Asthma and lower airway disease
The molecular phenotype of severe asthma in children

https://doi.org/10.1016/j.jaci.2010.01.048Get rights and content

Background

Although the clinical attributes of severe asthma in children have been well described, the differentiating features of the lower airway inflammatory response are less understood.

Objectives

We sought to discriminate severe from moderate asthma in children by applying linear discriminant analysis, a supervised method of high-dimensional data reduction, to cytokines and chemokines measured in the bronchoalveolar lavage (BAL) fluid and alveolar macrophage (AM) lysate.

Methods

Bronchoalveolar lavage fluid was available from 53 children with asthma (severe asthma, n = 31) undergoing bronchoscopy for clinical indications and 30 nonsmoking adults. Twenty-three cytokines and chemokines were measured by using bead-based multiplex assays. Linear discriminant analyses of the BAL fluid and AM analytes were performed to develop predictive models of severe asthma in children.

Results

Although univariate analysis of single analytes did not differentiate severe from moderate asthma in children, linear discriminant analyses allowed for near complete separation of the moderate and severe asthmatic groups. Significant correlations were also noted between several of the AM and BAL analytes measured. In the BAL fluid, IL-13 and IL-6 differentiated subjects with asthma from controls, whereas growth-related oncogene (CXCL1), RANTES (CCL5), IL-12, IFN-γ, and IL-10 best characterized severe versus moderate asthma in children. In the AM lysate, IL-6 was the strongest discriminator of all the groups.

Conclusion

Severe asthma in children is characterized by a distinct airway molecular phenotype that does not have a clear TH1 or TH2 pattern. Improved classification of children with severe asthma may assist with the development of targeted therapeutics for this group of children who are difficult to treat.

Section snippets

Sample

A convenience sample of asthmatic children 5 to 17 years of age undergoing bronchoscopy for clinical indications was obtained. All children met criteria for persistent asthma17 and had a history of at least a 12% change in FEV1 after bronchodilator administration.18 Severe asthma was diagnosed according to criteria developed by the Severe Asthma Research Program,1, 5 which were adapted from the American Thoracic Society's Report (see this article's Table E1 in the Online Repository at //www.jacionline.org

Results

Sixty children with asthma (severe asthma, n = 35) and 30 healthy adult controls participated in this study. However, 7 children (severe asthma, n = 4) infected with Streptococcus pneumoniae or Haemophilus influenzae were excluded from data analysis (see this article's Table E4 in the Online Repository at www.jacionline.org). The resulting sample included 30 controls, 22 subjects with moderate asthma, and 31 subjects with severe asthma. Children with moderate asthma had no evidence of

Discussion

To our knowledge, this is the first study to use high-dimensional data reduction techniques on BAL and AM inflammatory markers in children with severe asthma. By using the supervised method of linear discriminant analysis, we provide the first preliminary evidence of the molecular phenotype of severe asthma in children. Whereas cytokine and chemokine concentrations in the BAL and AM cell lysate did not differ between children with moderate and severe asthma, the linear combination of these

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  • Cited by (0)

    Supported by NIH/NINRKO1 NR010548, NIH/NCRRK12 RR017643, and NIH/NHLBI SARPRO1 HL69170.

    Disclosure of potential conflict of interest: W. G. Teague is on the speakers' bureau for Merck & Co and receives research support from the National Heart, Lung, and Blood Institute, the American Lung Association, and the Centers for Disease Control and Prevention. The rest of the authors have declared that they have no conflict of interest.

    Please refer to the acknowledgments for a complete listing of the Severe Asthma Research Program contributors.

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