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$20,000 - $50,000
<0.001
15 (7)
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Race or ethnic group (%)
<0.001
<0.001
0.22
16 (8) 11 (7) 14 (6) Don't know Values shown are mean ± SD or median (IQR) for continuous variables, and n (%) for proportions. P values shown are for analysis of variance for continuous variables, and χ2 test for proportions. *P < 0.05 compared with lean group
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Table 2: Asthma characteristics & pulmonary function Lean Age asthma onset (years)
Overweight 3
Obese
p value 3
14.9±16.7
21.7±22.7
3.6±2.8
4.1±3.0
4.0±3.1
0.8 0.09
Pack years
22.1±20.8
0.0001
5.21±1.08
5.08±1.05
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Number of Courses of Prednisone use in last 12 months (n{%})
404.2±96.1
398.6±95.1
385.9±93.4
0.12
84.6±13.4
3
0.01
91.8±13.0
3
<0.0001
0
177 (78)
146 (77)
183 (69)
1
32 (14)
28 (15)
≥2
17 (8)
15 (8)
1.43±0.68
1.52±0.71
45 (17)
36 (14)
ACQ (↓ score range, 0-6)1 AQLQ (↑ score range, 1-7)
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Pulmonary function measures, mean ± SD PEF (L/min)
88.4±13.5
2
85.6±13.2
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FEV1 (% predicted pre BD)
2
1.76±0.753,4
<0.0001
3,4
<0.0001
4.64±1.09
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Asthma questionnaires , mean ± SD
3
97.7±13.0
94.4±12.8
FEV1/FVC (pre BD)
75.6±9.2
74.3±9.1
75.7±7.6
0.16
FEV1 % change after BD
8.9±10.2
9.9±10.9
8.8±13.0
0.63
3
3
FVC (% predicted pre BD)
2.5±6.1
FVC % change after BD
4.5±9.1
4.5±11.1
Values shown are mean and SD, and are compared by analysis of variance and n (%) for proportions
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ACQ, Asthma Control Questionnaire AQLQ, Asthma Quality of Life Questionnaire PEF, morning peak expiratory flow
FEV1, forced expiratory volume in 1 second
BD, bronchodilator
↓, Lower score is better; ↑Higher score is better
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FVC, forced vital capacity
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Predicted values for FEV1 and FVC are taken from Hankinson et al.32
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p< 0.05 compared with lean group
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p < 0.01 compared with overweight group
< 0.001
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Table 3 Measures of psychological morbidity Lean
Overweight
Obese
p value
8 (4-24)
8 (4-24.5)
10 (5-16)
0.03
CES-D no depression
163 (80)
129 (79)
CES-D mild symptoms
26 (13)
25 (15)
CES-D probable depression
16 (7)
10 (6)
Self-efficacy
82.4±8.4
82.8±9.2
79.8±9.33,4
0.001
Attitude
85.4±7.2
85.5±7.6
85.3±6.4
0.96
12.0±2.8
3
3
1
CES-D level of depression 2 n (%)
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↓, Lower score is better
2
11.1±2.9
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Knowledge
169 (73) 37 (16)
11.0±3.0
CES-D, Center for Epidemiologic Studies Depression Scale, threshold for mild depressive symptoms ≥
16, probable depression ≥ 23.
KASE-AQ, Knowledge, Attitude, and Self-Efficacy Asthma Questionnaire ↑, Higher score is better
3
p< 0.05 compared to lean group
4
p < 0.05 compared to overweight group
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0.01
26 (11)
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KASE-AQ (1↑ score range, 5-100) mean ± SD
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CES-D ( ↓ score range, 0-60) median (IQR)
0.0005
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Table 4: Risk of Poor Asthma Control in those with Obesity and/or Depression CI
Obesity 1
2.06
1.48-2.88
Depression1
2.44
1.65-3.63
Obesity2
1.83
Depression2
2.08
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Odds Ratio
1.23-3.52
1.23-3.52
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Poor Asthma control was defined as a score of ≥ 1.5 on the Juniper Asthma Control questionnaire Uni-variate analysis for depression (using threshold of CES-D ≥ C16) and obesity separately.
