title: Fraction of exhaled nitric oxide and bronchial responsiveness are associated and continuous traits in young children independent of asthma.
abstract: BACKGROUND
  Elevated fraction of exhaled nitric oxide (FENO) and bronchial hyperresponsiveness are used as surrogate markers of asthma. These traits may be continuous in the population. The objective of this study was to investigate whether FENO and bronchial responsiveness are associated in both children with and children without a history of asthma symptoms.
  
  
  METHODS
  One hundred ninety-six 6-year-old children with no asthma symptoms, intermittent asthma symptoms, and persistent asthma were randomly included from the Copenhagen Prospective Study on Asthma in Childhood prospective clinical birth cohort of mothers with asthma. Bronchial responsiveness was assessed as the relative change in specific airway resistance after cold dry air hyperventilation. FENO measurements were performed prior to the hyperventilation test. The association between FENO and bronchial responsiveness was assessed by generalized linear models.
  
  
  RESULTS
  Bronchial responsiveness and FENO exhibited a significant and linear association in the population. A doubling of FENO corresponded to an 8.4% (95% CI, 3.7%-13.1%; P = .0006) increase in airway resistance after challenge testing and remained significant after adjustment for sex, allergic rhinitis, current asthma, inhaled corticosteroid treatment, and upper respiratory tract infections prior to testing. Stratified analyses showed similar associations in children with and without asthma.
  
  
  CONCLUSIONS
  FENO and bronchial responsiveness are associated and continuous traits in young children regardless of asthma symptoms, suggesting a continuous subclinical to clinical process underlying asthma. The findings also suggest caution against the use of these surrogate markers for a dichotomized approach to asthma diagnosis.
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark.
authors.forename: Ann-Marie Malby
authors.initials: AM
authors.lastname: Schoos
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark.
authors.forename: Bo Lund Krogsgaard
authors.initials: BLK
authors.lastname: Chawes
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
mesh_terms: D000388:Air; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism* / Q000503:physiopathology*; D002648:Child; D015331:Cohort Studies; D003080:Cold Temperature; D003718:Denmark; D045853:Exhalation; D005260:Female; D006801:Humans; D006985:Hyperventilation / Q000378:metabolism / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D009569:Nitric Oxide