Clinical aspects of exhaled nitric oxide in adults : Associations with atopy, bronchial hyperresponsiveness, smoking and chronic obstruction

Measurement of fractional exhaled nitric oxide (FENO) has proven useful in assessment of patients with respiratory symptoms, especially in predicting steroid response. The objective of these studies was to clarify issues relevant for the clinical use of FENO. The association between allergic sensitization and FENO among healthy subjects with no signs or symptoms of airway diseases was studied in order to assess whether allergic sensitization per se influences FENO. The association between airway inflammation and bronchial hyperresponsiveness (BHR) in steroid-naive subjects with symptoms suggesting asthma was examined, as well as the possible difference in this association between atopic and nonatopic subjects. Influence of smoking on FENO was compared between atopic and nonatopic steroid-naive asthmatics and healthy subjects. The short-term repeatability of FENO in COPD patients was examined in order to assess whether the degree of chronic obstruction influences the repeatability, and to assess the clinically significant change in FENO in COPD patients. For these purposes, we studied a random sample of 248 citizens of Helsinki, 227 army conscripts with current symptoms suggesting asthma, 19 COPD patients, and 39 healthy subjects. All subjects underwent FENO measurement, spirometry, and histamine and exercise challenges; atopy was assessed by skin prick tests. Among healthy subjects with no signs of airway diseases, median FENO values were similar in skin prick test-positive (13.2 ppb) and -negative (15.5 ppb) subjects (p=0.304), with the non-parametric one-tailed 95% upper limit of FENO respectively 29 and 31 ppb. In atopic and nonatopic subjects with symptoms suggesting asthma, BHR to histamine (HIB) did not significantly differ, but exercise-induced bronchoconstriction (EIB) was more severe among atopic subjects (p<0.01). FENO associated with severity of EIB and HIB only in atopic patients. FENO in smokers with steroid-naive asthma was significantly higher than in healthy smokers and nonsmokers (p=0.001, both comparisons). Among atopic asthmatics, FENO was significantly lower in smokers than in nonsmokers (p=0.002), but with no difference among nonatopic asthmatics (p=0.89). However, even among nonatopic asthmatic smokers, FENO was significantly higher than among healthy subjects (p=0.01). In COPD patients, the coefficient of variation (CoV) for measurements of FENO repeated after 24 h was 12.4% in COPD patients, and 15.9% in healthy subjects. Among COPD patients with GOLD stage 2 disease, the CoV was 13.7%, and among those with stage 3 or 4 disease, 10.5%. These findings indicate that allergic sensitization per se does not influence FENO, supporting the view that elevated FENO indicates NO-producing airway inflammation, and that the same reference range can be applied to both skin prick test-positive and negative subjects. The significant correlation between FENO and the degree of BHR only in atopic steroid-naive subjects with current asthma-like symptoms supports the view that the pathogenesis of BHR in atopic asthma is strongly involved in NO-producing airway inflammation, whereas in the development of BHR in nonatopic asthma other mechanisms may dominate. Attenuation of FENO only in atopic but not in nonatopic smokers with steroid-naive asthma may result from differences in the mechanisms of FENO formation as well as in the sensitivity of these mechanisms to smoking in atopic and nonatopic asthma. The results suggest, however, that in young adult smokers, FENO measurement may prove useful in assessment of asthmatic airway inflammation. The short-term repeatability of FENO in COPD patients with moderate to very severe disease and in healthy subjects was equally good. A change in FENO exceeding 24% is likely to reflect a significant change in COPD.