Regulatory T cell monitoring in severe eosinophilic asthma patients treated with mepolizumab

Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.