Heterogeneity in Severe Asthma

  • Theo J. Moraes
  • Wendy C. Moore
  • Padmaja SubbaraoEmail author
Part of the Respiratory Medicine book series (RM)


People with severe asthma make up a small proportion of the total number of people with asthma. However, despite being relatively uncommon, severe asthma utilizes the majority of asthma-related health-care expenditures. A personalized medicine approach to severe asthma has been suggested as severe asthma is difficult to treat and the population with severe asthma is very heterogeneous. In this chapter we discuss some of the ways in which people with severe asthma can be sub-classified. This includes a discussion of differences between children and adults, types of airway inflammation seen, and clinical characteristics. Understanding heterogeneity will lead to improved understanding of the pathophysiology underpinning the clinical presentation. However, future work will need to focus on characterizing subtypes of severe asthma in a fashion that has direct relevance for treatment and outcomes.


Severe asthma Phenotypes Pediatric asthma Lung function Cluster analysis 


  1. 1.
    Asher I, Pearce N. Global burden of asthma among children. Int J Tuberc Lung Dis. 2014;18(11):1269–78.CrossRefGoogle Scholar
  2. 2.
    To T, Wang C, Guan J, McLimont S, Gershon AS. What is the lifetime risk of physician-diagnosed asthma in Ontario, Canada? Am J Respir Crit Care Med. 2010;181(4):337–43.CrossRefGoogle Scholar
  3. 3.
    Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, et al. After asthma: redefining airways diseases. Lancet. 2018;391(10118):350–400.CrossRefGoogle Scholar
  4. 4.
    Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162(6):2341–51.Google Scholar
  5. 5.
    Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.CrossRefGoogle Scholar
  6. 6.
    Cisternas MG, Blanc PD, Yen IH, Katz PP, Earnest G, Eisner MD, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol. 2003;111(6):1212–8.CrossRefGoogle Scholar
  7. 7.
    Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J. 2002;19(1):61–7.CrossRefGoogle Scholar
  8. 8.
    Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA, McLaurin K. Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma. J Allergy Clin Immunol. 2012;129(5):1229–35.CrossRefGoogle Scholar
  9. 9.
    Kim SH, Kim TW, Kwon JW, Kang HR, Lee YW, Kim TB, et al. Economic costs for adult asthmatics according to severity and control status in Korean tertiary hospitals. J Asthma. 2012;49(3):303–9.CrossRefGoogle Scholar
  10. 10.
    Gendo K, Sullivan SD, Lozano P, Finkelstein JA, Fuhlbrigge A, Weiss KB. Resource costs for asthma-related care among pediatric patients in managed care. Ann Allergy Asthma Immunol. 2003;91(3):251–7.CrossRefGoogle Scholar
  11. 11.
    Serra-Batlles J, Plaza V, Morejon E, Comella A, Brugues J. Costs of asthma according to the degree of severity. Eur Respir J. 1998;12(6):1322–6.CrossRefGoogle Scholar
  12. 12.
    Antonicelli L, Bucca C, Neri M, De Benedetto F, Sabbatani P, Bonifazi F, et al. Asthma severity and medical resource utilisation. Eur Respir J. 2004;23(5):723–9.CrossRefGoogle Scholar
  13. 13.
    Fleming L, Murray C, Bansal AT, Hashimoto S, Bisgaard H, Bush A, et al. The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts. Eur Respir J. 2015;46(5):1322–33.CrossRefGoogle Scholar
  14. 14.
    Bisgaard H, Szefler S. Prevalence of asthma-like symptoms in young children. Pediatr Pulmonol. 2007;42(8):723–8.CrossRefGoogle Scholar
  15. 15.
    Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3):133–8.CrossRefGoogle Scholar
  16. 16.
    Nordlund B, Melen E, Schultz ES, Gronlund H, Hedlin G, Kull I. Prevalence of severe childhood asthma according to the WHO. Respir Med. 2014;108(8):1234–7.CrossRefGoogle Scholar
  17. 17.