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multivariate analysis combining depression and obesity in the same model, which also includes age, sex,
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race, education, employment, and income an interaction value for presence of obesity and depression (p =
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Table 5: Asthma control in relation to symptoms of depression in participants of differing BMI groups
No Depression
Mild Depression
Probable depression
p
1.36 ± 0.67
1.58 ± 0.56
1.89 ± 0.721
<0.01
Asthma Control
1.46 ± 0.66
1.62 ± 0.66
1.97± 1.21
Asthma Control
1.67 ± 0.74
2.05 ± 0.651
Asthma Control
Obese
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Values shown are mean ± SD from ACQ, Asthma Control Questionnaire
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Overweight
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Lean
1.96 ± 0.77
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Mild depression was defined using a threshold of CES-D ≥ 16, probable depression as CES-D ≥ 23 1 p < 0.05 compared with lean group
0.07
0.01
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Conflicts of Interest • Sonam Kapadia: has no conflicts of interest pertaining to this manuscript • Christine Wei: has no conflicts of interest pertaining to this manuscript • Susan Bartlett: has no conflicts of interest pertaining to this manuscript • Jason Lang: has no conflicts of interest pertaining to this manuscript • Robert Wise: has no conflicts of interest pertaining to this manuscript • Anne Dixon: has no conflicts of interest pertaining to this manuscript
S0954-6111(14)00199-1
DOI:
10.1016/j.rmed.2014.05.012
Reference:
YRMED 4517
To appear in:
Respiratory Medicine
Received Date: 4 December 2013 Revised Date:
23 May 2014
Accepted Date: 26 May 2014
Please cite this article as: Kapadia S, Wei C, Bartlett S, Lang J, Wise R, Dixon A, Obesity and symptoms of depression contribute independently to the poor asthma control of obesity, Respiratory Medicine (2014), doi: 10.1016/j.rmed.2014.05.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Obesity and symptoms of depression contribute independently to the poor asthma control of obesity.
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University of Vermont College of Medicine, Burlington, Vermont Johns Hopkins University, Baltimore, MD 3 McGill University, Montreal, Canada 4 Nemours Children’s Hospital, Orlando, FL 2
Department of Medicine, University of Vermont and Fletcher Allen Health Care
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Given D209
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89 Beaumont Avenue,
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Burlington, VT 05405
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Corresponding Author: [email protected] Phone: (802) 656-8812 Fax: (802) 656-3526
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Keywords: obesity; asthma; depression
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Kapadia SG,1 Wei C,2 Bartlett SJ,3 Lang J, 4 Wise RA,2 MD & AE Dixon1 for the American Lung Association Asthma Clinical Research Centers5
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Credit Roster: American Lung Association Asthma Clinical Research Centers
The following persons participated in the TAPE study
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Baylor College of Medicine, Houston: N. A. Hanania (principal investigator), M. Sockrider (co-principal investigator), L. Giraldo (principal clinic coordinator), R. Valdez (coordinator);
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Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla, N.Y.: A. Dozor (principal investigator), N. Amin and Y. C. Kim (co-principal investigator), I. Gherson (principal clinic coordinator), M. Heydendael and M. Key (coordinators);
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Columbia University–New York University Consortium, New York: J. Reibman (principal investigator), E. DiMango (co-principal investigator), W. Hoerning (clinic coordinator at New York University), J. Sormillon (clinic coordinator at Columbia University); Duke University Medical Center, Durham, N.C.: L. Williams (principal investigator), J. Sundy (co-principal investigator), G. Dudek (principal clinic coordinator), R. Newton (coordinator);
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Emory University School of Medicine, Atlanta: W.G. Teague (principal investigator), S. Khatri (co-principal investigator), J. Costolnick, (principal clinic coordinator), J. Peabody, R. Patel, E Hunter (coordinators); Illinois Consortium, Chicago: L. Smith (principal investigator), J. Moy, E Naureckas, C.S. Olopade (co-principal investigators), J. Hixon (principal clinic coordinator), A. Brees, G. Rivera, S. Sietsema, V. Zagaja (coordinators);
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Indiana University, Asthma Clinical Research Center, Indianapolis: M. Busk (principal investigator), F. Leickly, C. Williams (co-principal investigators), S. Lynch (principal clinic coordinator); P. Puntenney (coordinator); Jefferson Medical College, Philadelphia: F. Leone (principal investigator), M. HayesHampton (principal clinic coordinator);
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Louisiana State University Health Sciences Center, Ernest N. Morial Asthma, Allergy, and Respiratory Disease Center, New Orleans: W.R. Summer (principal investigator), C. Glynn (principal clinic coordinator); National Jewish Medical and Research Center, Denver: S. Wenzel (principal investigator), P Silkoff (co-principal investigator), R. Gibbs (principal clinic coordinator), L. Lopez, C. Ruis, B. Schoen (coordinators); Nemours Children’s Clinic–University of Florida Consortium, Jacksonville: J. Lima 2
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(principal investigator), K. Blake (co-principal investigator), A. Santos (principal clinic coordinator), L. Duckworth, D. Schaeffer (coordinators); North Shore–Long Island Jewish Health System, New Hyde Park, 485 N.Y.: J. Karpel (principal investigator), R. Cohen (co-principal investigator), R. Ramdeo (principal clinic coordinator);
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Northern New England Consortium formerly Vermont Lung Center at the University of Vermont), Colchester, Vt.: C.G. Irvin (principal investigator), A.E. Dixon, D.A. Kaminsky, E. Kent, T. Lahiri, P. Shapiro (co-principal investigators), S. Lang (principal clinic coordinator), J. Allen, A. Coote, L.M. Doucette, K. Girard, J. Lynn, L. Moon, T. Viola (coordinators);
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The Ohio State University Medical Center/Columbus Children’s Hospital, Columbus: J. Mastronarde (principal investigator), K. McCoy (co-principal investigator), J. Drake (principal clinic coordinator), R. Compton, L. Raterman (coordinators);
