We found significant relationships between FeNO levels and the degree of sensitization to aeroallergens in asthmatic children. We noted a weak but significantly greater elevation of FeNO levels in poly-sensitized asthmatics than in mono-sensitized asthmatics. FeNO levels were correlated with serum total IgE levels, blood eosinophils, serum ECP levels, and some spirometric parameters, to varying extents. These results are consistent with those of previous studies, and suggest that FeNO may be moderately correlated with the profiles of atopic sensitization and allergic inflammation.
Although several studies have shown that asthma and/or atopy are closely related to FeNO,9,10
these relationships are inconsistent in clinically selected samples.18,19
A previous study of 222 asthmatic children showed that FeNO levels are elevated in some, but not all children with atopic asthma.7
Prasad et al.8
demonstrated that FeNO levels are higher in atopic children than in non-atopic asthmatic children and non-atopic, non-asthmatic children in a study with a large pediatric asthmatic population. Furthermore, they showed that non-atopic children have no significant difference in FeNO levels whether they are asthmatic or not.
Previous studies suggested that the degree of atopy is associated with FeNO levels, and that increasing FeNO levels are related to the number of positive skin prick test results in asthmatic children.20
However, Moore et al.21
demonstrated that FeNO is not always associated with the number of positive skin test responses, blood eosinophils, or serum IgE levels in asthmatics. FeNO displays even greater independence from asthma and asthma-like symptoms after controlling for atopy. The relationship between FeNO and asthma is complex, and the mechanisms for increased FeNO levels require further investigation.
We divided the asthmatic children into three groups according to their different profiles of atopic sensitization. It was hypothesized that atopic sensitization could be a marker of airway inflammation in asthmatic children. This hypothesis is supported by a previous study, which reported correlations between serum total IgE levels and FeNO concentrations in asthmatics.7
However, it is problematic to explain airway inflammation in asthmatics by the presence of atopy alone. The degree of atopic sensitization is more important than simply the presence of atopy in further elucidation of the relationship between FeNO levels and atopy.
We also found a positive relationship between FeNO levels and atopy profiles, which is in agreement with previous studies. The relationship between FeNO levels and the degree of atopic sensitization potentially indicates that allergen sensitization may contribute to atopic airway inflammation in asthmatic subjects. A significant correlation between atopy scores and the severity of exercise-induced bronchoconstriction, which has been shown to be correlated with the markers of eosinophilic airway inflammation,22
also supports our contention that the degree of allergen sensitization may contribute to allergic airway inflammation. In contrast, Silvestri et al.23
did not find significant differences in the FeNO levels between mono-sensitized and poly-sensitized asthmatic children. This discrepancy may be explained by the small number of mono-sensitized children in that study.
Our results indicate that aeroallergen sensitization clearly plays an important role in determining FeNO levels in asthmatic children. Thus, it could be speculated that airway eosinophilic inflammation may increase with the degree of atopy. Although the mechanism by which an increase in the degree of atopic responsiveness induces a rise in FeNO is not fully understood, it is becoming evident that NO production correlates more specifically with airway inflammation where eosinophilia and clinical atopic features dominate.8
An increasing degree of atopic responsiveness leads to greater cellular activation with inflammation, and consequently upregulated production of inducible nitric oxide synthase (iNOS).4
Elevated FeNO levels are thought to result from increased expression and activity of iNOS in airway epithelial and inflammatory cells.24,25
In atopic asthmatics, the degree of atopic sensitization appears to reflect systemic (blood eosinophilis) and organ-specific (FeNO) markers of allergic inflammation.7,26
In the present study, the elevated FeNO concentrations in the poly-sensitized subjects reflected the presence of clinical inflammation and induction of iNOS by inflammatory cytokines.27
Inhaled allergens are thought to be an important cause of ongoing inflammation in the lungs of sensitized children who develop asthma.28
In the present study, exposure to inhaled allergens in the sensitized groups may have contributed to the elevated FeNO.
FeNO is significantly correlated with atopy in children with recent exposure to allergens, independent of symptoms, and during remission, asymptomatic adolescents with atopic asthma show elevated FeNO levels with increased eosinophilic activity in the biopsies of bronchial mucosa.29
Airway eosinophilia is a common feature of atopy, and FeNO levels may determine the clinical expression of atopy because atopy can be considered an immune disorder associated with increased airway inflammation.30
In contrast, we found an increasing tendency towards higher ECP in poly-sensitized than in mono-sensitized subjects, without statistical significance. Our borderline association between serum ECP concentrations and FeNO levels suggests that both markers participate in eosinophilic inflammation in asthmatics. ECP is a potent biomarker of asthma and has been used to assess inflammation in asthmatic children. FeNO has been reported to be well correlated with ECP concentrations in sputum4
or in bronchoalveolar lavage fluid.5
Thomas et al.4
reported that FeNO levels were significantly correlated with sputum ECP concentrations in a cohort of Australian children and had a positive relationship with sputum eosinophilia. In contrast, Piacentini et al.18
found no significant correlation between FeNO levels and serum ECP concentrations. Furthermore, although serum ECP levels are higher in children with atopic asthma, the wide ranges are likely to limit the relevance of measuring serum ECP levels in children as a guide to the diagnosis or management of asthma.31
The measurement of FeNO is easier and more reliable than that of serum ECP in pediatric patients, because the effort and coordination required are minimal and more organ-specific. Indeed, FeNO is a more sensitive indicator of disease severity than circulating markers of inflammation, such as serum ECP.27
In the present study, the non-sensitized subjects showed relatively high serum total IgE levels. It should be acknowledged that atopy is not always detectable by skin tests. We did not obtain sensitization profiles for food allergens or use other definitions of atopy, such as specific IgE levels or atopic scores. Therefore, it is possible that some of our non-sensitized subjects may have belonged in the sensitized group. In addition to subjects with the highest poly-sensitized levels, we enrolled mild to moderate asthmatic subjects. However, asthma severity itself might be associated with the degree of sensitization or FeNO levels. Investigators should be aware that asthma severity is one of the important confounding factors. Moreover, although our subjects were asked to cease medication 1 week prior to the test, FeNO could still be affected by asthma medications.
Some investigators have indicated elevated FeNO levels in subjects with allergic rhinitis other than asthmatics.19,32
In the present study, this is unlikely to have influenced the results of our analysis, because we excluded asthmatic patients who had concomitant allergic rhinitis symptoms.
In summary, FeNO levels were associated with both the presence and profiles of atopic sensitization as determined by positive skin prick test results to various classes of aeroallergens in asthmatic children. Meaningful interpretation of FeNO may only be possible when the presence and the degree of sensitization are considered.33
FeNO is a good biomarker for the severity of atopic inflammation, which indicates that poly-sensitized and/or strongly sensitized children are at a high risk of airway inflammation.