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Current Pediatric Reviews

Author(s): Nese Akcan* and Nerin N. Bahceciler

DOI: 10.2174/1573396315666191026100643

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Headliner in Physiology and Management of Childhood Asthma: Hypothalamic-Pituitary-Adrenal Axis

Page: [43 - 52] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Asthma is the most common chronic inflammatory disease of children. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy which are the most effective, commonly used treatment of persistent asthma. Mostly, studies on the relationship between asthma and cortisol have focused on side effects of treatment. Recently, asthmatic patients not treated with ICS have been reported to have an attenuated activity and/or responsiveness of their Hypothalamic-Pituitary- Adrenal (HPA) axis. Moreover, it has been proposed that asthma worsening with stress may be due to a dysfunctional HPA axis, or cortisol insensitivity due to chronic psychological stress through impaired glucocorticoid receptor expression or function. Although long-term ICS treatment might produce adrenal suppression or iatrogenic Cushing syndrome, improvement of adrenal function has also been detected in some of asthmatic cases. Thus, the response scheme of HPA axis still contains undiscovered features in asthma. The management of asthma can be improved by increasing knowledge on the role of HPA axis in asthma pathophysiology. The risk for side effects of ICS can be minimized through increased awareness, early recognition of at-risk patients and regular patient follow-up. This review was written to draw attention to the role of HPA axis in both asthma and its treatment and to illustrate a follow up algorithm of HPA axis in the management of asthma.

Keywords: Adrenal insufficiency, adrenal suppression, iatrogenic Cushing syndrome, Hypothalamic-Pituitary-Adrenal axis, inhaled corticosteroids.

Graphical Abstract

[1]
Kelsay K, Leung DY, Mrazek DA, Klinnert MD. Prospectively assessed early life experiences in relation to cortisol reactivity in adolescents at risk for asthma. Dev Psychobiol 2013; 55(2): 133-44.
[http://dx.doi.org/10.1002/dev.21006] [PMID: 22314999]
[2]
Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007; 62(6): 591-604.
[http://dx.doi.org/10.1111/j.1398-9995.2007.01394.x] [PMID: 17508962]
[3]
Priftis KN, Papadimitriou A, Nicolaidou P, Chrousos GP. Dysregulation of the stress response in asthmatic children. Allergy 2009; 64(1): 18-31.
[http://dx.doi.org/10.1111/j.1398-9995.2008.01948.x] [PMID: 19132973]
[4]
Elenkov IJ, Chrousos GP. Stress system--organization, physiology and immunoregulation. Neuroimmunomodulation 2006; 13(5-6): 257-67.
[http://dx.doi.org/10.1159/000104853] [PMID: 17709947]
[5]
Straub RH, Cutolo M. Glucocorticoids and chronic inflammation. Rheumatology (Oxford) 2016; 55(Suppl. 2): ii6-ii14.
[http://dx.doi.org/10.1093/rheumatology/kew348] [PMID: 27856655]
[6]
Priftis KN, Papadimitriou A, Nicolaidou P, Chrousos GP. The hypothalamic-pituitary-adrenal axis in asthmatic children. Trends Endocrinol Metab 2008; 19(1): 32-8.
[http://dx.doi.org/10.1016/j.tem.2007.10.005] [PMID: 18155557]
[7]
Liang Z, Liu L, Zhao H, et al. A Systemic Inflammatory Endotype of Asthma With More Severe Disease Identified by Unbiased Clustering of the Serum Cytokine Profile. Medicine (Baltimore) 2016; 95(25)e3774
[http://dx.doi.org/10.1097/MD.0000000000003774] [PMID: 27336865]
[8]
Girdhar A, Kumar V, Singh A, Menon B, Vijayan VK. Systemic inflammation and its response to treatment in patients with asthma. Respir Care 2011; 56(6): 800-5.
[http://dx.doi.org/10.4187/respcare.00601] [PMID: 21679494]
[9]
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest 2012; 142(1): 86-93.
[http://dx.doi.org/10.1378/chest.11-1838] [PMID: 22345378]
[10]
Landstra AM, Postma DS, Boezen HM, van Aalderen WM. Role of serum cortisol levels in children with asthma. Am J Respir Crit Care Med 2002; 165(5): 708-12.
[http://dx.doi.org/10.1164/ajrccm.165.5.2102115] [PMID: 11874819]
[11]
Gisslinger H, Svoboda T, Clodi M, et al. Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology 1993; 57(3): 489-95.
[http://dx.doi.org/10.1159/000126396] [PMID: 8391662]
[12]
Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993; 77(6): 1690-4.
