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

doi:10.1016/j.jaci.2013.10.011

Journal of Allergy and Clinical Immunology

Volume 133, Issue 6, June 2014, Pages 1557-1563.e5

https://doi.org/10.1016/j.jaci.2013.10.011 Get rights and content

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.

Section snippets

SARP

After establishing standard operating procedures, including a review by an independent data safety monitoring board and approval by the institutional review boards of all sites, study participants underwent comprehensive phenotypic characterization, as previously described.⁴ Briefly, 2 groups of nonsmoking asthmatic subjects (<5 pack years of tobacco use) were recruited. Those with severe asthma met the ATS definition of severe asthma.³ A second group of subjects with mild-to-moderate asthma

Subject selection

Four hundred twenty-three subjects in SARP underwent sputum induction and had complete data for analysis (244 subjects from Wake Forest University, 103 subjects from the University of Wisconsin, and 76 subjects from the University of Pittsburgh). A comparison of the demographics and baseline clinical characteristics of this subset of subjects with those of the larger SARP cohort used in the previous cluster analysis is shown in Table E1 in this article's Online Repository at www.jacionline.org.⁷

Discussion

The original SARP clinical cluster analysis identified 5 asthma phenotypes that differed in phenotypic characteristics, medication use, HCU, lung function, and responsiveness to bronchodilators.⁷ The current analysis integrates measures of cellular inflammation, clinical characteristics, and physiologic variables in a new cluster analysis on 423 subjects who had both blood and induced sputum cell differentials performed at 3 SARP clinical centers. Using a similar clustering approach, we

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: The Severe Asthma Research Program (SARP) is a multicenter asthma research group funded by the National Heart, Lung, and Blood Institute (NHLBI) and consisting of the following universities (principal investigators): Brigham & Women's Hospital—Elliot Israel; Cleveland Clinic—Serpil C. Erzurum; Emory University—Anne M. Fitzpatrick; Imperial College School of Medicine—Kian F. Chung; University of Pittsburgh—Sally E. Wenzel; University of Texas–Medical Branch—William J. Calhoun; University of Virginia—Benjamin Gaston, W. Gerald Teague; University of Wisconsin—William W. Busse; Wake Forest University—Eugene R. Bleecker; Washington University in St Louis—Mario Castro; Data Coordinating Center—Douglas Curran-Everett; NHLBI—Patricia Noel, Robert Smith.

: Supported by grants HL69116, HL69167, HL69174, and UL1RR025011.

: Disclosure of potential conflict of interest: W. C. Moore, A. T. Hastie, D. A. Meyers, and E. R. Bleecker have received research support from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI). W. W. Busse has received research support from the NIH/NHLBI and the NIH/National Institute of Allergy and Infectious Disease; has board membership with Merck; has consultant arrangements with Amgen, Novartis, GlaxoSmithKline, MedImmune, Genentech, Boston Scientific, and ICON; and has received royalties from Elsevier. S. E. Wenzel has consultant arrangements with TEVA, MedImmune, Gilead, and Amgen; has received research support from Merck, GlaxoSmithKline, Array, and Sanofi; and is on the long-acting β-agonist safety data and safety monitoring board for GlaxoSmithKline. S. P. Peters has received research and travel support from the NIH/NHLBI; has consultant arrangements with AstraZeneca, Aerocrine, Airsonett AB, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, Targacept, and TEVA; has received payment for lectures from Integrity CE and Merck; and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

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Asthma and lower airway diseaseSputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis

Background

Objective

Methods

Results

Conclusion

Section snippets

SARP

Subject selection

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Expert panel report 3: guidelines for the diagnosis and management of asthma

Global strategy for asthma management and prevention: GINA executive summary

Eur Respir J

Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society

Am J Respir Crit Care Med

Cluster analysis and clinical asthma phenotypes

Am J Respir Crit Care Med

Distinct clinical phenotypes of airways disease defined by cluster analysis

Eur Respir J

Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

Am J Respir Crit Care Med

Asthma and lower airway disease
Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis