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Severe asthma phenotypes

Sally Wenzel, MD
Section Editor
Peter J Barnes, DM, DSc, FRCP, FRS
Deputy Editor
Helen Hollingsworth, MD


Asthma is defined and diagnosed through a combination of clinical symptoms and physiologic abnormalities, generally without reliance upon pathologic or biologic markers. However, the physiologic definition of asthma is relatively nonspecific, consisting of airway hyperreactivity and airflow limitation during expiration, which is variable and/or reversible with bronchodilators. In most asthma patients, the presence of bronchial hyperreactivity is never objectively confirmed.

The data suggesting that multiple phenotypes exist within the classification of "severe asthma" are reviewed here. Details regarding the classification, evaluation, diagnosis, and treatment of severe asthma are provided separately. (See "An overview of asthma management" and "Evaluation of severe asthma in adolescents and adults" and "Diagnosis of asthma in adolescents and adults" and "Treatment of severe asthma in adolescents and adults" and "Mechanisms and clinical implications of glucocorticoid resistance in asthma".)


The diagnosis of asthma is based upon the presence or history of symptoms consistent with asthma (most commonly episodic cough, wheezing, or dyspnea) provoked by typical triggers, combined with the demonstration of variable expiratory airflow obstruction. After confirming a diagnosis of asthma and addressing comorbidities, severe asthma is that which requires treatment with high dose inhaled glucocorticoids plus a second controller and/or systemic glucocorticoids to prevent asthma from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy [1].


Patients with severe asthma present with a variety of clinical histories, physiologic changes (beyond changes in forced expiratory volume in one second [FEV1]), and airway inflammation, suggesting that severe asthma is not a single disease or is a single process that produces widely varying host responses. Patients with severe asthma may have manifested severe disease all their life, developed progressively more severe disease over time, or may never have had asthma (to the best of their recollection) until some point in their adult life, after which the disease progressed at a rapid pace [2]. Some patients with severe asthma have a clearly defined atopic history, while others give little indication of an allergic component.

In addition to the variability in clinical features, patients with asthma do not respond in a uniform fashion to asthma medications, particularly glucocorticoids and other nonspecific anti-inflammatory/cytotoxic medications. It is hoped that exploration of asthma phenotypes will translate into improved understanding of asthma pathophysiology and optimized medication selection [1,3].


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Literature review current through: Sep 2016. | This topic last updated: Jun 27, 2016.
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  1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343.
  2. Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181:315.
  3. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol 2015; 135:299.
  4. Newby C, Heaney LG, Menzies-Gow A, et al. Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One 2014; 9:e102987.
  5. Bourdin A, Molinari N, Vachier I, et al. Prognostic value of cluster analysis of severe asthma phenotypes. J Allergy Clin Immunol 2014; 134:1043.
  6. Wu W, Bleecker E, Moore W, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol 2014; 133:1280.
  7. Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004; 113:101.
  8. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178:218.
  9. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160:1001.
  10. Amelink M, de Groot JC, de Nijs SB, et al. Severe adult-onset asthma: A distinct phenotype. J Allergy Clin Immunol 2013; 132:336.
  11. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309.
  12. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184.
  13. van den Berge M, Heijink HI, van Oosterhout AJ, Postma DS. The role of female sex hormones in the development and severity of allergic and non-allergic asthma. Clin Exp Allergy 2009; 39:1477.
  14. Foschino Barbaro MP, Costa VR, Resta O, et al. Menopausal asthma: a new biological phenotype? Allergy 2010; 65:1306.
  15. Bachert C, Mannent L, Naclerio RM, et al. Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial. JAMA 2016; 315:469.
  16. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128:989.
  17. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131:110.
  18. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360:973.
  19. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380:651.
  20. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189.
  21. Wenzel SE, Vitari CA, Shende M, et al. Asthmatic granulomatosis: a novel disease with asthmatic and granulomatous features. Am J Respir Crit Care Med 2012; 186:501.
  22. Chipps BE, Szefler SJ, Simons FE, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2007; 119:1156.
  23. Sher ER, Leung DY, Surs W, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest 1994; 93:33.
  24. Adcock IM, Lane SJ, Brown CR, et al. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol 1995; 154:3500.
  25. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360:1715.
  26. Ayres JG, Miles JF, Barnes PJ. Brittle asthma. Thorax 1998; 53:315.
  27. Kupczyk M, ten Brinke A, Sterk PJ, et al. Frequent exacerbators--a distinct phenotype of severe asthma. Clin Exp Allergy 2014; 44:212.
  28. in 't Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000; 161:1902.
  29. ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005; 26:812.
  30. van Veen IH, Ten Brinke A, Sterk PJ, et al. Airway inflammation in obese and nonobese patients with difficult-to-treat asthma. Allergy 2008; 63:570.
  31. Gibeon D, Batuwita K, Osmond M, et al. Obesity-associated severe asthma represents a distinct clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest 2013; 143:406.
  32. Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev 2012; :CD009339.
  33. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088.
  34. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368:2455.
  35. Fajt ML, Gelhaus SL, Freeman B, et al. Prostaglandin D₂ pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol 2013; 131:1504.
  36. Muraro A, Lemanske RF Jr, Hellings PW, et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2016; 137:1347.
  37. Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med 2015; 3:290.
  38. Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 2013; 132:72.
  39. Wagener AH, de Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 2015; 70:115.
  40. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3:355.
  41. Yamamoto M, Tochino Y, Chibana K, et al. Nitric oxide and related enzymes in asthma: relation to severity, enzyme function and inflammation. Clin Exp Allergy 2012; 42:760.
  42. Wysocki K, Park SY, Bleecker E, et al. Characterization of factors associated with systemic corticosteroid use in severe asthma: data from the Severe Asthma Research Program. J Allergy Clin Immunol 2014; 133:915.
  43. Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A 2007; 104:15858.
  44. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009; 180:388.
  45. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130:647.
  46. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 2:879.
  47. Cowan DC, Cowan JO, Palmay R, et al. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 2010; 65:384.
  48. Hastie AT, Moore WC, Meyers DA, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010; 125:1028.
  49. Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25:755.
  50. Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest 2007; 132:1871.
  51. Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol 2014; 133:1557.