EDITORIALS Can the Blues Make It Harder to Breathe? Asthma is a complex chronic disorder of the airways frequently associated with other atopic conditions with underlying genetic and environmental influences (1). A link between psychological functioning and asthma, particularly mood disorders, has also been observed (2–6). It has been proposed that the association between depression and asthma may be explained by shared vulnerability to environmental factors such as higher life stressors, or sequelae of uncontrolled asthma (e.g., chronic systemic inflammation and intermittent hypoxia), medication effects leading to changes in the central nervous system, common underlying biological mechanisms (e.g., bidirectional interactive neuroimmune and endocrine regulatory processes in the lung and brain), or genetic associations that predispose to the development of both conditions (7–14). Although a large body of cross-sectional literature supports this link (4, 5), fewer longitudinal studies exist to examine whether increased depressive symptoms or a diagnosis of depression precedes the onset of asthma, supporting the hypothesis that depression may predispose to the development of asthma (2, 3, 15). In this issue of the Journal, Brunner and colleagues (pp. 1044–1051) add to this literature by longitudinally investigating the temporality of the association between depression and asthma in the Coronary Artery Risk Development in Young Adults (CARDIA) study (16). CARDIA is a longitudinal study that recruited black and white 18- to 30-year-old adults during 1985–1986 from four U.S. cities to study cardiovascular risk factors (17). Due to the characterization of the participants at baseline and follow-up visits, Brunner and colleagues were able to study the temporality of the relationship within the same study population. Consistent with other studies, cross-sectional analyses conducted using the 10-, 15-, 20-, and 25-year-visit data demonstrated statistically significant associations between prevalent asthma and elevated depressive symptoms. However, in longitudinal analyses over the 20 years of follow-up, prevalent elevated depressive symptoms were associated with a 1.26 increased relative hazard of incident asthma, whereas prevalent asthma was not detected as a risk factor for incident elevated depressive symptoms. Overall, the characterization of key variables and longitudinal follow-up with the ability to investigate the temporality of both disorders in the same study population using the same measures and methods of ascertainment are strengths. Although it is common to use validated screening tools and medications to define conditions in large, longitudinal studies, misclassification is possible, and there is likely overlap between related mood disorders also associated with asthma, such as anxiety. The rate of adult-onset asthma appears higher than expected, which the authors potentially attribute to the characteristics of the population, which consists of a larger percentage of African Americans and obese individuals. As discussed by Brunner and colleagues, few longitudinal studies have investigated the association between depression and asthma (3, 15), and additionally, in a recent study that included
a sample of over 30,000 African American women enrolled in the Black Women’s Health Study, Coogan and colleagues found that women in the category with highest depressive symptoms had over a twofold rate of incident asthma compared with women in the lowest category (2). Although the findings of Brunner and colleagues are supportive of a relationship between elevated depressive symptoms and subsequent asthma, future studies are needed that will further characterize mood disorders over time, associated patterns of atopy, airway inflammation, and lung function that may assist in identifying distinct phenotypes or underlying biologic mechanisms as well as take into consideration factors such as asthma control, medication use, comorbid conditions, and quality of life to better understand the impact of asthma on subsequent elevated depressive symptoms (14). In addition, adult-onset asthma is a rare condition that is associated with early-life respiratory outcomes; therefore, prenatal and pediatric cohorts may also provide insight regarding how maternal and early childhood socioemotional health and psychological functioning influence respiratory health (18). If findings that individuals with depression are at increased risk for developing asthma are confirmed, there are a number of potential pathophysiologic mechanisms that may ultimately help explain the relationship (8–10, 19). Autonomic nervous system dysfunction has been noted in individuals with asthma as evidenced by increased bronchial hypersensitivity to cholinergic agents such as methacholine and decreased reactivity to adrenergic agents, and whether autonomic nervous system dysregulation is a potential link between depression and asthma is an area of interest (7, 9, 20). The hypothalamic–pituitary–adrenal axis and the immune system are interrelated systems, and dysregulation of both systems has been associated with depression and asthma (7, 8, 21, 22). Interestingly, in a recent review, Slavich and Irwin discuss links between stress, inflammation, and depression and how certain social experiences potentially may be converted into pathophysiology underlying depression in the “social signal transduction theory of depression,” which proposes that stressor-induced bidirectional neuroimmune communication between the central nervous system and indirectly the peripheral immune and autonomic nervous systems may lead to several neurocognitive and behavioral alterations characteristic of depression in vulnerable individuals as well as other conditions associated with chronic systemic inflammation (8). In other evolving areas of research, depression has been associated with increased levels of oxidative stress in the brain and the periphery, and oxidative stress is also associated with asthma (23, 24). Further studies are needed to delineate whether oxidative stress serves as disease marker, establish the temporal relationship between depression and increased oxidative stress, and explore whether oxidative stress may play a role in associations between depression and asthma (7, 23, 24). Other novel areas of research include investigating the role of neurogenic inflammation or shared genetic susceptibility (7).
