Severe asthma in childhood: recent advances in phenotyping and pathogenesis

Abstract

Purpose of review: Children with severe asthma have a high degree of respiratory morbidity despite treatment with high doses of inhaled corticosteroids and are therefore very difficult to treat. This review will discuss phenotypic and pathogenic aspects of severe asthma in childhood, as well as remaining knowledge gaps.

Recent findings: As a group, children with severe asthma have a number of distinct phenotypic features compared with children with mild-to-moderate asthma. Clinically, children with severe asthma are differentiated by greater allergic sensitization, increased exhaled nitric oxide, and significant airflow limitation and air trapping that worsens as a function of age. These findings are accompanied by structural airway changes and increased and dysregulated airway inflammation and oxidant stress which may explain the differential nature of corticosteroid responsiveness in this population. Because children with severe asthma themselves are a heterogeneous group, current efforts are focused on improved definition and sub-phenotyping of the disorder. Whereas the clinical relevance of phenotyping approaches in severe asthma is not yet clear, they may provide important insight into the mechanisms underlying the disorder.

Summary: Improved classification of severe asthma through unified definitions, careful phenotypic analyses, and mechanism-focused endotyping approaches may ultimately advance knowledge and personalized treatment.

Figure 1

Publications on (A) severe asthma and (B) severe asthma in children from the 1950’s to present. Publications were limited to those indexed on PubMed and written in English. Searches were made for “severe asthma,” “difficult asthma,” and “difficult-to-treat asthma,” excluding “acute asthma” and animal studies.

Figure 2

The WHO definition of severe asthma.

Figure 3

Unbiased hierarchical cluster analysis reveals four clusters of asthma with shared phenotypic features. Although clusters 3 and 4 tend to be more “severe,” children with ATS-defined severe asthma are present in all clusters, thus highlighting the heterogeneity of the disorder [77].