[PMID: 8263159]
[13]
Slopen N, Kubzansky LD, McLaughlin KA, Koenen KC. Childhood adversity and inflammatory processes in youth: a prospective study. Psychoneuroendocrinology 2013; 38(2): 188-200.
[http://dx.doi.org/10.1016/j.psyneuen.2012.05.013] [PMID: 22727478]
[14]
Dreger LC, Kozyrskyj AL, HayGlass KT, Becker AB, MacNeil BJ. Lower cortisol levels in children with asthma exposed to recurrent maternal distress from birth. J Allergy Clin Immunol 2010; 125(1): 116-22.
[http://dx.doi.org/10.1016/j.jaci.2009.09.051] [PMID: 19962747]
[15]
Kazuma N, Otsuka K, Matsuoka I, Murata M. Heart rate variability during 24 hours in asthmatic children. Chronobiol Int 1997; 14(6): 597-606.
[http://dx.doi.org/10.3109/07420529709001450] [PMID: 9360026]
[16]
Van den Bergh BR, Van Calster B. Diurnal cortisol profiles and evening cortisol in post-pubertal adolescents scoring high on the Children’s Depression Inventory. Psychoneuroendocrinology 2009; 34(5): 791-4.
[http://dx.doi.org/10.1016/j.psyneuen.2008.12.008] [PMID: 19171435]
[17]
Rotenberg S, McGrath JJ. Inter-relation between autonomic and HPA axis activity in children and adolescents. Biol Psychol 2016; 117: 16-25.
[http://dx.doi.org/10.1016/j.biopsycho.2016.01.015] [PMID: 26835595]
[18]
Sutherland ER, Ellison MC, Kraft M, Martin RJ. Altered pituitary-adrenal interaction in nocturnal asthma. J Allergy Clin Immunol 2003; 112(1): 52-7.
[http://dx.doi.org/10.1067/mai.2003.1608] [PMID: 12847479]
[19]
Baker RW, Walker BR, Shaw RJ, et al. Increased cortisol: cortisone ratio in acute pulmonary tuberculosis. Am J Respir Crit Care Med 2000; 162(5): 1641-7.
[http://dx.doi.org/10.1164/ajrccm.162.5.9912119] [PMID: 11069789]
[20]
Hardy RS, Filer A, Cooper MS, et al. Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation. Arthritis Res Ther 2006; 8(4): R108.
[http://dx.doi.org/10.1186/ar1993] [PMID: 16846535]
[21]
Ahasan MM, Hardy R, Jones C, et al. Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells. Arthritis Rheum 2012; 64(7): 2404-13.
[http://dx.doi.org/10.1002/art.34414] [PMID: 22294469]
[22]
Bornstein SR, Engeland WC, Ehrhart-Bornstein M, Herman JP. Dissociation of ACTH and glucocorticoids. Trends Endocrinol Metab 2008; 19(5): 175-80.
[http://dx.doi.org/10.1016/j.tem.2008.01.009] [PMID: 18394919]
[23]
Duong-Thi-Ly H, Nguyen-Thi-Thu H, Nguyen-Hoang L, Nguyen-Thi-Bich H, Craig TJ, Duong-Quy S. Effects of genetic factors to inhaled corticosteroid response in children with asthma: a literature review. J Int Med Res 2017; 45(6): 1818-30.
[http://dx.doi.org/10.1177/0300060516683877] [PMID: 29251255]
[24]
Tsartsali L, Papadopoulos M, Lagona E, et al. Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids. Neuroimmunomodulation 2012; 19(2): 88-95.
[http://dx.doi.org/10.1159/000329592] [PMID: 22248724]
[25]
Goleva E, Hauk PJ, Hall CF, et al. Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol 2008; 122(3): 550-9.e3.
[http://dx.doi.org/10.1016/j.jaci.2008.07.007] [PMID: 18774390]
[26]
Durrington H, Farrow S, Ray D. Recent advances in chronotherapy for the management of asthma. ChronoPhysiology and Therapy 2014; 4: 125-35.
[http://dx.doi.org/10.2147/CPT.S70845]
[27]
Joachim RA, Quarcoo D, Arck PC, Herz U, Renz H, Klapp BF. Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma. Psychosom Med 2003; 65(5): 811-5.
[http://dx.doi.org/10.1097/01.PSY.0000088582.50468.A3] [PMID: 14508025]
[28]
Joachim RA, Sagach V, Quarcoo D, Dinh QT, Arck PC, Klapp BF. Effect of stress on eotaxin and expression of adhesion molecules in a murine model of allergic airway inflammation. J Neuroimmunol 2007; 182(1-2): 55-62.
