Biologics in the Treatment of Severe Uncontrolled Asthma in Children

Abstract

Asthma is the most common chronic disease in children, currently affecting about 7 million children. Severe uncontrolled asthma is rare in children with a prevalence of about 2.1% to 5%, but inflicts a disproportionate health burden. Children with severe asthma have increased risk of life threatening exacerbations, frequent hospitalization, worsening health-related quality of life, and impaired physical activity. Severe asthma in childhood is associated with long-term morbidities, such as bronchiolitis obliterans, impaired airway development, and development of chronic obstructive pulmonary disease in adulthood. Childhood asthma like adult-onset asthma, is classified into four cellular inflammatory phenotypes using induced sputum cytometry. The four phenotypes of asthma include eosinophilic asthma, neutrophilic asthma, paucigranulocytic asthma, and mixed cellularity asthma. The pathophysiological mechanisms of asthma involve airway inflammation and remodeling. Inflammatory mediators such as cytokines, chemokines, adhesion molecules, and growth factors play a key role in orchestration airway remodeling. During airway inflammation, cytokines secreted by type 2 helper (Th2) lymphocytes, such as interleukin-5 (IL-5), IL-4, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) play a key role in the pathogenesis of eosinophilic asthma. Whereas, the Th17 axis cytokines, including IL-17, IL-23, and IL-8 are responsible for the pathophysiology of neutrophilic asthma. The airway structural changes due to airway remodeling lead to thickening of the airway wall, narrowing of the bronchiolar lumen, airway obstruction, and decline in pulmonary function. Most of the children with asthma respond to low and medium inhaled corticosteroids, however a significant proportion still have severe asthma uncontrolled on the standard of care. The most common asthma phenotype in children is eosinophilic asthma, which responds superbly to biologic therapy. Children with severe asthma require add-on targeted interleukin antagonists (ILA), such as mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and dupilumab (anti-4Rα). ILAs have been shown to ameliorate asthma symptoms, reduce moderate and severe exacerbations, and improve pulmonary function. Additionally, ILAs have been demonstrated to improve the health-related quality of life, and have steroid sparing effect.