Am J Respir Crit Care Med Vol 189, Iss 9, pp 1013–1021, May 1, 2014 Internet address: www.atsjournals.org
Editorials
1013
EDITORIALS Elucidating the nature of the relationship between depression and asthma will involve unraveling the role of psychological stress— is stress-elicited disruption of interrelated biologic systems with resultant enhanced vulnerability to depression and asthma a key underlying mechanism, do depression and its associated physiologic perturbations play a causal role in asthma, or does depression lie in the pathway between psychological stress and asthma? Longitudinal investigations that include measures of psychosocial stressors as well as psychological correlates, including depression and anxiety, and physiological correlates, such as disrupted cortisol regulation or chronic inflammation, will be key. Overall, this study provides insight into the nature of relationship between depression and asthma and highlights the importance of conducting mental health screening, and a logical question for future investigations is whether prevention or effective treatment for depression may have implications for respiratory health in addition to psychological functioning and well-being. n Author disclosures are available with the text of this article at www.atsjournals.org. Kecia N. Carroll, M.D., M.P.H. Department of Pediatrics Vanderbilt University Medical Center Nashville, Tennessee
References 1. Martinez FD, Vercelli D. Asthma. Lancet 2013;382:1360–1372. 2. Coogan PF, Yu J, O’Connor GT, Brown TA, Palmer JR, Rosenberg L. Depressive symptoms and the incidence of adult-onset asthma in African American women. Ann Allergy Asthma Immunol 2014;112:333–338. 3. Loerbroks A, Apfelbacher CJ, Bosch JA, Sturmer ¨ T. Depressive symptoms, social support, and risk of adult asthma in a populationbased cohort study. Psychosom Med 2010;72:309–315. 4. Loerbroks A, Herr RM, Subramanian S, Bosch JA. The association of asthma and wheezing with major depressive episodes: an analysis of 245 727 women and men from 57 countries. Int J Epidemiol 2012;41:1436–1444. 5. Cazzola M, Calzetta L, Bettoncelli G, Novelli L, Cricelli C, Rogliani P. Asthma and comorbid medical illness. Eur Respir J 2011;38:42–49. 6. Janson C, Bjornsson ¨ E, Hetta J, Boman G. Anxiety and depression in relation to respiratory symptoms and asthma. Am J Respir Crit Care Med 1994;149:930–934. 7. Van Lieshout RJ, Bienenstock J, MacQueen GM. A review of candidate pathways underlying the association between asthma and major depressive disorder. Psychosom Med 2009;71:187–195. 8. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull (In press)