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University of Alabama at Birmingham, Birmingham: L.B. Gerald (principal investigator), W.C. Bailey (co-principal investigator), S. Erwin (principal clinic coordinator), H. Young, A. Kelley, D. Laken, B. Martin (coordinators); University of Miami, Miami–University of South Florida, Tampa: A. Wanner (principal investigator), R. Lockey (principal investigator), E. Mendes (principal clinic coordinator for University of Miami), M. Grandstaff (principal clinic coordinator for University of South Florida), B Fimbel (coordinator);
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University of Minnesota, Minneapolis: M.N. Blumenthal (508 principal investigator), G. Brottman, J. Hagen (co-principal investigators), A. Decker, D. Lascewski, S. Kelleher (principal clinic coordinators), K. Bachman, M. Sneen (coordinators);
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University of Missouri, Kansas City School of Medicine, Kansas City: G. Salzman (principal investigator), D. Pyszczynski (co-principal investigator), P. Haney (principal clinic coordinator); St. Louis Asthma Clinical Research Center: Washington University, St. Louis University, and Clinical Research Center, St. Louis: M. Castro (principal investigator), L. Bacharier, K. Sumino (co-investigators), M.E. Scheipeter (principal clinic coordinator), J. Tarsi (coordinator);
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University of California San Diego: S Wasserman (principal investigator), J Ramsdell (co-principal investigator) Chairman’s Office, Respiratory Hospital, Winnipeg, Man., Canada: N. Anthonisen (research group chair); Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore: R. Wise (center director), J. Holbrook (deputy director), E. Brown (principal 3
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coordinator), M. Dale, M. Daniel, G. Leatherman, C. Levine, J. Jones, R. Masih, S Modak, D. Nowakowski, N. Prusakowski, D. Shade, E. Sugar;
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Data and Safety Monitoring Board: L. Hudson (chair), V. Chinchilli, P. Lanken, B. McWilliams, C. Rinaldo, D. Tashkin;
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Abstract
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control in this patient population are unclear. Symptoms of depression have been associated with
5
poor asthma control, and increase with higher body mass index (BMI). The purpose of this study
6
was to assess whether depressive symptoms underlie poor asthma control in obesity.
7
Methods: We determined the relationship between BMI, psychological morbidity and asthma
8
control at baseline in a well-characterized patient population participating in a clinical trial
9
conducted by the American Lung Association-Asthma Clinical Research Centers.
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Obesity is a major risk factor for poorly controlled asthma, but the reasons for poor asthma
Results: Obese asthmatic participants had increased symptoms of depression (Center for
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Epidemiologic Studies Depression Scale score in lean 10·1±8·1, overweight 10·0±8·1, obese
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12·4±9·9; p=0·03), worse asthma control (Juniper Asthma Control Questionnaire score in lean
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1·43±0·68, overweight 1·52±0·71, obese 1·76±0·75; p<0·0001), and worse asthma quality of life
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(scores in lean 5·21±1·08, overweight 5·08±1·05, obese 4·64±1·09; p<0·0001). Asthmatics with
15
obesity and those with symptoms of depression both had a higher risk of having poorly
16
controlled asthma (adjusted odds ratio of 1·83 CI 1·23-3·52 for obesity, and 2·08 CI 1·23-3·52 for
17
depression), but there was no interaction between the two.
18
Conclusion: Obesity and symptoms of depression are independently associated with poor asthma
19
control. As depression is increased in obese asthmatics it may be an important co-morbidity
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contributing to poor asthma control in this population, but factors other than depression also
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contribute to poor asthma control in obesity.
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Introduction
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asthma control.1, 2 Depression and anxiety are likewise associated with poor asthma control, and
5
the prevalence of depression and anxiety are dramatically increased in obesity. The underlying
6
interaction between obesity, depression, and asthma is not well understood, yet may have critical
7
implications for asthma control in the setting of obesity.
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Obesity is a significant risk factor for developing asthma and is associated with poor
Obesity is associated with decreased responsiveness to controller medication and poor
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asthma control.3 One study found that obese asthmatics are hospitalized at nearly five times the
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rate of lean asthmatics.4 Given the ever increasing prevalence of obesity,5 obesity is contributing
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to an epidemic of poorly controlled asthma.
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A number of studies suggest that anxiety and depression adversely affect asthma
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symptom severity and there is a significant correlation between severity of depressive symptoms
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and poor asthma control.6, 7 Depressed asthmatics also have an increased risk of asthma-related
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emergency department visits and poor adherence to asthma medication regimens.8
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Depression is a very common comorbidity associated with obesity.9 The strong
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association between high BMI and depressive symptoms is more pronounced in women, the
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demographic group with the highest rate of asthma related to obesity.3 This relationship is
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reversible as weight reduction surgery significantly reduces symptoms of anxiety and depression
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among obese asthmatics,10 this surgery also improves asthma control.11
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Considering that
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depression is increased in obesity, such psychological comorbidity may contribute significantly
2
to the poor asthma control characteristic of obese asthmatics.
