Glucocorticoid Insensitive Asthma

  • Sally E. Wenzel
Part of the Allergy Frontiers book series (ALLERGY, volume 5)

It has been understood for some time that, although the majority of patients with asthma respond well to corticosteroid (CS) therapy, a small subgroup exists in whom CSs either have no effect on asthma or its components, or in whom the dose required to cause an improvement, greatly exceeds the usual therapeutic range. As CSs are widely recognized as the most effective therapy currently available for asthma, a poor response to CSs may contribute to the development of severe asthma. However, GC insensitive asthma is not synonymous with difficult-to-treat asthma, as it has been recognized that child and adult asthmatics with a wide range of severity may exhibit a lower than expected response [1, 2]. Yet, it is the group of patients with difficult-to-treat asthma, who are also refractory to treatment with CSs, who likely contribute to nearly 50% of the economic burden of the disease [3].

For many years, CS insensitivity was described as being related to a direct abnormality in the glucocorticoid (GC) pathway (i.e., receptor, translocation, transcription factor binding). However, it is now understood that GC insensitive asthma is likely to be much more complex than originally described, with numerous other factors also contributing to an absent or diminished CS response, which may have little to do with molecular pathways. After defining GC insensitivity, this review will describe the current understanding of four potential reasons for GC insensitivity. These include: (1) abnormal activation of the GC receptor and its nuclear inhibitory effects, (2) the presence of a “different” inflammatory process that may not respond to CS therapy, (3) the lack of any inflammatory process and (4) the presence of an inflammatory process in a region of the lung, poorly accessible to inhaled therapy. A fifth reason for GC insensitivity also exists, namely, non-adherence/compliance with CS medications. However, that reason for GC insensitivity will not be discussed further in this chapter. This chapter will conclude with a section on approaches to treatment of GC insensitive asthma (Table 1).