[http://dx.doi.org/10.1016/j.jneuroim.2006.09.010] [PMID: 17095099]
[29]
Silverman ES, Breault DT, Vallone J, et al. Corticotropin-releasing hormone deficiency increases allergen-induced airway inflammation in a mouse model of asthma. J Allergy Clin Immunol 2004; 114(4): 747-54.
[http://dx.doi.org/10.1016/j.jaci.2004.06.055] [PMID: 15480311]
[30]
Akcan N, Serakıncı N, Turkgenc B, Bundak R, Bahceciler N, Temel SGA. A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections. Front Endocrinol (Lausanne) 2017; 8: 64.
[http://dx.doi.org/10.3389/fendo.2017.00064] [PMID: 28458651]
[31]
Nezi M, Mastorakos G, Mouslech Z. Corticotropin Releasing Hormone And The Immune/Inflammatory Response Endotext Last Update 2015.
[32]
Chida Y, Sudo N, Sonoda J, Hiramoto T, Kubo C. Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus-pituitary-adrenal axis. Am J Respir Crit Care Med 2007; 175(4): 316-22.
[http://dx.doi.org/10.1164/rccm.200607-898OC] [PMID: 17110645]
[33]
Douros K, Moustaki M, Tsabouri S, Papadopoulou A, Papadopoulos M, Priftis KN. Prenatal Maternal Stress and the Risk of Asthma in Children. Front Pediatr 2017; 5: 202.
[http://dx.doi.org/10.3389/fped.2017.00202]
[34]
Chen E, Miller GE. Stress and inflammation in exacerbations of asthma. Brain Behav Immun 2007; 21(8): 993-9.
[http://dx.doi.org/10.1016/j.bbi.2007.03.009] [PMID: 17493786]
[35]
Sandberg S, Paton JY, Ahola S, et al. The role of acute and chronic stress in asthma attacks in children. Lancet 2000; 356(9234): 982-7.
[http://dx.doi.org/10.1016/S0140-6736(00)02715-X] [PMID: 11041399]
[36]
Rosenkranz MA, Busse WW, Johnstone T, et al. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci USA 2005; 102(37): 13319-24.
[http://dx.doi.org/10.1073/pnas.0504365102] [PMID: 16141324]
[37]
Sandberg S, Järvenpää S, Penttinen A, Paton JY, McCann DC. Asthma exacerbations in children immediately following stressful life events: a Cox’s hierarchical regression. Thorax 2004; 59(12): 1046-51.
[http://dx.doi.org/10.1136/thx.2004.024604] [PMID: 15563703]
[38]
Chida Y, Hamer M, Steptoe A. A bidirectional relationship between psychosocial factors and atopic disorders: a systematic review and meta-analysis. Psychosom Med 2008; 70(1): 102-16.
[http://dx.doi.org/10.1097/PSY.0b013e31815c1b71] [PMID: 18158379]
[39]
Chen E, Fisher EB, Bacharier LB, Strunk RC. Socioeconomic status, stress, and immune markers in adolescents with asthma. Psychosom Med 2003; 65(6): 984-92.
[http://dx.doi.org/10.1097/01.PSY.0000097340.54195.3C] [PMID: 14645776]
[40]
Chen E, Hanson MD, Paterson LQ, Griffin MJ, Walker HA, Miller GE. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress. J Allergy Clin Immunol 2006; 117(5): 1014-20.
[http://dx.doi.org/10.1016/j.jaci.2006.01.036] [PMID: 16675327]
[41]
Wright RJ, Finn P, Contreras JP, et al. Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin Immunol 2004; 113(6): 1051-7.
[http://dx.doi.org/10.1016/j.jaci.2004.03.032] [PMID: 15208584]
[42]
Miller GE, Chen E. Life stress and diminished expression of genes encoding glucocorticoid receptor and beta2-adrenergic receptor in children with asthma. Proc Natl Acad Sci USA 2006; 103(14): 5496-501.
[http://dx.doi.org/10.1073/pnas.0506312103] [PMID: 16567656]
[43]
Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol 2011; 7: 13.
[http://dx.doi.org/10.1186/1710-1492-7-13] [PMID: 21867553]
[44]
Fernandes RM, Wingert A, Vandermeer B, et al. Safety of corticosteroids in young children with acute respiratory conditions: a systematic review and meta-analysis. BMJ Open 2019; 9(8)e028511
[http://dx.doi.org/10.1136/bmjopen-2018-028511] [PMID: 31375615]
[45]
Khalilzadeh S, Boloorsaz MR, Safavi A, et al. Efficacy and safety of inhaled steroids in children with asthma: A comparison of fluticasone propionate with beclomethasone. Tanaffos 2007; 6(1): 29-35.
