Background: Asthma is characterized by a heterogeneous inflammatory profile and can be subdivided into\nT(h)2-high and T(h)2-low airway inflammation. Profiling of a broader panel of airway cytokines in large unselected\npatient cohorts is lacking.\nMethods: Patients (n = 205) were defined as being ââ?¬Å?cytokine-low/highââ?¬Â if sputum mRNA expression of a particular\ncytokine was outside the respective 10th/90th percentile range of the control group (n = 80). Unsupervised\nhierarchical clustering was used to determine clusters based on sputum cytokine profiles.\nResults: Half of patients (n = 108; 52.6%) had a classical T(h)2-high (ââ?¬Å?IL-4-, IL-5- and/or IL-13-highââ?¬Â) sputum cytokine\nprofile. Unsupervised cluster analysis revealed 5 clusters. Patients with an ââ?¬Å?IL-4- and/or IL-13-highââ?¬Â pattern\nsurprisingly did not cluster but were equally distributed among the 5 clusters. Patients with an ââ?¬Å?IL-5-, IL-17A-/F- and\nIL-25- highââ?¬Â profile were restricted to cluster 1 (n = 24) with increased sputum eosinophil as well as neutrophil\ncounts and poor lung function parameters at baseline and 2 years later. Four other clusters were identified:\nââ?¬Å?IL-5-high or IL-10-highââ?¬Â (n = 16), ââ?¬Å?IL-6-highââ?¬Â (n = 8), ââ?¬Å?IL-22-highââ?¬Â (n = 25). Cluster 5 (n = 132) consists of patients\nwithout ââ?¬Å?cytokine-highââ?¬Â pattern or patients with only high IL-4 and/or IL-13.\nConclusion: We identified 5 unique asthma molecular phenotypes by biological clustering. Type 2 cytokines cluster\nwith non-type 2 cytokines in 4 out of 5 clusters. Unsupervised analysis thus not supports a priori type 2 versus\nnon-type 2 molecular phenotypes. www.clinicaltrials.gov NCT01224938. Registered 18 October 2010
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