, Volume 191, Issue 1, pp 87–93 | Cite as

Identification of Subtypes of Refractory Asthma in Korean Patients by Cluster Analysis

  • An Soo Jang
  • Hyouk-Soo Kwon
  • You Sook Cho
  • Yun Jeong Bae
  • Tae Bum Kim
  • Jong Sook Park
  • Sung Woo Park
  • Soo-Taek Uh
  • Jae-Sung Choi
  • Yong-Hoon Kim
  • Hyeon-Kyu Hwang
  • Hee-Bom Moon
  • Choon Sik Park



Refractory asthma, a subtype of asthma with uncontrolled symptoms despite antiasthma medications, is a heterogeneous syndrome with variable clinical features, presumably different etiologies, and pathophysiological mechanisms. The heterogeneity of refractory asthma, however, is poorly understood. We aimed to characterize refractory asthma and to improve our understanding of the heterogeneity of refractory asthma patients.


We identified refractory asthma patients (n = 96) as defined by the American Thoracic Society’s criteria from a cohort of Korean asthma patients (n = 2,187). Then, cluster analysis was conducted to classify subtypes of refractory asthma.


Among the study group, 4.4 % (n = 96) of all asthma patients had refractory asthma. Cluster analysis identified four distinct groups of refractory asthma. Age at onset was younger in clusters 1 and 2 than in clusters 3 and 4. Patients in cluster 1 had the most well-preserved pulmonary function; patients in cluster 2 had a female predominance and the most severe airway obstruction; patients in cluster 3 were mostly female and had the most enhanced bronchial hyperresponsiveness; and patients in cluster 4 were most male and tended to be cigarette smokers.


The current results suggest that refractory asthma is a heterogeneous syndrome and could be classified into four subtypes. Underlying pathogenesis and therapeutic approaches may differ for the different subtypes and further research is needed.


Asthma Cluster analysis Airway obstruction Bronchial hyperreactivity 



American Thoracic Society


Bronchial hyperresponsiveness


Body mass index


Chronic obstructive pulmonary disease


European Network for Understanding Mechanism of Severe Asthma


Forced expiratory volume in 1 s


Forced vital capacity


Global Initiative for Asthma


Inhaled corticosteroid


Long-acting beta-agonist

PC20 M

Methacholine concentration that induced a 20 % decline of FEV1 from baseline FEV1


Quality of life


Severe Asthma Research Program


The Epidemiology and Natural history of asthma: Outcomes and treatment Regimens



This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs (A090548 and A040153), Republic of Korea, to CSP, HBM, and YSC.

Conflict of interest

The authors have no conflicts of interest to disclose.