[46]
Sannarangappa V, Jalleh R. Inhaled corticosteroids and secondary adrenal insufficiency. Open Respir Med J 2014; 8: 93-100.
[http://dx.doi.org/10.2174/1874306401408010093] [PMID: 25674179]
[47]
Hossny E, Rosario N, Lee BW, et al. The use of inhaled corticosteroids in pediatric asthma: update. World Allergy Organ J 2016; 9: 26.
[http://dx.doi.org/10.1186/s40413-016-0117-0] [PMID: 27551328]
[48]
Zöllner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E. Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics 2012; 130(6): e1512-9.
[http://dx.doi.org/10.1542/peds.2012-1147] [PMID: 23147980]
[49]
Zöllner EW, Lombard CJ, Galal U, Hough S, Irusen EM, Weinberg E. Screening for hypothalamic-pituitary-adrenal axis suppression in asthmatic children remains problematic: A cross-sectional study. BMJ Open 2013; 3(8) e002935
[http://dx.doi.org/10.1136/bmjopen-2013-002935] [PMID: 23906954]
[50]
Wolfgram PM, Allen DB. Effects of inhaled corticosteroids on growth, bone metabolism, and adrenal function. Adv Pediatr 2017; 64(1): 331-45.
[http://dx.doi.org/10.1016/j.yapd.2017.03.006] [PMID: 28688596]
[51]
Lapi F, Kezouh A, Suissa S, Ernst P. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur Respir J 2013; 42(1): 79-86.
[http://dx.doi.org/10.1183/09031936.00080912] [PMID: 23060630]
[52]
Issa-El-Khoury K, Kim H, Chan ES, Vander Leek T, Noya F. CSACI position statement: systemic effect of inhaled corticosteroids on adrenal suppression in the management of pediatric asthma. Allergy Asthma Clin Immunol 2015; 11(1): 9.
[http://dx.doi.org/10.1186/s13223-015-0075-z] [PMID: 25802532]
[53]
Schwartz RH, Neacsu O, Ascher DP, Alpan O. Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature. Clin Pediatr (Phila) 2012; 51(12): 1184-90.
[http://dx.doi.org/10.1177/0009922812462235] [PMID: 23043135]
[54]
Smith RW, Downey K, Gordon M, et al. Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid. Paediatr Child Health 2012; 17(5): e34-9.
[http://dx.doi.org/10.1093/pch/17.5.e34] [PMID: 23633903]
[55]
Molimard M, Girodet PO, Pollet C, et al. Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation. Drug Saf 2008; 31(9): 769-74.
[http://dx.doi.org/10.2165/00002018-200831090-00005] [PMID: 18707191]
[56]
Fujitaka M, Nomura S, Sakura N, Ueda K, Matuura R, Yumiba C. Morning and afternoon serum levels of cortisone and cortisol in asthmatic patients. Clin Chim Acta 2000; 299(1-2): 101-8.
[http://dx.doi.org/10.1016/S0009-8981(00)00278-3] [PMID: 10900296]
[57]
Reinke SN, Gallart-Ayala H, Gómez C, et al. Metabolomics analysis identifies different metabotypes of asthma severity. Eur Respir J 2017; 49(3)1601740
[http://dx.doi.org/10.1183/13993003.01740-2016] [PMID: 28356371]
[58]
Pilmis B, Coignard-Biehler H, Jullien V, et al. Iatrogenic Cushing’s syndrome induced by posaconazole. Antimicrob Agents Chemother 2013; 57(11): 5727-8.
[http://dx.doi.org/10.1128/AAC.00416-13] [PMID: 23979730]
[59]
Blondin MC, Beauregard H, Serri O. Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review. Endocr Pract 2013; 19(6): e138-41.
[http://dx.doi.org/10.4158/EP13122.CR] [PMID: 23807527]
[60]
Colpitts L, Murray TB, Tahhan SG, Boggs JP. Iatrogenic Cushing Syndrome in a 47-Year-Old HIV-Positive Woman on Ritonavir and Inhaled Budesonide. J Int Assoc Provid AIDS Care 2017; 16(6): 531-4.
[http://dx.doi.org/10.1177/2325957417736612] [PMID: 29108449]
[61]
Gómez-Cerquera JM, Hernando-López E, Blanco-Ramos JR. [Iatrogenic adrenal insufficiency secondary to an interaction between ritonavir and inhaled fluticasone. A review of the literature]. Enferm Infecc Microbiol Clin 2014; 32(10): 662-5.
[PMID: 24529679]
[62]
Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015; 3(3): 216-26.