    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(9643):1058–64.CrossRefGoogle Scholar
  18. 18.
    Lang A, Carlsen KH, Haaland G, Devulapalli CS, Munthe-Kaas M, Mowinckel P, et al. Severe asthma in childhood: assessed in 10 year olds in a birth cohort study. Allergy. 2008;63(8):1054–60.CrossRefGoogle Scholar
  19. 19.
    Barnes PJ, Jonsson B, Klim JB. The costs of asthma. Eur Respir J. 1996;9(4):636–42.CrossRefGoogle Scholar
  20. 20.
    Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide. J Allergy Clin Immunol. 2006;118(6):1218–25.CrossRefGoogle Scholar
  21. 21.
    Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbison GP, et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med. 2002;165(11):1480–8.CrossRefGoogle Scholar
  22. 22.
    Konradsen JR, Nordlund B, Lidegran M, Pedroletti C, Gronlund H, van Hage M, et al. Problematic severe asthma: a proposed approach to identifying children who are severely resistant to therapy. Pediatr Allergy Immunol. 2011;22(1 Pt 1):9–18.CrossRefGoogle Scholar
  23. 23.
    Tai A, Tran H, Roberts M, Clarke N, Gibson AM, Vidmar S, et al. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol. 2014;133(6):1572–8 e3.CrossRefGoogle Scholar
  24. 24.
    Moore WC, Peters SP. Severe asthma: an overview. J Allergy Clin Immunol. 2006;117(3):487–94; quiz 95.CrossRefGoogle Scholar
  25. 25.
    Jarjour NN, Erzurum SC, Bleecker ER, Calhoun WJ, Castro M, Comhair SA, et al. Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am J Respir Crit Care Med. 2012;185(4):356–62.CrossRefGoogle Scholar
  26. 26.
    Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119(2):405–13.CrossRefGoogle Scholar
  27. 27.
    Teague WG, Phillips BR, Fahy JV, Wenzel SE, Fitzpatrick AM, Moore WC, et al. Baseline features of the Severe Asthma Research Program (SARP III) Cohort: differences with age. J Allergy Clin Immunol Pract. 2018;6(2):545–54 e4.CrossRefGoogle Scholar
  28. 28.
    Fitzpatrick AM, Moore WC. Severe asthma phenotypes - how should they guide evaluation and treatment? J Allergy Clin Immunol Pract. 2017;5(4):901–8.CrossRefGoogle Scholar
  29. 29.
    Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113(1):101–8.CrossRefGoogle Scholar
  30. 30.
    ten Brinke A, van Dissel JT, Sterk PJ, Zwinderman AH, Rabe KF, Bel EH. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol. 2001;107(3):449–54.CrossRefGoogle Scholar
  31. 31.
    Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315–23.CrossRefGoogle Scholar
  32. 32.
    Lee JH, Haselkorn T, Borish L, Rasouliyan L, Chipps BE, Wenzel SE. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest. 2007;132(6):1882–9.CrossRefGoogle Scholar
  33. 33.
    Amelink M, de Nijs SB, Berger M, Weersink EJ, ten Brinke A, Sterk PJ, et al. Non-atopic males with adult onset asthma are at risk of persistent airflow limitation. Clin Exp Allergy. 2012;42(5):769–74.CrossRefGoogle Scholar
  34. 34.
    Bui DS, Burgess JA, Lowe AJ, Perret JL, Lodge CJ, Bui M, et al. Childhood lung function predicts adult chronic obstructive pulmonary disease and asthma-chronic obstructive pulmonary disease overlap syndrome. Am J Respir Crit Care Med. 2017;196(1):39–46.CrossRefGoogle Scholar
  35. 35.
    Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012;42(5):650–8.CrossRefGoogle Scholar
  36. 36.
    Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192(6):660–8.CrossRefGoogle Scholar
  37. 37.
    Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010;125(5):1028–36 e13.CrossRefGoogle Scholar
  38. 38.
    Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557–63 e5.CrossRefGoogle Scholar
  39. 39.
