Elevated Exhaled Nitric Oxide in High-Risk Neonates Precedes Transient Early but Not Persistent Wheeze

Rationale Elevated fractional exhaled nitric oxide (FENO) concentration has been suggested to predict early childhood wheeze and sensitization. Objectives: To investigate the association between FENO in asymptomatic neonates and the development of wheeze patterns and atopic intermediary phenotypes in the first 6 years of life. Methods: We measured FENO in 253 healthy 1-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood birth cohort and monitored prospectively wheezy episodes by daily diary cards during the first 6 years of life. Total IgE, specific IgE, and blood eosinophil count were assessed at age 6 months, 4 years, and 6 years. Associations were studied by Cox regression, logistic regression, and generalized linear models. Measurements and Main Results: Increased neonatal FENO level was significantly associated with the development of recurrent wheeze in the first year of life (hazard ratio, 2.63; 95% confidence interval, 1.1 to 6.2; P = 0.026) but not thereafter. The association was unaffected by environmental tobacco smoke exposure. FENO was not associated with elevated levels of total IgE, specific IgE, or blood eosinophil count at any age point and was unrelated to neonatal lung function. Conclusions: An elevated FENO level in asymptomatic neonates born to mothers with asthma preceded the development of transient early wheezing, but not persistent wheezing during preschool age, and was unrelated to atopy. This suggests an early disease process other than small airway caliber contributing to the transient wheezing phenotype.