3
The purpose of this study was first to determine if depression and obesity were associated
5
with poor asthma control, and then to determine if depression could explain poor asthma control
6
in obesity. We evaluated the relationship of both markers of depression and measures of asthma
7
control with obesity, hypothesizing that a significant interaction between obesity and depression
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would contribute to worse asthma control among obese asthmatics. This study was completed in
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a well characterized, patient population participating in a clinical trial of the placebo response in
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asthma.
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Methods
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multicenter clinical trial designed to assess the placebo effect in asthma performed by the
5
American Lung Association Asthma Clinical Research Centers. Details of the main study and
6
eligibility criteria have been published elsewhere, and are summarized below.12 The study was
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approved by the Institutional Review Boards at all participating centers, and all participants
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signed informed consent.
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Data on obesity and symptoms of depression were derived from participants in a
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Males and females at least 15 years of age who had been diagnosed with asthma by a
11
physician, regularly used any prescribed asthma medication in the last 12 months, and had a
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post-bronchodilator forced expiratory volume (FEV1) ≥ 75% predicted were included in the trial.
13
Participants had inadequate control of asthma symptoms indicated by one of the following:
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short-acting β2 agonist use two or more times per week for relief of asthma symptoms, nocturnal
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awakenings once or more per week due to asthma symptoms, or a Juniper Asthma Control
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Questionnaire (ACQ) score of ≥ 1·5 at their enrollment visit.
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Participants were excluded if they had a significant smoking history (≥ 10 pack years or
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active smoking in the past 6 months), or had used montelukast or other leukotriene antagonists
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within the past 14 days. Participants were also excluded if they reported a history of
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hospitalization, emergency department visits, or prednisone use for asthma within the past 3
22
months, past respiratory failure secondary to asthma, or prior adverse reaction to montelukast. At
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baseline, participants were extensively evaluated for their asthma characteristics with the Juniper
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Asthma Control Questionnaire,13 and the Juniper Asthma Quality of Life Questionnaire.14
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Spirometry was performed according to ATS guidelines.15
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measured by the Center for Epidemiological Studies Depression Score (CES-D).16,
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Participants’ asthma knowledge and sense of asthma self-efficacy were measured by the
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Knowledge, Attitude, and Self-efficacy Asthma Questionnaire (KASE-AQ).18
Symptoms of depression were
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Statistical Approach
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Descriptive statistics were used to summarize baseline characteristics of the study subjects, divided into three categories according to body mass index (BMI): lean (BMI 18·5-24·9
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kg/m2), overweight (BMI 25-29·9 kg/m2), and obese (BMI ≥ 30 kg/m2). Continuous variables
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were compared using analysis of variance, with log transformations for non-parametric variables,
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and proportions were compared using χ2 analysis. Post-hoc comparison of groups was performed
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using the Bonferroni procedure.
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We determined the risk of poor asthma control associated with obesity (defined as a BMI
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≥ 30) compared to non-obese (defined as those with a BMI < 30) and depression (defined as a
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CES-D score ≥ 16 compared to those with a score < 16). We performed multiple logistic
19
regression including sex, age, race, education, income and employment status in the final model.
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We evaluated the relationship between asthma control and symptoms of depression, using an
21
interaction term for obesity (BMI > 30 kg/m2) and significant symptoms of depression (defined
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as a CES-D score ≥ 16). Analyses were performed with STATA 10·0 (College Station, Texas).
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Role of Funding Source
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The study sponsors had no role in study design, data collection, data analysis, data interpretation
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or decision to submit manuscript. The corresponding author had full access to all the data, and
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the final responsibility for the decision to submit for publication.
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Results
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demographic characteristics are summarized in Table 1. The mean age of participants was 32
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years in the lean group, overweight and obese asthmatic participants were significantly older.
8
Most participants were female, constituting nearly 82% of the obese group. There was a higher
9
proportion of African American participants in the obese category. Obese asthmatics reported
10
completing less education than leaner participants, though there was no overall difference in
11
reported income. Employment status differed among the BMI categories, with a higher
12
proportion of students in the lean category.
Participant characteristics
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A total of 601 unique participants were enrolled in the primary study. Participant
14 15 16
Asthma characteristics
17
and overweight asthmatics reported significantly later-onset asthma than lean asthmatics. Obese
18
asthmatics tended to report more frequent use of oral prednisone for asthma. Obese participants
19
had worse asthma control as assessed by the Juniper Asthma Control Questionnaire (ACQ) and
20
worse asthma-related quality of life as assessed by the Asthma Quality of Life Questionnaire
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(AQLQ) compared with both lean and overweight asthmatics.
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Data on asthma characteristics in the distinct BMI groups are reported in Table 2. Obese
23
Data on pulmonary function are also provided in Table 2, and differed among
24
participants. Obese asthmatics had significantly lower FEV1 and FVC than lean asthmatics, and
25
obese and overweight asthmatics had greater change in FVC in response to bronchodilator than
26
lean asthmatics.
