Asthma and lower airway disease
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

https://doi.org/10.1016/j.jaci.2010.11.015Get rights and content

Background

Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities.

Objectives

This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity.

Methods

Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program.

Results

Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines.

Conclusion

Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.

Section snippets

Methods

The SARP is an NHLBI-supported research program with recruitment of children 6 to 17 years of age across 5 centers in the United States. Each of the SARP centers is affiliated with a major university teaching program, and children are recruited into SARP from the outpatient clinics and inpatient hospital wards of those academic centers. As a result, children enrolled in SARP are more likely to have difficult asthma and are representative of a referral population of children who receive care at

Results

Results from 273 children (mean age 10 years) enrolled in SARP across 4 centers in Atlanta, Ga, Winston-Salem, NC, Pittsburgh, Pa, St Louis, Mo, and Charlottesville, Va, were available for analysis. Of these, 112 were missing 1 or more of the cluster variables and were excluded. The features of excluded children did not differ from those of the final sample (see this article’s Table E6 in the Online Repository at www.jacionline.org). The final sample included 161 children. Features of the

Discussion

Asthma in children is a complicated and heterogeneous disorder with distinct phenotypes. By using an unsupervised cluster analysis in children with a wide range of asthma severity characterized in the SARP network, we have identified 4 clusters of childhood asthma with shared phenotypic features. Similar to the previous SARP report that described increased allergic sensitization in clusters of adults with early-onset asthma,21., 27. clusters of childhood asthma were all atopic, although the

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    Supported by National Institutes of Health grants RO1 HL069170, RO1 HL069167, RO1 HL069174, RO1 HL69149, and RO1 HL091762 and in part by the Center for Developmental Lung Biology, Children’s Healthcare of Atlanta, and PHS grants UL1 RR025008, KL2 RR025009, TL1 RR025010, and UL1 RR024992 from the Clinical and Translational Science Award Program, National Institutes of Health, National Center for Research Resources.

    Disclosure of potential conflict of interest: A. M. Fitzpatrick has received research support from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. W. G. Teague is a speaker for Merck, has received research support from the National Institutes of Health and the American Lung Association, and is a volunteer for Not One More Life. D. A. Meyers has received research support from the National Institutes of Health. S. P. Peters has received research support from the National Institutes of Health, National Heart, Lung, and Blood Institute Severe Asthma Research Program. M. Castro is a consultant for Electrocore, NKTT, Schering, Asthmatx, and Cephalon; is on the advisory board for Genentech; is a speaker for AstraZeneca, Boehringer-Ingelheim, Pfizer, Merck, and GlaxoSmithKline; has received grants from Asthmatx, Amgen, Ception, Genentech, Medimmune, Merck, Novartis, the National Institutes of Health, and GlaxoSmithKline; and has received royalties from Elsevier. L. B. Bacharier has received honoraria from AstraZeneca and has received honoraria from and is on the advisory board for Genentech, Glaxo-SmithKline, Merck, Schering-Plough, and Aerocrine. B. M. Gaston has received research support from the National Institutes of Health and has served as an expert witness on the topic of exhaled nitric oxide for Apieron. E. R. Bleecker is an advisor and consultant for Aerovance, AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, and Wyeth and has received research support from Aerovance, Amgen, AstraZeneca, Boehringer-Ingelheim, Centocor, Ception, Genentech, GlaxoSmithKline, the National Institutes of Health, Novartis, Pfizer, and Wyeth. The rest of the authors have declared that they have no conflict of interest.

    A complete listing of Severe Asthma Research Program investigators is provided in the acknowledgments.

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