9. Wright RJ. Stress-related programming of autonomic imbalance: role in allergy and asthma. Chem Immunol Allergy 2012;98:32–47. 10. Iwata M, Ota KT, Duman RS. The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 2013;31:105–114. 11. Di Marco F, Santus P, Centanni S. Anxiety and depression in asthma. Curr Opin Pulm Med 2011;17:39–44. 12. Amelink M, Hashimoto S, Spinhoven P, Pasma HR, Sterk PJ, Bel EH, Ten Brinke A. Anxiety, depression and personality traits in severe, prednisone-dependent asthma. Respir Med 2014;108:438–444. 13. Rosenkranz MA, Busse WW, Sheridan JF, Crisafi GM, Davidson RJ. Are there neurophenotypes for asthma? Functional brain imaging of the interaction between emotion and inflammation in asthma. PLoS ONE 2012;7:e40921. 14. O’Byrne PM, Pedersen S, Schatz M, Thoren A, Ekholm E, Carlsson LG, Busse WW. The poorly explored impact of uncontrolled asthma. Chest 2013;143:511–523. 15. Patten SB, Williams JV, Lavorato DH, Modgill G, Jette´ N, Eliasziw M. Major depression as a risk factor for chronic disease incidence: longitudinal analyses in a general population cohort. Gen Hosp Psychiatry 2008;30:407–413. 16. Brunner WM, Schreiner PJ, Sood A, Jacobs DR Jr. Depression and risk of incident asthma in adults: the CARDIA study. Am J Respir Crit Care Med 2014;189:1044–1051. 17. Friedman GD, Cutter GR, Donahue RP, Hughes GH, Hulley SB, Jacobs DR Jr, Liu K, Savage PJ. CARDIA: study design, recruitment, and some characteristics of the examined subjects. J Clin Epidemiol 1988;41:1105–1116. 18. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008;372:1058–1064. 19. Rod NH, Kristensen TS, Lange P, Prescott E, Diderichsen F. Perceived stress and risk of adult-onset asthma and other atopic disorders: a longitudinal cohort study. Allergy 2012;67:1408–1414. 20. Lewis MJ, Short AL, Lewis KE. Autonomic nervous system control of the cardiovascular and respiratory systems in asthma. Respir Med 2006;100:1688–1705. 21. Du YJ, Li B, Zhang HY, Cao YX, Duan XH, Gong WY, Dong JC. Airway inflammation and hypothalamic-pituitary-adrenal axis activity in asthmatic adults with depression. J Asthma 2013;50:274–281. 22. Owens M, Herbert J, Jones PB, Sahakian BJ, Wilkinson PO, Dunn VJ, Croudace TJ, Goodyer IM. Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms. Proc Natl Acad Sci USA 2014;111: 3638–3643. 23. Yager S, Forlenza MJ, Miller GE. Depression and oxidative damage to lipids. Psychoneuroendocrinology 2010;35:1356–1362. 24. Voynow JA, Kummarapurugu A. Isoprostanes and asthma. Biochim Biophys Acta 2011;1810:1091–1095.
Copyright © 2014 by the American Thoracic Society
What Is the Right Dose of Systemic Corticosteroids for Intensive Care Unit Patients with Chronic Obstructive Pulmonary Disease Exacerbations? A Question in Search of a Definitive Answer Chronic obstructive pulmonary disease (COPD) is characterized by systemic and bronchial inflammation and persistent and progressive airflow limitation (1). COPD exacerbations are usually precipitated by bacterial or viral respiratory tract infections and are associated with 1014
sharp declines in the lung function, reductions in activities of daily living, and increased risk of death (1). Severe exacerbations requiring ventilatory support in the intensive care unit (ICU) are especially concerning, with in-hospital mortality rates of up to 30% (2, 3).
