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

Rationale-Fraction of exhaled nitric oxide (F-ENO) is regarded as a marker of airway inflammation. It is unknown whether increased F-ENO in respiratorily healthy subjects increases the risk of developing wheeze. Objectives: To examine if increased levels of F-ENO 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 F-ENO. At follow-up 4 years later, all subjects were mailed a respiratory questionnaire. The association between incident wheeze and baseline levels of F-ENO 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 F-ENO 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, F-ENO 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 F-ENO is associated with an increased risk of developing wheeze. The results also support the hypothesis that increased level of F-ENO among subjects without respiratory symptoms is a sign of subclinical airways inflammation.