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1 2 3
Psychological morbidity
4
Epidemiologic Studies Depression Scale (CES-D) and more frequently surpassed the reported
5
thresholds for mild depressive symptoms (a score of 16 and above)
6
depression (a score of 23 and above) (Table 3).17 Obese asthmatics also reported significantly
7
lower self-efficacy related to asthma compared with lean and obese asthmatics, and both obese
8
and overweight asthmatics had lower asthma knowledge, as assessed by the Knowledge,
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Attitude, and Self-Efficacy Asthma Questionnaire (KASE-AQ).
Obese asthmatics had higher depression scores as assessed by the Center for
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as well as probable
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Combined effect of depression and obesity
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controlled asthma, as defined by a score of 1·5 or greater on the Juniper Asthma Control Score
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(311 out of 605 participants had a score of 1·5 or greater when depression symptoms were
16
assessed at the second study visit) (Table 4).
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When both obesity and depression were considered in the same model, there was little
18
change in the odds of having poorly controlled asthma, and the interaction between obesity and
19
asthma was not significant (p = 0·58), suggesting that obesity and depression contribute
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independently to poor asthma control. Depressed patients had worse asthma control in all BMI
21
groups, suggesting that the contribution of depression to poor asthma control was not unique to
22
obesity (Table 5).
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Discussion
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specific quality of life, and suffer a greater burden of symptoms of depression than leaner
5
asthmatics. Obesity and symptoms of depression are both independently related to poor asthma
6
control, without a significant interaction between the two comorbidities. This suggests that
7
depression should be considered in managing obese patients with poor asthma control as the
8
prevalence of depression increases with BMI, but that poor asthma control in obesity is also
9
related to factors other than depression. This study has important clinical implications with
10
regard to understanding the physical and mental underpinnings of poor asthma control among
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obese asthmatics.
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This study demonstrates that obese asthmatics have poor asthma control, worse asthma-
12
The present study provides further evidence of the relationship between obesity and poor
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asthma control as well as worse asthma-related quality of life. Obesity is not only a risk factor
15
for incident asthma, but is also associated with worse control characterized by increased
16
symptoms, more frequent use of rescue bronchodilator medications, increased risk of
17
hospitalizations for asthma, and missed work days.2, 7, 19 Obesity is a significant cause of poorly
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controlled asthma due to many factors such as altered lung mechanics, altered responses to
19
medications, elevated airway oxidative stress, effects of adipokines and cytokines, and other co-
20
morbidities which occur in obesity such depression and obstructive sleep apnea.3 We have
21
previously reported that symptoms of obstructive sleep apnea are associated with worse asthma
22
control,20 but few studies have investigated the role of psychological morbidity in the poor
23
asthma control of obesity.
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Asthmatics are more likely to suffer from anxiety and depression than the general
2
population, irrespective of BMI.21 Data from the 2002 World Health Survey collected by the
3
World Health Organization across 54 countries suggested that depression was significantly
4
associated with asthma in 65% of countries.22 There may be a causal link between depression
5
and asthma; in a longitudinal 20 year follow up CARDIA study by Brunner et al, elevated
6
depressive symptoms were associated with a 1.26 increased risk of developing incident asthma
7
(independent of BMI).23 Depression in asthmatics has been associated with poor asthma
8
control,21, 24 with one study reporting that comorbid depression was associated with greater health
9
care utilization and 51% higher health care costs.25 Depression may contribute to poor asthma
10
control through a number of pathways. Asthmatics with psychological comorbidity may perceive
11
a greater intensity of breathlessness.21 Asthmatics with depressive symptoms may also develop
12
cholinergic-mediated airway constriction in the event of psychological stress.26,
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may also affect medication adherence: high levels of depressive symptoms are associated with an
14
11-fold increase in odds of poor adherence (measured electronically) to inhaled corticosteroid
15
therapy after hospitalization for an asthma exacerbation.27 It is also possible that poor asthma
16
control contributes to the development of depression. In the current study we found that over
17
20% of the study population reached the threshold for mild depression on the validated CES-D
18
questionnaire, which is in line with previous reports on the prevalence of depression in asthma.8,6
19
Asthmatic participants with symptoms of depression were approximately twice as likely to have
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poor asthma control as those without symptoms of depression. Our data provide further evidence
21
that symptoms of depression are associated with poor asthma control and worse asthma quality
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of life.
27
Depression
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Many studies suggest there is a significant relationship between depression and obesity.
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Meta-analyses of cohort studies suggest a significant association between obesity and
3
depression;9,
4
participants reported a significant association between depression and obesity, particularly
5
among females (OR, 1·26; 95% CI, 1·17-1·36).9 Our current study demonstrates that obese
6
asthmatics had significantly higher scores on the CES-D questionnaire and a higher prevalence
7
of depression. Many factors may contribute to the increased risk of depression with obesity.
