title: Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.
abstract: BACKGROUND
  Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology.
  
  
  OBJECTIVE
  Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation.
  
  
  METHODS
  Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated.
  
  
  RESULTS
  A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83–0.95); serum CXCL10, 0.83 (95% CI, 0.70–0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78–0.93), respectively.
  
  
  CONCLUSIONS
  The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.
authors.affiliation: Institute for Lung Health, University of Leicester, Leicester, United Kingdom.
authors.forename: Mona
authors.initials: M
authors.lastname: Bafadhel
authors.forename: Susan
authors.initials: S
authors.lastname: McKenna
authors.forename: Sarah
authors.initials: S
authors.lastname: Terry
authors.forename: Vijay
authors.initials: V
authors.lastname: Mistry
authors.forename: Carlene
authors.initials: C
authors.lastname: Reid
authors.forename: Pranabashis
authors.initials: P
authors.lastname: Haldar
authors.forename: Margaret
authors.initials: M
authors.lastname: McCormick
authors.forename: Koirobi
authors.initials: K
authors.lastname: Haldar
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kebadze
authors.forename: Annelyse
authors.initials: A
authors.lastname: Duvoix
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad
authors.forename: Hemu
authors.initials: H
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Rugman
authors.forename: Paul
authors.initials: P
authors.lastname: Dodson
authors.forename: Martin
authors.initials: M
authors.lastname: Jenkins
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: Paul
authors.initials: P
authors.lastname: Newbold
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Green
authors.forename: Per
authors.initials: P
authors.lastname: Venge
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barer
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.forename: Ian D
authors.initials: ID
authors.lastname: Pavord
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001424:Bacterial Infections / Q000378:metabolism / Q000382:microbiology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000097:blood; D016000:Cluster Analysis; D004804:Eosinophils / Q000378:metabolism / Q000382:microbiology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000378:metabolism / Q000382:microbiology*; D012372:ROC Curve; D012720:Severity of Illness Index; D013183:Sputum / Q000378:metabolism / Q000382:microbiology
chemical_list: D015415:Biomarkers; D054357:Chemokine CXCL10; D053583:Interleukin-1beta