  1. 1.
    Wenzel S (2005) Severe asthma in adults. Am J Respir Crit Care Med 172:149–160PubMedCrossRefGoogle Scholar
  2. 2.
    Chanez P, Wenzel SE, Anderson GP et al (2007) Severe asthma in adults: what are the important questions? J Allergy Clin Immunol 119:1337–1348PubMedCrossRefGoogle Scholar
  3. 3.
    Barnes PJ, Woolcock AJ (1998) Difficult asthma. Eur Respir J 12:1209–1218PubMedCrossRefGoogle Scholar
  4. 4.
    Green RH, Brightling CE, Bradding P (2007) The reclassification of asthma based on subphenotypes. Curr Opin Allergy Clin Immunol 7:43–50PubMedCrossRefGoogle Scholar
  5. 5.
    Holgate ST, Polosa R (2006) The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 368:780–793PubMedCrossRefGoogle Scholar
  6. 6.
    Pavord ID, Birring SS, Berry M et al (2006) Multiple inflammatory hits and the pathogenesis of severe airway disease. Eur Respir J 27:884–888PubMedGoogle Scholar
  7. 7.
    Moore WC, Meyers DA, Wenzel SE et al (2010) Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 181(4):315–323PubMedCrossRefGoogle Scholar
  8. 8.
    Louis R (2009) Severe asthma: how can we differentiate phenotypes? Swiss Med Wkly 139:274–277PubMedGoogle Scholar
  9. 9.
    Moore WC, Bleecker ER, Curran-Everett D et al (2007) Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol 119:405–413PubMedCrossRefGoogle Scholar
  10. 10.
    Lee JH, Haselkorn T, Borish L et al (2007) Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest 132:1882–1889PubMedCrossRefGoogle Scholar
  11. 11.
    Abraham B, Antó JM, Barreiro E, Bel EH et al (2003) The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J 22:470–477Google Scholar
  12. 12.
    Mascia K, Haselkorn T, Deniz YM et al (2005) Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 116:970–975PubMedCrossRefGoogle Scholar
  13. 13.
    Busacker A, Newell JD, Keefe T et al (2009) A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest 135:48–56PubMedCrossRefGoogle Scholar
  14. 14.
    Brasier AR, Victor S, Boetticher G et al (2008) Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage-derived cytokines. J Allergy Clin Immunol 121(30–37):e36Google Scholar
  15. 15.
    Shaya FT, Dongyi D, Akazawa MO et al (2008) Burden of concomitant asthma and COPD in a Medicaid population. Chest 134:14–19PubMedCrossRefGoogle Scholar
  16. 16.
    Wenzel SE (2006) Asthma: defining of the persistent adult phenotypes. Lancet 368:804–813PubMedCrossRefGoogle Scholar
  17. 17.
    Haldar P, Pavord ID, Shaw DE et al (2008) Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 178:218–224PubMedCrossRefGoogle Scholar
  18. 18.
    Bradding P, Green RH (2010) Subclinical phenotypes of asthma. Curr Opin Allergy Clin Immunol 10(1):54–59PubMedCrossRefGoogle Scholar
  19. 19.
    Polosa R, Benfatto GT (2009) Managing patients with chronic severe asthma: rise to the challenge. Eur J Intern Med 20:114–124PubMedCrossRefGoogle Scholar
  20. 20.
    Wenzel SE, Fahy JV, Irvin C et al (2000) Proceedings of the ATS Workshop on Refractory Asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 162:2341–2351Google Scholar
  21. 21.
    Ball GH, Hall DJ (1967) A clustering technique for summarizing multivariate data. Behav Sci 12:153–155PubMedCrossRefGoogle Scholar
  22. 22.
    Siroux VI, Boudier A, Bousquet J et al (2009) Phenotypic determinants of uncontrolled asthma. J Allergy Clin Immunol 124(681–687):e683Google Scholar
  23. 23.
    Dolan CM, Fraher KE, Bleecker ER et al (2004) Design and baseline characteristics of The Epidemiology and Natural history of asthma: outcomes and treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 92:32–39PubMedCrossRefGoogle Scholar
  24. 24.
    Global Initiative for Asthma (2002) Global Strategy for Asthma Management and Prevention. Available from Accessed 20 April 2011
  25. 25.
    Gibson PG, Simpson JL (2009) The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 64:728–735PubMedCrossRefGoogle Scholar
  26. 26.
    Boulet LP, Lemiere C, Archambault F et al (2006) Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation. Chest 129:661–668PubMedCrossRefGoogle Scholar
  27. 27.
    Kim TB, Park CS, Bae YJ et al (2009) Factors associated with severity and exacerbation of asthma: a baseline analysis of the cohort for reality and evolution of adult asthma in Korea (COREA). Ann Allergy Asthma Immunol 103:311–317PubMedCrossRefGoogle Scholar
  28. 28.
    Gusbin N, Garzaniti N, Louis R (2006) Asthma and tobacco. Rev Med Liege 61:81–86PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • An Soo Jang
    • 1
  • Hyouk-Soo Kwon
    • 2
  • You Sook Cho
    • 2
  • Yun Jeong Bae
    • 2
  • Tae Bum Kim
    • 2
  • Jong Sook Park
    • 1
  • Sung Woo Park
    • 1
  • Soo-Taek Uh
    • 3
  • Jae-Sung Choi
    • 4
  • Yong-Hoon Kim
    • 4
  • Hyeon-Kyu Hwang
    • 5
  • Hee-Bom Moon
    • 2
  • Choon Sik Park
    • 1
  1. 1.Division of Allergy and Respiratory Medicine, Genome Research Center for Allergy and Respiratory DiseasesSoonchunhyang University Bucheon HospitalGyeonggi-doRepublic of Korea
  2. 2.Department of Allergy and Clinical Immunology, Asan Medical CenterUniversity of Ulsan, College of MedicineSeoulRepublic of Korea
  3. 3.Division of Allergy and Respiratory MedicineSoonchunhyang University Seoul HospitalSeoulRepublic of Korea
  4. 4.Division of Allergy and Respiratory DiseaseSoonchunhyang University Cheonan HospitalCheonanRepublic of Korea
  5. 5.Division of Allergy and Respiratory DiseaseSoonchunhyang University Gumi HospitalGyeongsangbuk-doRepublic of Korea

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