title: The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma.
abstract: BACKGROUND
  The role of systemic inflammation in asthma is unclear. The aim of this study was to compare systemic inflammation in subjects with stable asthma, categorized by airway inflammatory phenotype, with healthy control subjects.
  
  
  METHODS
  Adults with stable asthma (n = 152) and healthy control subjects (n = 83) underwent hypertonic saline challenge and sputum induction. Differential leukocyte counts were performed on selected sputum. Plasma high-sensitivity C-reactive protein (CRP), IL-6, and tumor necrosis factor-α levels and sputum IL-8 and neutrophil elastase levels were determined by enzyme-linked immunosorbent assay. Sputum IL-8 receptor α (IL-8RA) and IL-8 receptor β (IL-8RB) messenger RNA expression were determined by real-time polymerase chain reaction.
  
  
  RESULTS
  Subjects with asthma were classified as having nonneutrophilic asthma or neutrophilic asthma. The asthma (neutrophilic) group had increased systemic inflammation compared with the asthma (nonneutrophilic) and healthy control groups, with median (interquartile range) CRP levels of 5.0 (1.6-9.2), 1.8 (0.9-5.3), and 1.8 (0.8-4.1) mg/L (P = .011), respectively, and IL-6 levels of 2.1 (1.5-3.1), 1.4 (1.0-2.1), and 1.1 (0.8-1.5) pg/mL (P < .001), respectively. The proportion of subjects with elevated CRP and IL-6 levels was also higher in the asthma (neutrophilic) group. Sputum IL-8 and neutrophil elastase protein and IL-8RA and IL-8RB gene expression were significantly increased in the asthma (neutrophilic) group. In multiple regression analysis of subjects with asthma, sex, BMI, statin use, and percent sputum neutrophils were significant predictors of log(10)CRP. Sex, BMI, and %FEV(1) were significant predictors of log(10)IL-6.
  
  
  CONCLUSIONS
  Systemic inflammation is increased in patients with asthma with neutrophilic airway inflammation and associated with worse clinical outcomes. Systemic inflammation may contribute to the pathophysiology of neutrophilic asthma.
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, and Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia. Electronic address: lisa.wood@newcastle.edu.au.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Wood
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, and Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, and Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, and Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Hayley A
authors.initials: HA
authors.lastname: Scott
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, and Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000145:classification* / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology*; D010641:Phenotype; D013183:Sputum / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D019272:Leukocyte Elastase