    Lemiere C, Ernst P, Olivenstein R, Yamauchi Y, Govindaraju K, Ludwig MS, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol. 2006;118(5):1033–9.CrossRefGoogle Scholar
  40. 40.
    Hekking PP, Bel EH. Developing and emerging clinical asthma phenotypes. J Allergy Clin Immunol Pract. 2014;2(6):671–80; quiz 81.CrossRefGoogle Scholar
  41. 41.
    Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218–24.CrossRefGoogle Scholar
  42. 42.
    Siroux V, Basaga√±a X, Boudier A, Pin I, Garcia-Aymerich J, Vesin A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J. 2011;38(2):310–7.CrossRefGoogle Scholar
  43. 43.
    Kim T-B, Jang A-S, Kwon H-S, Park J-S, Chang Y-S, Cho S-H, et al. Identification of asthma clusters in two independent Korean adult asthma cohorts. Eur Respir J. 2013;41(6):1308–14.CrossRefGoogle Scholar
  44. 44.
    Amelink M, de Nijs SB, de Groot JC, van Tilburg PMB, van Spiegel PI, Krouwels FH, et al. Three phenotypes of adult-onset asthma. Allergy. 2013;68:674–80.CrossRefGoogle Scholar
  45. 45.
    Schatz M, Hsu JW, Zeiger RS, Chen W, Dorenbaum A, Chipps BE, et al. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2013;133(6):1549–56.CrossRefGoogle Scholar
  46. 46.
    Newby C, Heaney LG, Menzies-Gow A, Niven RM, Mansur A, Bucknall C, et al. Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One. 2014;9(7):e102987.CrossRefGoogle Scholar
  47. 47.
    Zaihra T, Walsh CJ, Ahmed S, Fugere C, Hamid QA, Olivenstein R, et al. Phenotyping of difficult asthma using longitudinal physiological and biomarker measurements reveals significant differences in stability between clusters. BMC Pulm Med. 2016;16(1):74.CrossRefGoogle Scholar
  48. 48.
    Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol. 2017;139(6):1797–807.CrossRefGoogle Scholar
  49. 49.
    Loza MJ, Djukanovic R, Chung KF, Horowitz D, Ma K, Branigan P, et al. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res. 2016;17(1):165.CrossRefGoogle Scholar
  50. 50.
    Boudier A, Curjuric I, Basagana X, Hazgui H, Anto JM, Bousquet J, et al. Ten-year follow-up of cluster-based asthma phenotypes in adults. A pooled analysis of three cohorts. Am J Respir Crit Care Med. 2013;188(5):550–60.CrossRefGoogle Scholar
  51. 51.
    Sakagami T, Hasegawa T, Koya T, Furukawa T, Kawakami H, Kimura Y, et al. Cluster analysis identifies characteristic phenotypes of asthma with accelerated lung function decline. J Asthma. 2014;51(2):113–8.CrossRefGoogle Scholar
  52. 52.
    Ilmarinen P, Tuomisto LE, Niemela O, Tommola M, Haanpaa J, Kankaanranta H. Cluster analysis on longitudinal data of patients with adult-onset asthma. J Allergy Clin Immunol Pract. 2017;5(4):967–78 e3.CrossRefGoogle Scholar
  53. 53.
    Wu W, Bleecker E, Moore W, Busse WW, Castro M, Chung KF, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol. 2014;133(5):1280–8.CrossRefGoogle Scholar
  54. 54.
    Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2013;133(6):1557–63 e5.CrossRefGoogle Scholar
  55. 55.
    Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, et al. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol. 2011;127(2):382–9 e1-13.CrossRefGoogle Scholar
  56. 56.
    Howrylak JA, Fuhlbrigge AL, Strunk RC, Zeiger RS, Weiss ST, Raby BA. Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications. J Allergy Clin Immunol. 2014;133(5):1289–300, 300 e1-12.CrossRefGoogle Scholar
  57. 57.
    Just J, Gouvis-Echraghi R, Rouve S, Wanin S, Moreau D, Annesi-Maesano I. Two novel, severe asthma phenotypes identified during childhood using a clustering approach. Eur Respir J. 2012;40(1):55–60.CrossRefGoogle Scholar
  58. 58.