8
Obesity and depression share common risk factors such as low socioeconomic status and
9
insufficient physical activity.29 Psychological distress may be worsened by obesity because of
10
social stigmatization which produces low self-worth and self-esteem, a negative body image,
11
guilt, and peer isolation.9,
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psychological distress elevates circulating cortisol levels which may contribute to abdominal
13
obesity. Depression and obesity likely share common risk factors and may in part share a
14
common pathophysiology, whether these factors interact with each other to produce the worse
15
asthma control characteristic of obesity is not known.
one meta-analysis of 17 community based studies encompassing 204,507
29
Hypothalamic-pituitary-adrenal axis dysfunction from
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A few studies have addressed the potential for a concurrent interaction between obesity
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and depression in mediating poor asthma outcomes. Data collected from the 2006 European
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National Health and Wellness Survey of 37,476 adults demonstrated that less educated, obese,
20
and depressed asthmatics experience significantly poorer asthma control.30 Acosta-Perez et al
21
examined the effects of obesity and depressive/anxiety disorders co-occurring in a community
22
sample of Puerto Rican youth 10 to 19 years of age diagnosed with asthma: depression/anxiety
23
was three times more common in the obese, but asthma exacerbations were associated with an
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increased prevalence of psychological comorbidity among the non-obese youth only.31 A recent
2
single center Canadian study reported that depression appeared to explain poor asthma control in
3
obese asthmatics, this differs from our own findings; these differing results are likely related to
4
differences in the two study patient populations (our own being a multi-center study with a
5
younger more diverse U.S. patient population).32 Our current study demonstrates a clinically
6
meaningful effect of obesity and depression independently contributing to significantly poorer
7
asthma control. The presence of depression contributed to poor asthma control in all BMI
8
groups. Contrary to our hypothesis, there was no significant interaction between obesity and
9
depression, suggesting that the mechanisms linking depression and asthma are the same in lean
10
patients as they are in obese patients, though obese patients have a higher prevalence of
11
depression. Awareness of the finding that depression contributes to poor asthma control is likely
12
critical in the management of both lean and obese patients with asthma.
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This study does have some limitations. The patient population was recruited for a clinical
14
trial and so may not reflect the general asthma population, although ethnic and economic
15
diversity in the population was strong. This was a cross-sectional study, and so we cannot draw
16
any conclusions about the direction of the association between asthma and depression.
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This study shows that depression likely contributes to poor asthma control in obese
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patients, as obese patients have a higher prevalence of depression than lean asthmatics, and
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depression is associated with poor asthma control. However, obesity also contributes to poor
20
asthma control independent of depression; understanding poor asthma control in obesity requires
21
research into the pathophysiology of airway disease in obesity. This study suggests that
22
interventions to address psychological comorbidity should be studied in obese asthmatics, and
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that improving asthma control in obese asthmatics will require a holistic approach to improve
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asthma outcomes.
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Funding: Supported by the American Lung Association, and NIH grants R01HL073494 and P30 RR031158-01
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References
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1. Ronmark E, Andersson C, Nystrom L, Forsberg B, Jarvholm B, Lundback B. Obesity increases the risk of incident asthma among adults. The European respiratory journal 2005; 25(2): 282-8. 2. Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype? Journal of applied physiology 2010; 108(3): 729-34. 3. Dixon AE, Holguin F, Sood A, et al. An official American Thoracic Society Workshop report: obesity and asthma. Proceedings of the American Thoracic Society 2010; 7(5): 325-35. 4. Mosen DM, Schatz M, Magid DJ, Camargo CA, Jr. The relationship between obesity and asthma severity and control in adults. The Journal of allergy and clinical immunology 2008; 122(3): 507-11 e6. 5. Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377(9765): 557-67. 6. Wilson DH, Appleton SL, Taylor AW, et al. Depression and obesity in adults with asthma: multiple comorbidities and management issues. The Medical journal of Australia 2010; 192(7): 381-3. 7. Lavoie KL, Bacon SL, Labrecque M, Cartier A, Ditto B. Higher BMI is associated with worse asthma control and quality of life but not asthma severity. Respiratory medicine 2006; 100(4): 648-57. 8. Cazzola M, Segreti A, Calzetta L, Rogliani P. Comorbidities of asthma: current knowledge and future research needs. Current opinion in pulmonary medicine 2013; 19(1): 36-41. 9. de Wit L, Luppino F, van Straten A, Penninx B, Zitman F, Cuijpers P. Depression and obesity: a meta-analysis of community-based studies. Psychiatry research 2010; 178(2): 230-5. 10. Andersen JR, Aasprang A, Bergsholm P, Sletteskog N, Vage V, Natvig GK. Anxiety and depression in association with morbid obesity: changes with improved physical health after duodenal switch. Health and quality of life outcomes 2010; 8: 52. 11. Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. The Journal of allergy and clinical immunology 2011; 128(3): 508-15 e1-2. 12. Wise RA, Bartlett SJ, Brown ED, et al. Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers. The Journal of allergy and clinical immunology 2009; 124(3): 436-44, 44e1-8. 13. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. The European respiratory journal 1999; 14(4): 902-7. 14. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. The American review of respiratory disease 1993; 147(4): 832-8. 15. Standardization of Spirometry, 1994 Update. American Thoracic Society. American journal of respiratory and critical care medicine 1995; 152(3): 1107-36. 16. Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. American journal of epidemiology 1977; 106(3): 203-14. 17. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1977; 1: 6. 18. Wigal JK, Stout C, Brandon M, et al. The Knowledge, Attitude, and Self-Efficacy Asthma Questionnaire. Chest 1993; 104(4): 1144-8. 19. Grammer LC, Weiss KB, Pedicano JB, et al. Obesity and asthma morbidity in a community-based adult cohort in a large urban area: the Chicago Initiative to Raise Asthma Health Equity (CHIRAH). The Journal of asthma : official journal of the Association for the Care of Asthma 2010; 47(5): 491-5.
