We identified several predictors of FeNO levels in children with asthma. FeNO levels were higher among those children with higher baseline FeNO levels, higher in the fall and lower in the summer, higher among children who were sensitized to one or more allergens, and lower among children who were reportedly using inhaled steroids. Our study also provides information on seasonal changes and FeNO trends over time. These findings indicate that FeNO levels respond to many common asthma triggers and mediators. An ideal biomarker for asthma control would reflect pharmacologic intervention, as well as respond to changes in an individual’s exposure to environmental triggers. FeNO appears to fit these characteristics.
We found that baseline FeNO levels were associated with subsequent FeNO levels. This finding is consistent with work by Roberts et al.18
In their study, Roberts et al. used standardized FeNO levels to account for some of the individual differences in FeNO. Our inclusion of baseline visit FeNO levels in the models, which should have adjusted for the individual differences in FeNO levels, indicate that using population standard or “normal” FeNO levels may be insufficient. Thus, it is important to consider an individual’s baseline FeNO levels for managing children with asthma. Indeed, the relationship of age and FeNO was not significant upon inclusion of baseline FeNO levels suggesting that if baseline FeNO is considered, the previously identified age and FeNO relationship is not as important. Ultimately, these differences in FeNO may also help to identify children who have a specific variant of asthma, more severe asthma, or that may benefit from control of environmental triggers.
We found that FeNO levels varied by season among children with atopic and nonatopic asthma. In a study by Koenig et al, the authors reported that mean FeNO levels were higher in the winter than the spring (19.9±12.4 ppb vs. 12.7±6.7 ppb), but the differences were not statistically different.24
In the present study, the highest levels of FeNO occurred in the fall, followed by spring, winter, and summer. The seasonal variation in FeNO levels did not differ when stratified by overall allergen sensitization status or tobacco smoke exposure levels, but there were seasonal differences in FeNO levels among children who were sensitized to dog or dust mite allergen.
Seasonal variation could be due to infectious agents or allergen exposures. We did not find that FeNO levels were associated with parent reported respiratory illness, but FeNO may rise in the presence of select infectious agents.42
The higher levels of FeNO in the fall might also be due to higher levels of exposure to dog or dust mite allergen. Dust mite allergen levels are higher in the fall, for example, and this might explain the elevation of FeNO levels among dust mite sensitized children during that season.43
The seasonal variation in FeNO levels could also be due to seasonal variation of ambient pollution or outdoor allergens, such as pollens and fungal spores.
Consistent with prior research, we found that being sensitized to common allergens was associated with increased FeNO levels.17,25,41
In secondary analyses we found that this relationship was driven by sensitization to cat allergen and dust mite allergen, perhaps because of the higher prevalence of sensitization to cat and dust mite allergen in our cohort. Studies of children with higher prevalence of sensitization to dog or cockroach allergen may find that dog and cockroach allergen sensitization is associated with FeNO levels. Regardless, consistent with other studies, these data indicate that allergen sensitization clearly plays a large role in determining FeNO levels in children.
The finding that inhaled steroid use predicts lower FeNO levels is consistent with previous work.12,44
In fact, the FDA approved the use of FeNO in individuals with asthma to monitor response to anti-inflammatory agents.44
The results of the present study confirm that FeNO may be a valuable biomarker of response to inhaled anti-inflammatory therapy in children with asthma.
The relationship between tobacco smoke exposure and FeNO levels in children who have asthma is unclear.21,22,45
We found a good correlation between the tobacco smoke exposure measures in this study (E table 4, 5, & 6), but the reported number of cigarettes smoked in the home decreased during the study while the biomarkers of exposure did not. This suggests that reported exposure was subject to recall bias. We found that tobacco smoke exposure, as measured by airborne nicotine, was associated with lower FeNO levels. In contrast, neither the biomarkers nor parent reported tobacco smoke exposure was associated with FeNO levels. Since the majority of tobacco smoke measures in this study were not related to FeNO levels, tobacco smoke exposure may not affect FeNO levels in children with asthma. Alternatively, airborne nicotine may be a more direct measure of the fraction of tobacco smoke that affects the lung and therefore affects FeNO levels.
There are several limitations to this study. First, the cohort only included tobacco smoke exposed children with asthma; there was not an unexposed control group. There was, however, a wide range of exposure to tobacco smoke and we included extensive measures of exposure that allowed us to test and quantify for effects of exposure. Moreover, data from nationally representative samples suggests that 85% of children 4 to 16 years of age have measurable levels of tobacco smoke exposure.46
Thus, our findings should be representative of a large proportion of children with asthma. A second potential limitation is that we only had baseline measures of settled dust allergens. Although some investigators have found that a single measurement of settled dust allergens may be a good proxy for one year exposure, this limitation prevented us from evaluating whether changes in settled allergen exposures were associated with changes in FeNO.47
A third potential limitation is that we relied on parent reported medication use. Still, reported medication is a relatively accurate measure of use.48
A fourth limitation is that we were not able to measure flow during our FeNO collection, but we had a restricted range of flows. This limitation means that our FeNO levels while generalizable to other groups may not be comparable to those groups using a specific flow rate beyond the range we used. Our method was replicable, demonstrating a coefficient of variation of 17% in other studies (unpublished data).
This study has shown that FeNO reflects anti-inflammatory therapy and recognized environmental triggers such as allergen sensitization and season. These results also suggest that clinicians and researchers may need to consider an individual’s baseline FeNO levels to manage children with asthma. With these factors in mind, FeNO may help physicians assess airway inflammation to tailor individual asthma management through pharmacologic and environmental interventions. Thus, these results hold promise for the use of FeNO in asthma management.