Eosinophils in the Pathogenesis of Paediatric Severe Asthma
Eosinophils in the Pathogenesis of Paediatric Severe Asthma
In the context of severe asthma, it is apparent that eosinophils are the prominent inflammatory cell type. In a cohort of children in whom underlying modifiable factors for poor disease control, such as poor adherence and persistent allergen exposure, had been excluded, the dominant inflammatory phenotype was eosinophilic. This was true for both airway luminal samples [induced sputum and broncho-alveolar lavage (BAL)] as well as within the airway wall (endobronchial biopsy).
An important consideration when determining inflammatory phenotype in the context of severe disease in patients that are on high dose inhaled and/or oral steroid therapy is the relationship between pulmonary eosinophilia and peripheral blood eosinophils. Samples that reflect pulmonary inflammation either require invasive techniques (bronchoscopy) and/or a significant amount of resource utlilization in processing (induced sputum). Thus their clinical utility needs significant justification, especially in children. However, when high-dose inhaled steroids are prescribed, and efforts have been made to ensure they are being taken, it is apparent that an absence of peripheral blood eosinophilia does not equate to the same either in the airways or tissue. Similarly, an attempt to determine whether relatively less invasive markers of inflammation than induced sputum, such as exhaled nitric oxide, serum IgE and peripheral eosinophils, could be used as a surrogate for sputum eosinophil percentages in adults within the severe asthma research program showed none of the non-invasive markers individually, or in combination, could be used reliably to represent sputum eosinophils. These observations in severe asthma have very important clinical implications. Although elevated blood eosinophils may reflect airway eosinophilia, normal blood counts do not reliably exclude airway eosinophilia. Thus it is clear that peripheral counts should not be used to guide therapy or determine phenotypes in children with severe disease. Moreover, in children with severe asthma, the use of sputum eosinophils to guide alterations in inhaled corticosteroid therapy was not beneficial. In fact, in children with severe asthma, sputum inflammatory phenotype does not remain stable over time. Therefore, improvement of control in patients after therapies targeting eosinophils have not been uniform and have been met with limited success, suggesting that a much more complex relationship between eosinophils and induced lung pathology exists.
There are emerging data to suggest that markers of eosinophil activity, rather than numbers per se, may better dictate disease status. The propensity of blood eosinophils to lyse and release free extracellular granules is increased with increasing asthma severity in children. Blood eosinophil morphology was used as a marker of activated eosinophils which were higher in asymptomatic asthmatic patients compared with controls, and numbers were further increased during an exacerbation. In an adult study, patients with fewer granules in tissue eosinophils had better asthma control. It is possible that assessment of markers of eosinophil activity in both pulmonary tissue and airway lumen may better reflect disease control.
A limitation of induced sputum samples obtained from children is that they are not always of adequate quality for a reliable leukocyte count. A potential test that may address both the issue of measuring eosinophil activity and difficulty in obtaining an adequate cell count from sputum samples is an eosinophil peroxidase ELISA-based assay for sputum supernatants. This provided a reliable and eosinophil-specific surrogate for sputum eosinophil numbers and activity.
Paediatric Severe Asthma Is Eosinophilic
In the context of severe asthma, it is apparent that eosinophils are the prominent inflammatory cell type. In a cohort of children in whom underlying modifiable factors for poor disease control, such as poor adherence and persistent allergen exposure, had been excluded, the dominant inflammatory phenotype was eosinophilic. This was true for both airway luminal samples [induced sputum and broncho-alveolar lavage (BAL)] as well as within the airway wall (endobronchial biopsy).
An important consideration when determining inflammatory phenotype in the context of severe disease in patients that are on high dose inhaled and/or oral steroid therapy is the relationship between pulmonary eosinophilia and peripheral blood eosinophils. Samples that reflect pulmonary inflammation either require invasive techniques (bronchoscopy) and/or a significant amount of resource utlilization in processing (induced sputum). Thus their clinical utility needs significant justification, especially in children. However, when high-dose inhaled steroids are prescribed, and efforts have been made to ensure they are being taken, it is apparent that an absence of peripheral blood eosinophilia does not equate to the same either in the airways or tissue. Similarly, an attempt to determine whether relatively less invasive markers of inflammation than induced sputum, such as exhaled nitric oxide, serum IgE and peripheral eosinophils, could be used as a surrogate for sputum eosinophil percentages in adults within the severe asthma research program showed none of the non-invasive markers individually, or in combination, could be used reliably to represent sputum eosinophils. These observations in severe asthma have very important clinical implications. Although elevated blood eosinophils may reflect airway eosinophilia, normal blood counts do not reliably exclude airway eosinophilia. Thus it is clear that peripheral counts should not be used to guide therapy or determine phenotypes in children with severe disease. Moreover, in children with severe asthma, the use of sputum eosinophils to guide alterations in inhaled corticosteroid therapy was not beneficial. In fact, in children with severe asthma, sputum inflammatory phenotype does not remain stable over time. Therefore, improvement of control in patients after therapies targeting eosinophils have not been uniform and have been met with limited success, suggesting that a much more complex relationship between eosinophils and induced lung pathology exists.
There are emerging data to suggest that markers of eosinophil activity, rather than numbers per se, may better dictate disease status. The propensity of blood eosinophils to lyse and release free extracellular granules is increased with increasing asthma severity in children. Blood eosinophil morphology was used as a marker of activated eosinophils which were higher in asymptomatic asthmatic patients compared with controls, and numbers were further increased during an exacerbation. In an adult study, patients with fewer granules in tissue eosinophils had better asthma control. It is possible that assessment of markers of eosinophil activity in both pulmonary tissue and airway lumen may better reflect disease control.
A limitation of induced sputum samples obtained from children is that they are not always of adequate quality for a reliable leukocyte count. A potential test that may address both the issue of measuring eosinophil activity and difficulty in obtaining an adequate cell count from sputum samples is an eosinophil peroxidase ELISA-based assay for sputum supernatants. This provided a reliable and eosinophil-specific surrogate for sputum eosinophil numbers and activity.