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20. Dixon AE, Clerisme-Beaty EM, Sugar EA, et al. Effects of obstructive sleep apnea and gastroesophageal reflux disease on asthma control in obesity. The Journal of asthma : official journal of the Association for the Care of Asthma 2011; 48(7): 707-13. 21. Thomas M, Bruton A, Moffat M, Cleland J. Asthma and psychological dysfunction. Primary care respiratory journal : journal of the General Practice Airways Group 2011; 20(3): 250-6. 22. Wong KO, Hunter Rowe B, Douwes J, Senthilselvan A. Asthma and wheezing are associated with depression and anxiety in adults: an analysis from 54 countries. Pulmonary medicine 2013; 2013: 929028. 23. Brunner WM, Schreiner PJ, Sood A, Jacobs DR, Jr. Depression and Risk of Incident Asthma in Adults. The CARDIA Study. American journal of respiratory and critical care medicine 2014; 189(9): 104451. 24. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respiratory medicine 2005; 99(10): 1249-57. 25. Richardson LP, Russo JE, Lozano P, McCauley E, Katon W. The effect of comorbid anxiety and depressive disorders on health care utilization and costs among adolescents with asthma. General hospital psychiatry 2008; 30(5): 398-406. 26. Miller BD, Wood BL. Influence of specific emotional states on autonomic reactivity and pulmonary function in asthmatic children. Journal of the American Academy of Child and Adolescent Psychiatry 1997; 36(5): 669-77. 27. Nadel JA, Barnes PJ. Autonomic regulation of the airways. Annual review of medicine 1984; 35: 451-67. 28. Dockray S, Susman EJ, Dorn LD. Depression, cortisol reactivity, and obesity in childhood and adolescence. The Journal of adolescent health : official publication of the Society for Adolescent Medicine 2009; 45(4): 344-50. 29. Faith MS, Butryn M, Wadden TA, Fabricatore A, Nguyen AM, Heymsfield SB. Evidence for prospective associations among depression and obesity in population-based studies. Obesity reviews : an official journal of the International Association for the Study of Obesity 2011; 12(5): e438-53. 30. Demoly P, Paggiaro P, Plaza V, et al. Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK. European respiratory review : an official journal of the European Respiratory Society 2009; 18(112): 105-12. 31. Acosta-Perez E, Canino G, Ramirez R, Prelip M, Martin M, Ortega AN. Do Puerto Rican youth with asthma and obesity have higher odds for mental health disorders? Psychosomatics 2012; 53(2): 162-71. 32. Boudreau M, Bacon SL, Ouellet K, Jacob A, Lavoie KL. Mediator effect of depressive symptoms on the association between body mass index and asthma control in adult asthmatics. Chest 2014 (in press).
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Table 1: Baseline characteristics of participants Lean
Overweight
Obese
205 (34%)
164 (27%)
232 (39%)
32.4±13.3
40.5±14.9*
41.1±12.6*
<0.0001
22.3 (20.9-23.7)
27.2 (26.0 – 28.3)
35.0 (32.6-41.1)
< 0.001
140 (68)
106 (63)
191 (82)
White
144 (69)
104 (64)
114 (49)
Black
45 (22)
54 (32)
102 (44)
Hispanic
6 (3)
1 (1)
1 (0)
Other
10 (6)
5 (3)
n (%)
p value
Age (years) 2
BMI (kg/m ) Women
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Demographic characteristics
Highest level of Education (%) 19 (9)
High school
20 (10)
Some college
81 (39)
Bachelor’s degree
48 (23)
Some post-graduate
15 (7)
Post-graduate degree
22(11)
Employment status (%) 64 (30)
Student
16 (8)
Full time Part time Retired Disabled Household Income (%) < $20,000
45 (20)
62 (37)
117(50)
38 (23)
27 (12)
10 (6)
11 (5)
21 (13)
13 (6)
19 (12)
16 (7)
15 (9)
30 (13)
94 (57)
114 (49)
25 (12)
16 (9)
29 (13)
6 (3)
12 (7)
12(5)
3 (1)
3 (2)
19 (8)
5 (2)
5 (3)
12 (5)
48 (23)
21 (13)
59 (25)
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19(8)
22 (13)
86 (42)
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Not working
11 (7)
57 (28)
52 (31)
74 (32)
$50,000 - $75,000
24 (12)
21 (13)
23 (10)
> $75,000
23 (11)
23 (14)
20 (9)
Declined to answer
37 (18)
36 (22)
42 (18)
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<0.001
15 (7)
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<0.001
<0.001
0.22
16 (8) 11 (7) 14 (6) Don't know Values shown are mean ± SD or median (IQR) for continuous variables, and n (%) for proportions. P values shown are for analysis of variance for continuous variables, and χ2 test for proportions. *P < 0.05 compared with lean group
