Severe Asthma Phenotypes - How Should They Guide Evaluation and Treatment?

Abstract

Although patients with "severe" asthma tend to be characterized by ongoing symptoms and airway inflammation despite treatment with high doses of inhaled and systemic corticosteroids, there is increasing recognition of marked phenotypic heterogeneity within affected patients. Although "precision medicine" approaches for patients with severe asthma are needed, there are many hurdles that must be overcome in daily practice. The National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) has been at the forefront of phenotype discovery in severe asthma for the past decade. SARP, along with other international groups, has described clinical severe asthma phenotypes in both adults and children that can be evaluated in the clinical setting. Although these clinical phenotypes provide a good "starting point" for addressing disease heterogeneity in severe asthma in everyday practice, more efforts are needed to understand how these phenotypes relate to underlying disease mechanisms and pharmacological treatment responses. This review highlights the clinical asthma phenotypes identified to date, their associations with underlying endotypes and potential biomarkers, and remaining knowledge gaps that must be addressed before precision medicine can become a reality for patients with severe asthma.

Keywords: Biomarker; Cluster analysis; Endotype; Precision medicine; SARP; Severe asthma phenotypes.

Figure 1

A schematic of the adult and pediatric severe asthma phenotypes identified in the SARP cluster analyses.^, Heterogeneity within each phenotype is indicated by the shape of the diamond; the “width” represents heterogeneity in the age of asthma onset (median line, IQR), the “height” symbolizes heterogeneity of lung function within each group (IQR). Note that the majority of severe asthma subjects had abnormal baseline lung function when bronchodilators were appropriately withhold prior to spirometry, reinforcing the importance of extended lung function testing in the clinic.

Figure 2

SARP algorithm for cluster assignment in subjects > 12 years of age. Using three variables (1) Baseline FEV1 (with a bronchodilator withhold), (2) Maximal “Max” FEV1 (after 6-8 puffs of albuterol) and (3) age of onset of asthma, subjects can be assigned to the five clinical asthma phenotypes. Clusters 3, 4 and 5 are the severe asthma clusters; Color Key: Yellow, late onset nonatopic asthma; Orange, severe atopic asthma; Red, severe asthma with fixed airflow.

Figure 3

Sputum inflammatory profiles in Adult SARP severe asthma cluster phenotypes show heterogeneity within each cluster with no clear predominant pattern. Inflammatory profiles were determined for individual subjects based on % eosinophils (≥ 2%) and % neutrophils ≥ 40% in induced sputum as previously described. Color Key: Blue, paucigranulocytic; Green, neutrophil predominant; Red, eosinophil predominant; Purple, mixed granulocytic.

Figure 4

Association between exhaled nitric oxide values and blood eosinophils in the SARP pediatric severe asthma clinical clusters. Percentages reflect the percentage of children in the cluster. Although there was modest agreement between the biomarkers, heterogeneity in biomarker presentation was present in both clusters.

Figure 5

Potential approach for selection of biological therapy in severe asthma patients, utilizing phenotyping by clinical characteristics and biomarker assessment. IgE = immunoglobulin E, IL = interleukin, CRTH2 = chemokine receptor homologous molecule expressed on Th2 lymphocyte, PDE4 = phosphodiesterase 4