title: Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis.
abstract: BACKGROUND
  Acute pulmonary exacerbations accelerate pulmonary decline in cystic fibrosis (CF). There is a critical need for better predictors of treatment response.
  
  
  OBJECTIVE
  To test whether expression of a panel of leucocyte genes directly measured from whole blood predicts reductions in sputum bacterial density.
  
  
  METHODS
  A previously validated 10-gene peripheral blood mononuclear cell (PBMC) signature was prospectively tested in PBMC and whole blood leucocyte RNA isolated from adult subjects with CF at the beginning and end of treatment for an acute pulmonary exacerbation. Gene expression was simultaneously quantified from PBMCs and whole blood RNA using real-time PCR amplification. Test characteristics including sensitivity, specificity, positive and negative predictive values were calculated and receiver operating characteristic curves determined the best cut-off to diagnose a microbiological response. The findings were then validated in a smaller independent sample.
  
  
  RESULTS
  Whole blood transcript measurements are more accurate than forced expiratory volume in 1 s (FEV(1)) or C reactive protein (CRP) alone in identifying reduction of airway infection. When added to FEV(1), the whole blood gene panel improved diagnostic accuracy from 64% to 82%. The specificity of the test to detect reduced infection was 88% and the positive predictive value for the presence of persistent infection was 86%. The area under the curve for detecting treatment response was 0.81. Six genes were the most significant predictors for identifying reduction in airway bacterial load beyond FEV(1) or CRP alone. The high specificity of the test was replicated in the validation cohort.
  
  
  CONCLUSIONS
  The addition of blood leucocyte gene expression to FEV(1) and CRP enhances specificity in predicting reduced pulmonary infection and may bolster the assessment of CF treatment outcomes.
authors.affiliation: Department of Medicine, National Jewish Health, , Denver, Colorado, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Nick
authors.forename: L A
authors.initials: LA
authors.lastname: Sanders
authors.forename: B
authors.initials: B
authors.lastname: Ickes
authors.forename: N J
authors.initials: NJ
authors.lastname: Briones
authors.forename: S M
authors.initials: SM
authors.lastname: Caceres
authors.forename: K C
authors.initials: KC
authors.lastname: Malcolm
authors.forename: S J
authors.initials: SJ
authors.lastname: Brayshaw
authors.forename: C S
authors.initials: CS
authors.lastname: Chacon
authors.forename: C M
authors.initials: CM
authors.lastname: Barboa
authors.forename: M C
authors.initials: MC
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: St Clair
authors.forename: J L
authors.initials: JL
authors.lastname: Taylor-Cousar
authors.forename: D P
authors.initials: DP
authors.lastname: Nichols
authors.forename: S D
authors.initials: SD
authors.lastname: Sagel
authors.forename: M
authors.initials: M
authors.lastname: Strand
authors.forename: M T
authors.initials: MT
authors.lastname: Saavedra
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis*; D003550:Cystic Fibrosis / Q000097:blood* / Q000175:diagnosis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008168:Lung / Q000503:physiopathology*; D008297:Male; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000097:blood*; D060888:Real-Time Polymerase Chain Reaction; D013183:Sputum; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D012333:RNA, Messenger; D002097:C-Reactive Protein
keywords: Cystic Fibrosis; Lymphocyte Biology; Neutrophil Biology; Respiratory Infection