Defining Phenotypes in Asthma: A Step Towards Personalized Medicine

Abstract

Asthma is a common disease with a complex pathophysiology. It can present in various clinical forms and with different levels of severity. Unbiased cluster analytic methods have unravelled several phenotypes in cohorts representative of the whole spectrum of severity. Clusters of severe asthma include those on high-dose corticosteroid treatment, often with both inhaled and oral treatment, usually associated with severe airflow obstruction. Phenotypes with concordance between symptoms and sputum eosinophilia have been reported, including an eosinophilic inflammation-predominant group with few symptoms and late-onset disease who have a high prevalence of rhinosinusitis, aspirin sensitivity, and exacerbations. Sputum eosinophilia is also a biomarker that can predict therapeutic responses to antibody-based treatments to block the effects of the T-helper (Th)-2 cytokine, interleukin (IL)-5. Low Th2-expression has been predictive of poor therapeutic response to inhaled corticosteroid therapy. Current asthma schedules emphasise a step-up approach to treating asthma in relation to increasing severity, but, in more severe disease, phenotyping or endotyping of asthma will be necessary to determine new treatment strategies as severe asthma is recognized as being a particularly heterogeneous disease. Much less is known about 'non-eosinophilic' asthma. Phenotypic characterisation of corticosteroid insensitivity and chronic airflow obstruction of severe asthma is also needed. Phenotype-driven treatment of asthma will be further boosted by the advent of transcriptomic and proteomic technologies, with the application of systems biology or medicine approaches to defining phenotypes and biomarkers of disease and therapeutic response. This will pave the way towards personalized medicine and healthcare for asthma.

A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED

“…This may not be surprising considering the complexity of immunoinflammatory mechanisms and the diversity of cell types implicated in asthma (24)(25)(26)(27). Deriving asthma clusters according to differentially-expressed genes may be a better approach to capture the diverse pathways of asthma pathobiology that could lead to the identification of important targets for therapy and offer insights towards achieving personalized medicine (20,28,29). This approach has been used to identify genes from sputum cells that linked pathway-based transcriptomic clusters to clinically-important features of asthma (30).…”

Neutrophilic and Pauci-immune Phenotypes in Severe Asthma

“…The lack of airway inflammatory cells or biomarkers in the presence of airway obstruction and AHR defines pauci-immune or pauci-granulocytic asthma. 7 Characterization of novel therapeutic approaches targeting neutrophilic or pauci-immune asthma may have a profound impact on decreasing asthma exacerbations.…”

Phenotyping Asthma: Linking Clinical Features to Biomolecular Pathways

“…Finally, when these mechanisms have been shown to be underlying the clinical-physiological inflammatory processes of that phenotype, we can then define endotypes of asthma 3 . Endotypes will be most useful in defining targets for the development of new therapies and treatments for different endotypes of asthma, an important path towards the personalisation of treatment approaches 4 . Integration of biological and -omics data with clinical-physiological inflammatory parameters is challenging and will require mathematical modelling such as machine learning approaches or network models; in fact, new methods for integrative data analyses are required to overcome the computational challenges of these methods 5 (Fig.…”

“…Members of the Th2 pathway, such as IL-5, IL-4, and IL-13, have been targeted using humanised monoclonal antibodies directed towards these cytokines or their receptors and used as treatments for severe asthma 85 . Demonstration of efficacy of new therapies will depend in part on the precision by which patients can be endotyped for specific therapies 4,86 . Initially, the anti-IL-5 antibody mepolizumab was shown to have no beneficial effects on symptom control or exacerbations in a cohort of moderately severe asthmatics, despite reducing the levels of blood eosinophilia 87 .…”