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 9 | May 1 2014
a sample of over 30,000 African American women enrolled in the Black Women’s Health Study, Coogan and colleagues found that women in the category with highest depressive symptoms had over a twofold rate of incident asthma compared with women in the lowest category (2). Although the findings of Brunner and colleagues are supportive of a relationship between elevated depressive symptoms and subsequent asthma, future studies are needed that will further characterize mood disorders over time, associated patterns of atopy, airway inflammation, and lung function that may assist in identifying distinct phenotypes or underlying biologic mechanisms as well as take into consideration factors such as asthma control, medication use, comorbid conditions, and quality of life to better understand the impact of asthma on subsequent elevated depressive symptoms (14). In addition, adult-onset asthma is a rare condition that is associated with early-life respiratory outcomes; therefore, prenatal and pediatric cohorts may also provide insight regarding how maternal and early childhood socioemotional health and psychological functioning influence respiratory health (18). If findings that individuals with depression are at increased risk for developing asthma are confirmed, there are a number of potential pathophysiologic mechanisms that may ultimately help explain the relationship (8–10, 19). Autonomic nervous system dysfunction has been noted in individuals with asthma as evidenced by increased bronchial hypersensitivity to cholinergic agents such as methacholine and decreased reactivity to adrenergic agents, and whether autonomic nervous system dysregulation is a potential link between depression and asthma is an area of interest (7, 9, 20). The hypothalamic–pituitary–adrenal axis and the immune system are interrelated systems, and dysregulation of both systems has been associated with depression and asthma (7, 8, 21, 22). Interestingly, in a recent review, Slavich and Irwin discuss links between stress, inflammation, and depression and how certain social experiences potentially may be converted into pathophysiology underlying depression in the “social signal transduction theory of depression,” which proposes that stressor-induced bidirectional neuroimmune communication between the central nervous system and indirectly the peripheral immune and autonomic nervous systems may lead to several neurocognitive and behavioral alterations characteristic of depression in vulnerable individuals as well as other conditions associated with chronic systemic inflammation (8). In other evolving areas of research, depression has been associated with increased levels of oxidative stress in the brain and the periphery, and oxidative stress is also associated with asthma (23, 24). Further studies are needed to delineate whether oxidative stress serves as disease marker, establish the temporal relationship between depression and increased oxidative stress, and explore whether oxidative stress may play a role in associations between depression and asthma (7, 23, 24). Other novel areas of research include investigating the role of neurogenic inflammation or shared genetic susceptibility (7).
Am J Respir Crit Care Med Vol 189, Iss 9, pp 1013–1021, May 1, 2014 Internet address: www.atsjournals.org
Editorials
1013
EDITORIALS Elucidating the nature of the relationship between depression and asthma will involve unraveling the role of psychological stress— is stress-elicited disruption of interrelated biologic systems with resultant enhanced vulnerability to depression and asthma a key underlying mechanism, do depression and its associated physiologic perturbations play a causal role in asthma, or does depression lie in the pathway between psychological stress and asthma? Longitudinal investigations that include measures of psychosocial stressors as well as psychological correlates, including depression and anxiety, and physiological correlates, such as disrupted cortisol regulation or chronic inflammation, will be key. Overall, this study provides insight into the nature of relationship between depression and asthma and highlights the importance of conducting mental health screening, and a logical question for future investigations is whether prevention or effective treatment for depression may have implications for respiratory health in addition to psychological functioning and well-being. n Author disclosures are available with the text of this article at www.atsjournals.org. Kecia N. Carroll, M.D., M.P.H. Department of Pediatrics Vanderbilt University Medical Center Nashville, Tennessee
