Asthma Endotypes and an Overview of Targeted Therapy for Asthma

Abstract

Guidelines for the management of severe asthma do not emphasize the measurement of the inflammatory component of airway disease to indicate appropriate treatments or to monitor response to treatment. Inflammation is a central component of asthma and contributes to symptoms, physiological, and structural abnormalities. It can be assessed by a number of endotyping strategies based on “omics” technology such as proteomics, transcriptomics, and metabolomics. It can also be assessed using simple cellular responses by quantitative cytometry in sputum. Bronchitis may be eosinophilic, neutrophilic, mixed-granulocytic, or paucigranulocytic (eosinophils and neutrophils not elevated). Eosinophilic bronchitis is usually a Type 2 (T2)-driven process and therefore a sputum eosinophilia of greater than 3% usually indicates a response to treatment with corticosteroids or novel therapies directed against T2 cytokines such as IL-4, IL-5, and IL-13. Neutrophilic bronchitis represents a non-T2-driven disease, which is generally a predictor of response to antibiotics and may be a predictor to therapies targeted at pathways that lead to neutrophil recruitment such as TNF, IL-1, IL-6, IL-8, IL-23, and IL-17. Paucigranulocytic disease may not warrant anti-inflammatory therapy. These patients, whose symptoms may be driven largely by airway hyper-responsiveness may benefit from smooth muscle-directed therapies such as bronchial thermoplasty or mast-cell directed therapies. This review will briefly summarize the current knowledge regarding “omics-based signatures” and cellular endotyping of severe asthma and give an overview of segmentation of asthma therapeutics guided by the endotype.

IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

“…Further, it may help identify responders to new therapies that directly target type-2 cells and their development, such agents blocking CRTh2 and TSLP. 2,73,74 In summary, our study shows for the first time that IL-2 reduces GC responsiveness of human Th2 cells by downregulating GR expression, supporting both their survival and pro-inflammatory capacity in the face of GC treatment. These results suggest that a patient's potential to produce IL-2 may be a determinant in asthma severity and that measuring peripheral levels of IL-2 could help identify those in need of increased ICS dose and/or alternative therapies.…”

“…Asthma is a syndrome characterized by symptoms of diverse pathogenesis . Type 2 cytokines promote many of the processes responsible for the development of asthma and symptom manifestation.…”

Modeling asthma: Pitfalls, promises, and the road ahead

“…29 Severe asthma has been defined as either T2 hi (eosinophilic) and T2 lo (noneosinophilic). 28,29 Within the T2 hi group, nonallergic asthma may be driven by epithelial damage/activation due to pollutants, infection, or even allergens containing protease activity (e.g. house dust mite, molds), resulting in activation of the IL-25/IL-33 TSLP-ILC2 pathway without a concomitant IgE response.…”

IL-2 Modulates Th2 cell Responses to Glucocorticoid: A Cause of Persistent Type 2 Inflammation?

“…Using a cell based approach, such as eosinophils and/or Th2 cells, to classify type 2-high asthma may improve identification of the phenotype as well as response to therapies directly target type-2 cells, i.e. CRTh2 antagonist (2,68).…”