Increased Fraction of Exhaled Nitric Oxide Predicts New-Onset Wheeze in a General Population

RATIONALE: Fraction of exhaled nitric oxide (Fe(NO)) is regarded as a marker of airway inflammation. It is unknown whether increased Fe(NO) in respiratorily healthy subjects increases the risk of developing wheeze. OBJECTIVES: To examine if increased levels of Fe(NO) predicts later onset of wheeze. METHODS: We followed up 2,200 men and women from a general population-based study. At baseline, the subjects were investigated with questionnaires, blood samples, pulmonary function tests, and Fe(NO). At follow-up 4 years later, all subjects were mailed a respiratory questionnaire. The association between incident wheeze and baseline levels of Fe(NO) over the 90th percentile were evaluated calculating hazard ratios using Cox regression models adjusted for smoking habits, age, height, sex, and atopy. MEASUREMENTS AND MAIN RESULTS: The follow-up questionnaire was completed by 1,896 subjects (86.2%). All subjects reporting wheeze, asthma, or asthma symptoms at baseline were excluded resulting in a study population of 1,506 subjects. Of these, 49 subjects reported new-onset wheeze. The median concentration of Fe(NO) at baseline was significantly higher among those with new-onset wheeze (18.8 ppb vs. 15.8 ppb, P = 0.03). In a Cox regression model including all subjects, Fe(NO) over the 90th percentile predicted onset of wheeze (hazard ratio 2.7; 95% confidence interval, 1.4-5.4). In stratified models, this was most apparent among never-smokers and in atopic subjects, for whom the odds ratios were higher. CONCLUSIONS: Our results indicate that increased Fe(NO) is associated with an increased risk of developing wheeze. The results also support the hypothesis that increased level of Fe(NO) among subjects without respiratory symptoms is a sign of subclinical airways inflammation.