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Table 2: Asthma characteristics & pulmonary function Lean Age asthma onset (years)
Overweight 3
Obese
p value 3
14.9±16.7
21.7±22.7
3.6±2.8
4.1±3.0
4.0±3.1
0.8 0.09
Pack years
22.1±20.8
0.0001
5.21±1.08
5.08±1.05
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Number of Courses of Prednisone use in last 12 months (n{%})
404.2±96.1
398.6±95.1
385.9±93.4
0.12
84.6±13.4
3
0.01
91.8±13.0
3
<0.0001
0
177 (78)
146 (77)
183 (69)
1
32 (14)
28 (15)
≥2
17 (8)
15 (8)
1.43±0.68
1.52±0.71
45 (17)
36 (14)
ACQ (↓ score range, 0-6)1 AQLQ (↑ score range, 1-7)
1
Pulmonary function measures, mean ± SD PEF (L/min)
88.4±13.5
2
85.6±13.2
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2
1.76±0.753,4
<0.0001
3,4
<0.0001
4.64±1.09
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3
97.7±13.0
94.4±12.8
FEV1/FVC (pre BD)
75.6±9.2
74.3±9.1
75.7±7.6
0.16
FEV1 % change after BD
8.9±10.2
9.9±10.9
8.8±13.0
0.63
3
3
FVC (% predicted pre BD)
2.5±6.1
FVC % change after BD
4.5±9.1
4.5±11.1
Values shown are mean and SD, and are compared by analysis of variance and n (%) for proportions
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ACQ, Asthma Control Questionnaire AQLQ, Asthma Quality of Life Questionnaire PEF, morning peak expiratory flow
FEV1, forced expiratory volume in 1 second
BD, bronchodilator
↓, Lower score is better; ↑Higher score is better
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Predicted values for FEV1 and FVC are taken from Hankinson et al.32
3
p< 0.05 compared with lean group
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p < 0.01 compared with overweight group
< 0.001
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Table 3 Measures of psychological morbidity Lean
Overweight
Obese
p value
8 (4-24)
8 (4-24.5)
10 (5-16)
0.03
CES-D no depression
163 (80)
129 (79)
CES-D mild symptoms
26 (13)
25 (15)
CES-D probable depression
16 (7)
10 (6)
Self-efficacy
82.4±8.4
82.8±9.2
79.8±9.33,4
0.001
Attitude
85.4±7.2
85.5±7.6
85.3±6.4
0.96
12.0±2.8
3
3
1
CES-D level of depression 2 n (%)
1
↓, Lower score is better
2
11.1±2.9
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Knowledge
169 (73) 37 (16)
11.0±3.0
CES-D, Center for Epidemiologic Studies Depression Scale, threshold for mild depressive symptoms ≥
16, probable depression ≥ 23.
KASE-AQ, Knowledge, Attitude, and Self-Efficacy Asthma Questionnaire ↑, Higher score is better
3
p< 0.05 compared to lean group
4
p < 0.05 compared to overweight group
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0.01
26 (11)
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KASE-AQ (1↑ score range, 5-100) mean ± SD
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0.0005
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Table 4: Risk of Poor Asthma Control in those with Obesity and/or Depression CI
Obesity 1
2.06
1.48-2.88
Depression1
2.44
1.65-3.63
Obesity2
1.83
Depression2
2.08
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Odds Ratio
1.23-3.52
1.23-3.52
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Poor Asthma control was defined as a score of ≥ 1.5 on the Juniper Asthma Control questionnaire Uni-variate analysis for depression (using threshold of CES-D ≥ C16) and obesity separately.
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multivariate analysis combining depression and obesity in the same model, which also includes age, sex,
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Table 5: Asthma control in relation to symptoms of depression in participants of differing BMI groups
No Depression
Mild Depression
Probable depression
p
1.36 ± 0.67
1.58 ± 0.56
1.89 ± 0.721
<0.01
Asthma Control
1.46 ± 0.66
1.62 ± 0.66
1.97± 1.21
Asthma Control
1.67 ± 0.74
2.05 ± 0.651
Asthma Control
Obese
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Lean
1.96 ± 0.77
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0.07
0.01
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Conflicts of Interest • Sonam Kapadia: has no conflicts of interest pertaining to this manuscript • Christine Wei: has no conflicts of interest pertaining to this manuscript • Susan Bartlett: has no conflicts of interest pertaining to this manuscript • Jason Lang: has no conflicts of interest pertaining to this manuscript • Robert Wise: has no conflicts of interest pertaining to this manuscript • Anne Dixon: has no conflicts of interest pertaining to this manuscript