[http://dx.doi.org/10.1016/S2213-8587(14)70142-1] [PMID: 25098712]
[63]
Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin test in hypothalamic-pituitary adrenal insufficiency: corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a meta-analysis. J Clin Endocrinol Metab 2008; 93: 4245-53.
[http://dx.doi.org/10.1210/jc.2008-0710] [PMID: 18697868]
[64]
Kazlauskaite R, Maghnie M. Pitfalls in the diagnosis of central adrenal insufficiency in children. Endocr Dev 2010; 17: 96-107.
[http://dx.doi.org/10.1159/000262532] [PMID: 19955760]
[65]
Ambrosi B, Barbetta L, Re T, Passini E, Faglia G. The one microgram adrenocorticotropin test in the assessment of hypothalamic-pituitary-adrenal function. Eur J Endocrinol 1998; 139(6): 575-9.
[http://dx.doi.org/10.1530/eje.0.1390575] [PMID: 9916859]
[66]
Ambrosi B, Barbetta L. The role of the low dose ACTH test in the evaluation of central hypoadrenalism. J Endocrinol Invest 1999; 22(6): 492-5.
[http://dx.doi.org/10.1007/BF03343596] [PMID: 10435862]
[67]
Kamps AW, Molenmaker M, Kemperman R, van der Veen BS, Bocca G, Veeger NJ. Children with asthma have significantly lower long-term cortisol levels in their scalp hair than healthy children. Acta Paediatr 2014; 103(9): 957-61.
[http://dx.doi.org/10.1111/apa.12685] [PMID: 24814069]
[68]
Smy L, Shaw K, Smith A, et al. Hair cortisol as a novel biomarker of HPA suppression by inhaled corticosteroids in children. Pediatr Res 2015; 78(1): 44-7.
[http://dx.doi.org/10.1038/pr.2015.60] [PMID: 25790275]
[69]
Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of secondary adrenal insufficiency in patients with hypothalamic-pituitary disease: comparison between serum and salivary cortisol during the high-dose short synacthen test. Eur J Endocrinol 2009; 160(1): 9-16.
[http://dx.doi.org/10.1530/EJE-08-0600] [PMID: 18952762]
[70]
Deutschbein T, Broecker-Preuss M, Flitsch J, et al. Salivary cortisol as a diagnostic tool for Cushing’s syndrome and adrenal insufficiency: improved screening by an automatic immunoassay. Eur J Endocrinol 2012; 166(4): 613-8.
[http://dx.doi.org/10.1530/EJE-11-0945] [PMID: 22214924]
[71]
Cornes MP, Ashby HL, Khalid Y, Buch HN, Ford C, Gama R. Salivary cortisol and cortisone responses to tetracosactrin (synacthen). Ann Clin Biochem 2015; 52(Pt 5): 606-10.
[http://dx.doi.org/10.1177/0004563215577838] [PMID: 25724424]
[72]
Zhang L, Prietsch SO, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: effects on growth. Cochrane Database Syst Rev 2014; (7): CD009471
[http://dx.doi.org/10.1002/ebch.1988] [PMID: 25030198]
[73]
Nascimento I, Nardi AE, Valença AM, et al. Psychiatric disorders in asthmatic outpatients. Psychiatry Res 2002; 110(1): 73-80.
[http://dx.doi.org/10.1016/S0165-1781(02)00029-X] [PMID: 12007595]
[74]
Katon W, Lozano P, Russo J, McCauley E, Richardson L, Bush T. The prevalence of DSM-IV anxiety and depressive disorders in youth with asthma compared with controls. J Adolesc Health 2007; 41(5): 455-63.
[http://dx.doi.org/10.1016/j.jadohealth.2007.05.023] [PMID: 17950165]
[75]
Tonelli LH, Katz M, Kovacsics CE, et al. Allergic rhinitis induces anxiety-like behavior and altered social interaction in rodents. Brain Behav Immun 2009; 23(6): 784-93.
[http://dx.doi.org/10.1016/j.bbi.2009.02.017] [PMID: 19268702]
[76]
Buske-Kirschbaum A, von Auer K, Krieger S, Weis S, Rauh W, Hellhammer D. Blunted cortisol responses to psychosocial stress in asthmatic children: a general feature of atopic disease? Psychosom Med 2003; 65(5): 806-10.
[http://dx.doi.org/10.1097/01.PSY.0000095916.25975.4F] [PMID: 14508024]
[77]
Caulfield JI, Caruso MJ, Bourne RA, et al. Asthma induction during development and adult lung function, Behavior and Brain Gene Expression Front Behav Neurosci 2018; 30: 12.