Rationale-Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model.Objectives-To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups.Methods-We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care.Measurements and Main Results-Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractoryCorrespondence and requests for reprints should be addressed to Dr. P. Haldar, M.R.C.P., Institute for Lung Health, Glenfield Hospital, Leicester, LE3 9QP, UK. ph62@le.ac.uk. Conflict of Interest Statement: P.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.D.P. received $2,000 for speaking at conferences organized by GlaxoSmithKline and $5,000 for speaking at conferences organized by AstraZeneca; he is in receipt of a $500,000 grant for a study of severe asthma from GlaxoSmithKline. D.E.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.B. has received lecture fees and conference support from AstraZeneca and GlaxoSmithKline. M.T. has received speaker's honoraria in the last 3 years for speaking at meetings sponsored by the following companies marketing respiratory products: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Schering-Plough, Teva; he has received honoraria for attending advisory panels with Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Merck Respiratory, Schering-Plough, Teva; he has received sponsorships to attend international scientific meetings from GlaxoSmithKline, MSD, AstraZeneca; he has received funding for research projects from GlaxoSmithKline, MSD, AstraZeneca; he holds a research fellowship from Asthma UK. C.E.B. has received a total of $2.2 million in research funding over the last 3 years (or is pending) from AstraZeneca, Cambridge Antibody Technology, GlaxoSmithKline; he has received less than $10,000 per annum from consultancy fees from Cambridge Antibody Technology...

Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach. @ERSpublications Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

Background: Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo-controlled studies examining the effect of inhaled corticosteroids. Methods: Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with noneosinophilic asthma and 10 healthy controls. The patients with non-eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double-blind, placebo-controlled crossover study in which the effects of inhaled mometasone 400 mg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated. Conclusions: Non-eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor shortterm response to treatment with inhaled corticosteroids.