title: Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.
  
  
  OBJECTIVE
  We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis.
  
  
  METHODS
  We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD).
  
  
  RESULTS
  Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study.
  
  
  CONCLUSIONS
  Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; NIHR Respiratory Biomedical Research Unit, University Hospitals of Leicester, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ghebre
authors.affiliation: Department of Respiratory Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Mona
authors.initials: M
authors.lastname: Bafadhel
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; NIHR Respiratory Biomedical Research Unit, University Hospitals of Leicester, Leicester, United Kingdom.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Desai
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Cohen
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Newbold
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Rapley
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Jo
authors.initials: J
authors.lastname: Woods
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Rugman
authors.affiliation: Department of Respiratory Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Pavord
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; NIHR Respiratory Biomedical Research Unit, University Hospitals of Leicester, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Newby
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.affiliation: MedImmune Ltd, Milstein Building, Granta Park, Cambridge, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: May
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; NIHR Respiratory Biomedical Research Unit, University Hospitals of Leicester, Leicester, United Kingdom. Electronic address: ceb17@le.ac.uk.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Brightling
mesh_terms: D000368:Aged; D001249:Asthma / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D016000:Cluster Analysis; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D013183:Sputum / Q000166:cytology / Q000276:immunology*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D016207:Cytokines
keywords: Asthma and COPD overlap; cytokines; factor and cluster analyses