The molecular phenotype of severe asthma in children

Abstract

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-gamma, 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 T(H)1 or T(H)2 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.

Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1

Scatterplot of the discriminant functions generated from 23 BAL fluid cytokines and chemokines. Each data point represents a single subject. The plot depicts clustering and clear separation of children with severe asthma (white diamonds) from children with moderate asthma (black triangles) and healthy controls (gray circles).

Figure 2

Scatterplot of the discriminant functions generated from 11 AM lysate cytokines and chemokines. Each data point represents a single subject. The plot depicts clustering and clear separation of children with severe asthma (white diamonds) from children with moderate asthma (black triangles) and healthy controls (gray circles).