Severe Asthma Allergy Clin Immunol Respir Crit Eosinophilic Inflammation Distal Lung 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM, Lemanske RF, Jr., Strunk RC, Larsen G, Spahn JD, et al. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 2006;117:45–52CrossRefPubMedGoogle Scholar
  2. 2.
    Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, et al. Significant variability in response to inhaled corti-costeroids for persistent asthma. J Allergy Clin Immunol 2002;109:410–418CrossRefPubMedGoogle Scholar
  3. 3.
    Chung KF, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, Bel E, Burney P, Chanez P, Connett G, et al. Difficult/therapy-resistant asthma: The need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. Ers task force on difficult/therapy-resistant asthma. European respiratory society. Eur Resp J 1999;13:1198–1208Google Scholar
  4. 4.
    Wenzel SE. Inflammation, leukotrienes and the pathogenesis of the late asthmatic response. Clin Exp Allergy 1999;29:1–3CrossRefPubMedGoogle Scholar
  5. 5.
    Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am J Respir Crit Care Med 2005;172:559–565CrossRefPubMedGoogle Scholar
  6. 6.
    Haldar P, Pavord ID. Noneosinophilic asthma: A distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007;119:1043–1052; quiz 1053–1044CrossRefPubMedGoogle Scholar
  7. 7.
    Carmichael J, Paterson IC, Diaz P, Crompton GK, Kay AB, Grant IW. Corticosteroid resistance in chronic asthma. Br Med J (Clinical Research ed 1981;282:1419–1422CrossRefGoogle Scholar
  8. 8.
    Woolcock AJ. Corticosteroid-resistant asthma. Definitions. Am J Respir Crit Care Med 1996;154:S45–S48PubMedGoogle Scholar
  9. 9.
    Sher ER, Leung D Y, Surs W, Kam JC, Zieg G, Kamada AK, Szefler SJ. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Investig 1994;93:33–39CrossRefPubMedGoogle Scholar
  10. 10.
    Leung DY, Martin RJ, Szefler SJ, Sher ER, Ying S, Kay AB, Hamid Q. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 1995;181:33–40CrossRefPubMedGoogle Scholar
  11. 11.
    Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006;117:522–543CrossRefPubMedGoogle Scholar
  12. 12.
    Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY. A novel action of il-13: Induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol 1996;157:2654–2659PubMedGoogle Scholar
  13. 13.
    Hamid QA, Wenzel SE, Hauk PJ, Tsicopoulos A, Wallaert B, Lafitte JJ, Chrousos GP, Szefler SJ, Leung DY. Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 1999;159:1600–1604PubMedGoogle Scholar
  14. 14.
    Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol 2000;105:943–950CrossRefPubMedGoogle Scholar
  15. 15.
    Gagliardo R, Chanez P, Vignola AM, Bousquet J, Vachier I, Godard P, Bonsignore G, Demoly P, Mathieu M. Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma. Am J Respir Crit Care Med 2000;162:7–13PubMedGoogle Scholar
  16. 16.
    Torrego A, Pujols L, Roca-Ferrer J, Mullol J, Xaubet A, Picado C. Glucocorticoid receptor isoforms alpha and beta in in vitro cytokine-induced glucocorticoid insensitivity. Am J Respir Crit Care Med 2004;170:420–425CrossRefPubMedGoogle Scholar
  17. 17.
    Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995;154:4719–4725PubMedGoogle Scholar
  18. 18.
    Strickland I, Kisich K, Hauk PJ, Vottero A, Chrousos GP, Klemm DJ, Leung DY. High constitutive glucocorticoid receptor beta in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids. J Exp Med 2001;193:585–593CrossRefPubMedGoogle Scholar
  19. 19.
    Wenzel SE, Szefler SJ, Leung DYM, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma: Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156:737–743PubMedGoogle Scholar
  20. 20.
    Adcock IM, Lane SJ, Brown CR, Peters MJ, Lee TH, Barnes PJ. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol 1995;154:3500–3505PubMedGoogle Scholar
  21. 21.
    Adcock IM, Lane SJ, Brown CR, Lee TH, Barnes PJ. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med 1995;182:1951–1958CrossRefPubMedGoogle Scholar
  22. 22.
    Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and t lymphocytes. J Clin Investig 1998;102:2156–2164CrossRefPubMedGoogle Scholar
  23. 23.
    Sousa AR, Lane SJ, Soh C, Lee TH. In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of jun n-terminal kinase and failure of predni-solone to inhibit jun n-terminal kinase phosphorylation. J Allergy Clin Immunol 1999;104:565–574CrossRefPubMedGoogle Scholar
  24. 24.
    Tsitoura DC, Rothman PB. Enhancement of mek/erk signaling promotes glucocorticoid resistance in cd4+ t cells. J Clin Investig 2004;113:619–627PubMedGoogle Scholar
  25. 25.
    Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. P38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma. J Allergy Clin Immunol 2002;109:649–657CrossRefPubMedGoogle Scholar
  26. 26.
    Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, et al. Reversing the defective induction of il-10-secreting regulatory t cells in glucocorticoid-resistant asthma patients. J Clin Investig 2006;116:146–155CrossRefPubMedGoogle Scholar
  27. 27.
    Burnstein KL, Jewell CM, Cidlowski JA. Human glucocorticoid receptor cdna contains sequences sufficient for receptor down-regulation. J Biol Chem 1990;265:7284–7291PubMedGoogle Scholar
