Abstract

It remains unclear whether a persistently high exhaled nitric oxide fraction (FeNO) in patients with controlled asthma is associated with the progressive loss of lung function. This was a 3-year prospective study. We examined the changes in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) and FeNO in 140 patients with controlled asthma. We initially determined the FeNO cut-off point for identifying patients with a rapid decline in FEV1 (>40 mL/yr). Next, a total of 122 patients who maintained high or non-high FeNO were selected, and the associations between the FeNO trend and changes in FEV1 and bronchodilator response (BDR) were investigated. A FeNO level >40.3 ppb yielded 43% sensitivity and 86% specificity for identifying patients with a rapid decline in FEV1. Patients with persistently high FeNO had higher rates of decline in FEV1 (42.7 ± 37.5 mL/yr) than patients with non-high FeNO (16.7 ± 31.5 mL/yr) (p < 0.0005). The changes in BDR from baseline to the end of the study, in patients who had high or non-high levels of FeNO were −0.8% and 0.1%, respectively (p < 0.01). In a multivariate analysis adjusted by age, body mass index, asthma control, blood eosinophil numbers, and FEV1% of predicted, a FeNO level of ≥40 ppb was independently associated with an accelerated decline in FEV1 (p < 0.05). This study suggests that FeNO is potentially valuable tool for identifying individuals who are at risk of a progressive loss of lung function among patients with controlled asthma.

Abstract

Inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines and iNOS activity in bronchial epithelial cells is a major determinant of fractional exhaled nitric oxide (FeNO) levels. The aim of this study was to investigate the association of iNOS promoter gene polymorphisms and FeNO levels in Japanese asthmatics before the introduction of asthma treatment. Asthmatics were recruited from Fukushima Medical University Hospital. Genotyping of the pentanucleotide repeat (CCTTT)n and seven previously detected single nucleotide polymorphisms (SNPs) in the iNOS promoter lesion was performed. The relationships between the genotypes and FeNO levels before the introduction of asthma treatment were compared. In 91 asthmatics, the number of microsatellite repeats ranged from 9 to 20 and showed a bimodal distribution. According to this distribution, asthmatics were divided into two groups: genotypes with at least one long allele with more than 14 repeats (L/s or L/L) and genotypes with both short alleles with 14 or fewer repeats (s/s). No significant differences were observed in each parameter between the two groups. The mean FeNO level before treatment was significantly higher in the L/s or L/L subjects than in the s/s subjects. After treatment, the lowest FeNO level did not differ between the two groups. Three SNPs detected in the Japanese subjects were not associated with FeNO levels. The number of CCTTT repeats in the iNOS promoter region was associated with FeNO levels in asthmatics before treatment, suggesting the importance of iNOS genotype in the clinical application of FeNO for asthmatics.