Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients

Abstract

BackgroundAsthma is characterized by a heterogeneous inflammatory profile and can be subdivided into T(h)2-high and T(h)2-low airway inflammation. Profiling of a broader panel of airway cytokines in large unselected patient cohorts is lacking.MethodsPatients (n = 205) were defined as being “cytokine-low/high” if sputum mRNA expression of a particular cytokine was outside the respective 10th/90th percentile range of the control group (n = 80). Unsupervised hierarchical clustering was used to determine clusters based on sputum cytokine profiles.ResultsHalf of patients (n = 108; 52.6%) had a classical T(h)2-high (“IL-4-, IL-5- and/or IL-13-high”) sputum cytokine profile. Unsupervised cluster analysis revealed 5 clusters. Patients with an “IL-4- and/or IL-13-high” pattern surprisingly did not cluster but were equally distributed among the 5 clusters. Patients with an “IL-5-, IL-17A-/F- and IL-25- high” profile were restricted to cluster 1 (n = 24) with increased sputum eosinophil as well as neutrophil counts and poor lung function parameters at baseline and 2 years later. Four other clusters were identified: “IL-5-high or IL-10-high” (n = 16), “IL-6-high” (n = 8), “IL-22-high” (n = 25). Cluster 5 (n = 132) consists of patients without “cytokine-high” pattern or patients with only high IL-4 and/or IL-13.ConclusionWe identified 5 unique asthma molecular phenotypes by biological clustering. Type 2 cytokines cluster with non-type 2 cytokines in 4 out of 5 clusters. Unsupervised analysis thus not supports a priori type 2 versus non-type 2 molecular phenotypes. www.clinicaltrials.gov NCT01224938. Registered 18 October 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0524-y) contains supplementary material, which is available to authorized users.

Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma

“…As indicated in the introduction, other recent studies in severe asthma have reported mainly transcriptomic gene expression data from various cell sources, including sputum, epithelial brush and biopsy, [24][25][26][27][28] in addition to more limited information for protein analysis. Proteins identified by Somascan in sputum supernatants of U-BIOPRED subjects presented only mild/moderate asthma, or severe asthma data (either smoking or not) compared to healthy controls subjects, without comparison between mild/moderate and severe asthma groups.…”

“…Moreover, this approach avoids reliance on measures of mRNA which lack linear association with actual protein synthesized . Although several recent reports have examined gene expression patterns in sputum and bronchial epithelial samples from subjects with severe asthma, these have included more limited information on corresponding protein analyses . One report from U‐BIOPRED, examining protein differences between 4 clinically identified cluster groups, found 9 differentially abundant sputum proteins in more severe clusters compared to moderate, well‐controlled asthma with normal FEV1 .…”

“…23 Although several recent reports have examined gene expression patterns in sputum and bronchial epithelial samples from subjects with severe asthma, these have included more limited information on corresponding protein analyses. [24][25][26][27] One report from U-BIOPRED, examining protein differences between 4 clinically identified cluster groups, found 9 differentially abundant sputum proteins in more severe clusters compared to moderate, well-controlled asthma with normal FEV1. 28 However, the 1 cluster group with greatest number of differentially abundant proteins was characterized by 16-packyear smoking history which may influence and contribute to these elevated proteins.…”

EUFOREA consensus on biologics for CRSwNP with or without asthma

“…15,16 Both CRSwNP and asthma share common underlying pathophysiological mechanisms driving the disease (endotype), of which type 2 inflammation is the most prominent. 13,[17][18][19] Type 2 inflammation is characterized by the presence of eosinophilic airway inflammation associated with type 2-related cytokines (IL4, IL5, and/or IL13) and circulating and/or local IgE. 13,20 The management guideline in Europe for CRS, the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), has been developed to provide physicians with comprehensive tables of levels of evidence and helpful management algorithms.…”

Basophil Membrane Expression of Epithelial Cytokine Receptors in Patients with Severe Asthma

“…Both IL-25 and IL-33 cytokines have been related to airway changes which could be associated with the severity of asthma. Seys et al [18] analyzed the mRNA expression of sputum cells from patients with asthma characterized by poor asthma control and refractoriness; they found that IL-25, together with IL-5 and IL-17A, is associated with asthma endotypes refractory to CS. Cellular targets of IL-25 are not only basophils and other cells of innate immunity, e.g., type 2 innate lymphoid cells, mast cells, macrophages, and dendritic cells, but also structural cells like epithelial cells, endothelial cells, smooth-muscle cells, and fibroblasts [19].…”