  28. 28.
    Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST. Association of vitamin d receptor gene polymorphisms with childhood and adult asthma. Am J Resp Crit Care Med 2004;170:1057–1065CrossRefPubMedGoogle Scholar
  29. 29.
    Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: Inactivation of histone deacetylase. Lancet 2004;363:731–733CrossRefPubMedGoogle Scholar
  30. 30.
    Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. New Engl J Med 2005;352:1967–1976CrossRefPubMedGoogle Scholar
  31. 31.
    Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 2002;166:392–396CrossRefPubMedGoogle Scholar
  32. 32.
    Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J R Crit Care Med 2006;174:134–141CrossRefGoogle Scholar
  33. 33.
    Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 2002;99:8921–8926CrossRefPubMedGoogle Scholar
  34. 34.
    ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT, Zwinderman AH, Rabe KF, Bel EH. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:812–818CrossRefPubMedGoogle Scholar
  35. 35.
    Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: A randomised controlled trial. Lancet 2002;360:1715–1721CrossRefPubMedGoogle Scholar
  36. 36.
    Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160:1532–1539PubMedGoogle Scholar
  37. 37.
    Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: Identification of a subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–879CrossRefPubMedGoogle Scholar
  38. 38.
    Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, Thomson NC. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Resp Crit Care Med 2006;174:127–133CrossRefPubMedGoogle Scholar
  39. 39.
    Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, DiMango E, Fish JE, Ford JG, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Resp Crit Care Med 2007;175:783–790CrossRefPubMedGoogle Scholar
  40. 40.
    Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 2005;60:282–287CrossRefPubMedGoogle Scholar
  41. 41.
    McSharry CP, McKay IC, Chaudhuri R, Livingston E, Fraser I, Thomson NC. Short and longterm effects of cigarette smoking independently influence exhaled nitric oxide concentration in asthma. J Allergy Clin Immunol 2005;116:88–93CrossRefPubMedGoogle Scholar
  42. 42.
    Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: Assessment and identification using induced sputum. Respirology 2006;11:54–61CrossRefPubMedGoogle Scholar
  43. 43.
    Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phe-notypes: Role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004;113:101–108CrossRefPubMedGoogle Scholar
  44. 44.
    White SR, Dorscheid DR. Corticosteroid-induced apoptosis of airway epithelium: A potential mechanism for chronic airway epithelial damage in asthma. Chest 2002;122:278S–284SCrossRefPubMedGoogle Scholar
  45. 45.
    Olivieri D, Chetta A, Del Donno M, Bertorelli G, Casalini A, Pesci A, Testi R, Foresi A. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: A placebo-controlled study. Am J Resp Crit Care Med 1997;155:1864–1871PubMedGoogle Scholar
  46. 46.
    Komakula S, Khatri S, Mermis J, Savill S, Haque S, Rojas M, Brown L, Teague GW, Holguin F. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Resp Res 2007;8:32CrossRefGoogle Scholar
  47. 47.
    Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM. Influence of body mass index on the response to asthma controller agents. Eur Respir J 2006;27:495–503CrossRefPubMedGoogle Scholar
  48. 48.
    Borer H, Hanni P, Schoenenberger RA. Vocal cord dysfunction: An important differential diagnosis of brittle asthma. Resp; Int Rev Thorac Dis 2001;68:318Google Scholar
  49. 49.
    Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: An observational study in adults with asthma. Clin Exp Allergy 2005;35:1175–1179CrossRefPubMedGoogle Scholar
  50. 50.
    Silkoff PE, Lent AM, Busacker AA, Katial RK, Balzar S, Strand M, Wenzel SE. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. The J Allergy Clin Immunol 2005;116:1249–1255CrossRefGoogle Scholar
  51. 51.
    Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002;20:254–259CrossRefPubMedGoogle Scholar
  52. 52.
    Balzar S, Chu HW, Strand M, Wenzel S. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Resp Crit Car Med 2005;171:431–439CrossRefGoogle Scholar
  53. 53.
    Balkissoon RC, Balzar S, Rhodes D, Trudeau JB, Wenzel S. Eosinophils persist in the distal lung of severe asthma despite low numbers of proximal airways. 2006 ATS Annual Meeting, San Diego, CA, American Thoracic Society; 2006, p. A15Google Scholar
  54. 54.
    Berry M, Hargadon B, Morgan A, Shelley M, Richter J, Shaw D, Green RH, Brightling C, Wardlaw AJ, Pavord ID. Alveolar nitric oxide in adults with asthma: Evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005;25:986–991CrossRefPubMedGoogle Scholar
  55. 55.
    Lemiere C, Ernst P, Olivenstein R, Yamauchi Y, Govindaraju K, Ludwig MS, Martin JG, Hamid Q. Airway inflammation assessed by invasive and noninvasive means in severe asthma: Eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol 2006;118:1033–1039CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.University of PittsburghPittsburghUSA

Personalised recommendations