    Just J, Gouvis-Echraghi R, Couderc R, Guillemot-Lambert N, Saint-Pierre P. Novel severe wheezy young children phenotypes: boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze. J Allergy Clin Immunol. 2012;130(1):103–10 e8.CrossRefGoogle Scholar
  59. 59.
    Moore WC, Fitzpatrick AM, Li X, Hastie AT, Li H, Meyers DA, et al. Clinical heterogeneity in the severe asthma research program. Ann Am Thorac Soc. 2013;10(Suppl):S118–24.CrossRefGoogle Scholar
  60. 60.
    Patrawalla P, Kazeros A, Rogers L, Shao Y, Liu M, Fernandez-Beros M-E, et al. Application of the asthma phenotype algorithm from the severe asthma research program to an urban population. PLoS One. 2012;7(9):e44540.CrossRefGoogle Scholar
  61. 61.
    Kuhlen JL Jr, Wahlquist AE, Nietert PJ, Bains SN. Identification of asthma phenotypes in a tertiary care medical center. Am J Med Sci. 2014;348(6):480–5.CrossRefGoogle Scholar
  62. 62.
    Bourdin A, Molinari N, Vachier I, Varrin M, Marin G, Gamez AS, et al. Prognostic value of cluster analysis of severe asthma phenotypes. J Allergy Clin Immunol. 2014;134(5):1043–50.CrossRefGoogle Scholar
  63. 63.
    Kupczyk M, Dahlen B, Sterk PJ, Nizankowska-Mogilnicka E, Papi A, Bel EH, et al. Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma. Allergy. 2014;69(9):1198–204.CrossRefGoogle Scholar
  64. 64.
    Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med. 2017;195(3):302–13.CrossRefGoogle Scholar
  65. 65.
    Opina MT, Moore WC. Phenotype-Driven Therapeutics in Severe Asthma. Curr Allergy Asthma Rep. 2017;17(2):10.CrossRefGoogle Scholar
  66. 66.
    Schatz M, Rosenwasser L. The allergic asthma phenotype. J Allergy Clin Immunol Pract Nov-Dec. 2014;2(6):645–8; quiz 9.CrossRefGoogle Scholar
  67. 67.
    Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.Google Scholar
  68. 68.
    Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–96.CrossRefGoogle Scholar
  69. 69.
    Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and safety of Dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475–85.CrossRefGoogle Scholar
  70. 70.
    Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy. Ann Intern Med. 2011;154(9):573–82.CrossRefGoogle Scholar
  71. 71.
    Amelink M, de Groot JC, de Nijs SB, Lutter R, Zwinderman AH, Sterk PJ, et al. Severe adult-onset asthma: A distinct phenotype. J Allergy Clin Immunol. 2013;132(2):336.CrossRefGoogle Scholar
  72. 72.
    Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.CrossRefGoogle Scholar
  73. 73.
    Ortega H, Li H, Suruki R, Albers F, Gordon D, Yancey S. Cluster analysis and characterization of response to mepolizumab. A step closer to personalized medicine for patients with severe asthma. Ann Am Thorac Soc. 2014;11(7):1011–7.CrossRefGoogle Scholar
  74. 74.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.CrossRefGoogle Scholar
  75. 75.
    Bel EH, Ten Brinke A. New anti-eosinophil drugs for asthma and COPD: targeting the trait! Chest. 2017;152(6):1276–82.CrossRefGoogle Scholar
  76. 76.
    Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448–58.CrossRefGoogle Scholar
  77. 77.
    Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Theo J. Moraes
    • 1
  • Wendy C. Moore
    • 2
  • Padmaja Subbarao
    • 1
    • 3
    Email author
  1. 1.Department of PediatricsUniversity of Toronto and Translational Medicine, SickKids Research InstituteTorontoCanada
  2. 2.Wake Forest School of Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic DiseasesWinston SalemUSA
  3. 3.The Hospital for Sick ChildrenTorontoCanada

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