References 1. Martinez FD, Vercelli D. Asthma. Lancet 2013;382:1360–1372. 2. Coogan PF, Yu J, O’Connor GT, Brown TA, Palmer JR, Rosenberg L. Depressive symptoms and the incidence of adult-onset asthma in African American women. Ann Allergy Asthma Immunol 2014;112:333–338. 3. Loerbroks A, Apfelbacher CJ, Bosch JA, Sturmer ¨ T. Depressive symptoms, social support, and risk of adult asthma in a populationbased cohort study. Psychosom Med 2010;72:309–315. 4. Loerbroks A, Herr RM, Subramanian S, Bosch JA. The association of asthma and wheezing with major depressive episodes: an analysis of 245 727 women and men from 57 countries. Int J Epidemiol 2012;41:1436–1444. 5. Cazzola M, Calzetta L, Bettoncelli G, Novelli L, Cricelli C, Rogliani P. Asthma and comorbid medical illness. Eur Respir J 2011;38:42–49. 6. Janson C, Bjornsson ¨ E, Hetta J, Boman G. Anxiety and depression in relation to respiratory symptoms and asthma. Am J Respir Crit Care Med 1994;149:930–934. 7. Van Lieshout RJ, Bienenstock J, MacQueen GM. A review of candidate pathways underlying the association between asthma and major depressive disorder. Psychosom Med 2009;71:187–195. 8. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull (In press)
9. Wright RJ. Stress-related programming of autonomic imbalance: role in allergy and asthma. Chem Immunol Allergy 2012;98:32–47. 10. Iwata M, Ota KT, Duman RS. The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 2013;31:105–114. 11. Di Marco F, Santus P, Centanni S. Anxiety and depression in asthma. Curr Opin Pulm Med 2011;17:39–44. 12. Amelink M, Hashimoto S, Spinhoven P, Pasma HR, Sterk PJ, Bel EH, Ten Brinke A. Anxiety, depression and personality traits in severe, prednisone-dependent asthma. Respir Med 2014;108:438–444. 13. Rosenkranz MA, Busse WW, Sheridan JF, Crisafi GM, Davidson RJ. Are there neurophenotypes for asthma? Functional brain imaging of the interaction between emotion and inflammation in asthma. PLoS ONE 2012;7:e40921. 14. O’Byrne PM, Pedersen S, Schatz M, Thoren A, Ekholm E, Carlsson LG, Busse WW. The poorly explored impact of uncontrolled asthma. Chest 2013;143:511–523. 15. Patten SB, Williams JV, Lavorato DH, Modgill G, Jette´ N, Eliasziw M. Major depression as a risk factor for chronic disease incidence: longitudinal analyses in a general population cohort. Gen Hosp Psychiatry 2008;30:407–413. 16. Brunner WM, Schreiner PJ, Sood A, Jacobs DR Jr. Depression and risk of incident asthma in adults: the CARDIA study. Am J Respir Crit Care Med 2014;189:1044–1051. 17. Friedman GD, Cutter GR, Donahue RP, Hughes GH, Hulley SB, Jacobs DR Jr, Liu K, Savage PJ. CARDIA: study design, recruitment, and some characteristics of the examined subjects. J Clin Epidemiol 1988;41:1105–1116. 18. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008;372:1058–1064. 19. Rod NH, Kristensen TS, Lange P, Prescott E, Diderichsen F. Perceived stress and risk of adult-onset asthma and other atopic disorders: a longitudinal cohort study. Allergy 2012;67:1408–1414. 20. Lewis MJ, Short AL, Lewis KE. Autonomic nervous system control of the cardiovascular and respiratory systems in asthma. Respir Med 2006;100:1688–1705. 21. Du YJ, Li B, Zhang HY, Cao YX, Duan XH, Gong WY, Dong JC. Airway inflammation and hypothalamic-pituitary-adrenal axis activity in asthmatic adults with depression. J Asthma 2013;50:274–281. 22. Owens M, Herbert J, Jones PB, Sahakian BJ, Wilkinson PO, Dunn VJ, Croudace TJ, Goodyer IM. Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms. Proc Natl Acad Sci USA 2014;111: 3638–3643. 23. Yager S, Forlenza MJ, Miller GE. Depression and oxidative damage to lipids. Psychoneuroendocrinology 2010;35:1356–1362. 24. Voynow JA, Kummarapurugu A. Isoprostanes and asthma. Biochim Biophys Acta 2011;1810:1091–1095.
Copyright © 2014 by the American Thoracic Society
What Is the Right Dose of Systemic Corticosteroids for Intensive Care Unit Patients with Chronic Obstructive Pulmonary Disease Exacerbations? A Question in Search of a Definitive Answer Chronic obstructive pulmonary disease (COPD) is characterized by systemic and bronchial inflammation and persistent and progressive airflow limitation (1). COPD exacerbations are usually precipitated by bacterial or viral respiratory tract infections and are associated with 1014
sharp declines in the lung function, reductions in activities of daily living, and increased risk of death (1). Severe exacerbations requiring ventilatory support in the intensive care unit (ICU) are especially concerning, with in-hospital mortality rates of up to 30% (2, 3).
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 9 | May 1 2014
