Steroid Refractory Airway Type-2 Inflammation in Severe Asthma

Published online: March 7, 2018

Airway type-2 inflammation, or allergic inflammation, is mediated by the type-2 cytokines (IL-4, IL-5, and IL-13) and is a key pathologic mechanism of asthma. Inhaled corticosteroids work by decreasing airway inflammation, but many asthmatics continue to experience asthma symptoms despite aggressive treatment with inhaled corticosteroids. Patients with this steroid resistance are commonly classified as having severe asthma and account for much of the public health burden of asthma. The pathobiology mechanisms that contribute to this steroid resistance remain unknown.

In a recently published study in The Journal of Allergy & Clinical Immunology (JACI), Peters and colleagues use a composite metric of airway type-2 cytokine gene expression, called the Type-2 Gene mean “T2GM”, to quantify airway type-2 inflammation in severe asthma patients on inhaled corticosteroids, non-severe asthma patients on inhaled corticosteroids, and healthy control subjects. The authors explored relationships between asthma outcomes and the T2GM, and the utility of non-invasive biomarkers of the airway T2GM.

The authors found that gene expression measures of airway type-2 inflammation were elevated in approximately half of severe asthma patients treated with inhaled corticosteroids. Furthermore, they found that a systemic dose of corticosteroids did not suppress airway type-2 inflammation in a large number of these patients. The authors classified the patients with high airway type-2 measures despite corticosteroid treatment as having steroid resistant type-2 high asthma. These steroid resistant type-2 high patients were characterized by older age and more severe disease when compared to patients with steroid treated type-2 low asthma.   

In an additional analysis the authors investigated the performance characteristics of blood and breath-based biomarkers of airway type-2 inflammation. Using the T2GM as a gold standard measure of airway type-2 inflammation the authors found that age and body mass index significantly modified the performance of blood-based biomarkers of airway type-2 inflammation. For example, serum IgE levels strongly correlated with T2GM measures in younger patients, but correlated poorly with the T2GM in older patients. Similarly, blood eosinophil levels were strongly correlated with the T2GM in patients with normal body mass index, but this relationship was significantly lower in morbidly obese patients. These findings have important implications for how blood-based biomarkers of type-2 inflammation may be used to identify patients in clinical trials in asthma.

Many asthmatics treated with inhaled corticosteroids have increased type 2 inflammation in their airways.  These steroid refractory type 2-high patients are older and have more severe asthma. This asthma subgroup is eligible for adjunctive treatment with specific inhibitors of type 2 inflammation, but care needs to be exercised in identifying eligible patients using blood- or breath-based biomarkers, because age and body mass index can modify the performance of these biomarkers as indicators of refractory airway type 2 inflammation.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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