Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis

J Allergy Clin Immunol. 2014 Jun;133(6):1557-63.e5. doi: 10.1016/j.jaci.2013.10.011. Epub 2013 Dec 9.


Background: Clinical cluster analysis from the Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes that represent the severity spectrum of early-onset allergic asthma, late-onset severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics. Analysis of induced sputum from a subset of SARP subjects showed 4 sputum inflammatory cellular patterns. Subjects with concurrent increases in eosinophil (≥2%) and neutrophil (≥40%) percentages had characteristics of very severe asthma.

Objective: To better understand interactions between inflammation and clinical subphenotypes, we integrated inflammatory cellular measures and clinical variables in a new cluster analysis.

Methods: Participants in SARP who underwent sputum induction at 3 clinical sites were included in this analysis (n = 423). Fifteen variables, including clinical characteristics and blood and sputum inflammatory cell assessments, were selected using factor analysis for unsupervised cluster analysis.

Results: Four phenotypic clusters were identified. Cluster A (n = 132) and B (n = 127) subjects had mild-to-moderate early-onset allergic asthma with paucigranulocytic or eosinophilic sputum inflammatory cell patterns. In contrast, these inflammatory patterns were present in only 7% of cluster C (n = 117) and D (n = 47) subjects who had moderate-to-severe asthma with frequent health care use despite treatment with high doses of inhaled or oral corticosteroids and, in cluster D, reduced lung function. The majority of these subjects (>83%) had sputum neutrophilia either alone or with concurrent sputum eosinophilia. Baseline lung function and sputum neutrophil percentages were the most important variables determining cluster assignment.

Conclusion: This multivariate approach identified 4 asthma subphenotypes representing the severity spectrum from mild-to-moderate allergic asthma with minimal or eosinophil-predominant sputum inflammation to moderate-to-severe asthma with neutrophil-predominant or mixed granulocytic inflammation.

Keywords: Severe Asthma Research Program; cluster analysis; eosinophils; neutrophils; phenotype; severe asthma; sputum.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Asthma / blood
  • Asthma / diagnosis*
  • Asthma / physiopathology
  • Cluster Analysis*
  • Female
  • Granulocytes
  • Humans
  • Leukocyte Count*
  • Male
  • Middle Aged
  • Neutrophils*
  • Phenotype*
  • Respiratory Function Tests
  • Risk Factors
  • Severity of Illness Index*
  • Sputum / cytology*
  • Young Adult