Original Article
Systemic Corticosteroid Responses in Children with Severe Asthma: Phenotypic and Endotypic Features

https://doi.org/10.1016/j.jaip.2016.08.001Get rights and content

Background

Severe asthma in children is a heterogeneous disorder associated with variable responses to corticosteroid treatment. Criterion standards for corticosteroid responsiveness assessment in children are lacking.

Objective

This study sought to characterize systemic corticosteroid responses in children with severe asthma after treatment with intramuscular triamcinolone and to identify phenotypic and molecular predictors of an intramuscular triamcinolone response.

Methods

Asthma-related quality of life, exhaled nitric oxide, blood eosinophils, lung function, and inflammatory cytokine and chemokine mRNA gene expression in peripheral blood mononuclear cells were assessed in 56 children with severe asthma at baseline and 14 days after intramuscular triamcinolone injection. The Asthma Control Questionnaire was used to classify children with severe asthma into corticosteroid response groups.

Results

Three groups of children with severe asthma were identified: controlled severe asthma, children who achieved control after triamcinolone, and children who did not achieve control. At baseline, these groups were phenotypically similar. After triamcinolone, discordance between symptoms, lung function, exhaled nitric oxide, and blood eosinophils was noted. Clinical phenotypic predictors were of limited utility in predicting the triamcinolone response, whereas systemic mRNA expression of inflammatory cytokines and chemokines related to IL-2, IL-10, and TNF signaling pathways, namely, AIMP1, CCR2, IL10RB, and IL5, strongly differentiated children who failed to achieve control with triamcinolone administration.

Conclusions

Systemic corticosteroid responsiveness in children with severe asthma is heterogeneous. Alternative prediction models that include molecular endotypic as well as clinical phenotypic features are needed to identify which children derive the most clinical benefit from systemic corticosteroid step-up therapy given the potential side effects.

Section snippets

Methods

Children aged 6 to 17 years with physician-diagnosed asthma treated with high-dose ICS and a second controller medication were recruited from an outpatient severe asthma clinic in Atlanta, Georgia. All children met published criteria for severe asthma1 including adherence to ICS evidenced by 10 or more monthly electronic prescription refills over the previous 12 months. Each participant had a history of either 12% or more reversibility in FEV1 after bronchodilator administration or airway

Results

Enrollment for the study occurred year-round between March 2010 and March 2014. Sixty-six children with severe asthma were enrolled and 56 children completed the study (see Figure E1 in this article's Online Repository at www.jaci-inpractice.org). The features of children who were lost to follow-up were not significantly different (age, 12 ± 5 years; 64% males; 86% black). Participants were treated for 12 months or more before enrollment with high-dose ICS (827 ± 295 μg/d inhaled fluticasone

Discussion

High doses of corticosteroids are the cornerstone of therapy for children with severe asthma, but responses to corticosteroids are variable and difficult to assess in the clinical setting. Using a clinically accessible questionnaire of asthma control, we identified 3 groups of children with severe asthma, including 1 group of children who failed to achieve asthma control after receipt of intramuscular triamcinolone. These children had overall reductions in blood eosinophil percentages and

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    This study was funded by grant number R01 NR012021 and was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (award no. UL1 TR000454).

    Conflicts of interest: A. M. Fitzpatrick has received money for consultancy from Genentech and Boehringer Ingelheim. A. M. Fitzpatrick's institution, S. T. Stephenson's institution, M. R. Brown's institution, K. Nguyen's institution, S. Douglas' institution, and L. A. S. Brown's institution have received a grant from the National Institutes of Health (NIH)/National Institute of Nursing Research (grant no. R01NR012021).

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