Severe Asthma in Children: Therapeutic Considerations

Louise Selby; Sejal Saglani


Curr Opin Allergy Clin Immunol. 2019;19(2):132-140. 

In This Article

Future Directions: Targeting Neutrophils in Severe Therapy-resistant Asthma

Are Neutrophils Helpful or Harmful in Childhood Severe Therapy-resistant Asthma?

Asthma has been traditionally associated with Th2 cells producing signature cytokines IL-4, IL-5 and IL-13; however, cluster analyzes in adults have shown 'Th2 low' and 'Th2 high' phenotypes.[51,52] In childhood, there appears to be a close association between pathophysiological phenotype and age. A paediatric cluster analysis revealed age-related inflammatory clusters with a neutrophilic steroid-refractory cluster with a mean age of 40 months comprising severe preschool wheezers, whereas a steroid-refractory eosinophilic cluster had a mean age of 11 years.[21]

Neutrophilic inflammation has been associated with severe disease in adult asthma[53,54] and increased levels of IL-17 in bronchoalveolar lavage (BAL), blood and sputum have also been associated with more severe disease.[55] A Brazilian prospective cohort study of 48 children aged 6–18 years investigated sputum inflammatory profiles in STRA children and compared them to children with difficult asthma who achieved symptom control. Nonasthmatic controls were not included. Study participants underwent three visits, with confirmation of STRA at the last visit (defined as ACT score <20, frequent severe exacerbations with >2 courses of systemic corticosteroids and at least one hospital admission requiring high dependency or ventilation and an FEV1 <80% throughout the study period). Of the 42, 13 (32.5% children) were classified as STRA and had higher induced sputum neutrophils at the third study visit and higher levels of IL-10, IFN-γ, TNF-α and granulocyte-macrophage colony-stimulating-factor (GM-CSF). TNF-α and GM-CSF negatively correlated with ACT scores.[56] A further study has defined neutrophil-high and neutrophil-low STRA sub-groups based on inflammation in BAL and shown children with neutrophil-predominant phenotypes had pro-inflammatory neutrophils with increased neutrophil activation, recruitment/migration, granule release and enhanced survival.[57] Again, comparisons were made within the severe asthma subgroup, not with non-asthmatic controls. Comparison of STRA children to non-asthmatic controls has not revealed increased airway neutrophils in BAL or in the submucosal region of bronchial biopsies. However, location-specific examination of endobronchial biopsies showed significantly increased intra-epithelial neutrophils in a sub-group of children with STRA associated with better lung function, symptom control and lower prescribed doses of ICS.[58] Although this data may appear to contradict the other two studies, it must be remembered that the airway compartments analyzed were different and highlights the importance of relationships and interactions between inflammatory and structural cells in determining functional outcomes. BAL and biopsy IL-17A were not significantly different between controls and STRA children, although IL-17 receptor expression was increased in STRA.[58] Blockade of this receptor has been associated with reduced airway inflammation and hyper-reactivity in murine models,[59] but a clinical trial has not shown benefit.[60] The functional role of neutrophils and IL-17A in driving disease in paediatric STRA remains uncertain. We do not know whether both may be induced by steroid therapy, with no functional consequence,[61] or whether either or both are disease-causing contributing to severity. It may be that luminal neutrophils are pro-inflammatory in STRA because they are required to fight infection or external exposures such as pollution. Subclinical microbial dysbiosis which may only be detected using molecular diagnostic techniques may explain the highly activated and increased luminal neutrophils in this subgroup.[57] A potential therapeutic approach for this 'Th-2 low' asthma phenotype is azithromycin, which has anti-inflammatory properties, and has been shown to reduce exacerbations with regular use in adults with persistent, uncontrolled asthma.[62] However, there are no data for efficacy in children, and key to understanding whether neutrophils may be protective or pathogenic in childhood STRA is not to extrapolate data from adult studies,[56,63] but to undertake interventional studies incorporating mechanistic and functional outcomes in accurately clinically phenotyped sub-groups.