Despite efforts over the past decade to better understand the relationships between FeNO and the development of asthma and allergic disease, “normal” FeNO levels in early school aged children are not well established. We report FeNO measurements obtained with on-line technique in a large cohort of children at 6 and 8 years of age, allowing for effective comparisons with previously published studies. We clearly show that in our high-risk birth cohort, FeNO was most significantly associated with atopic (the presence of allergic sensitization) status. In fact, FeNO was only elevated in children with asthma and atopic dermatitis who also demonstrated allergic sensitization. Interestingly, rhinitis without detectable allergic sensitization was significantly associated with elevations in FeNO at age 8 yrs, albeit less so than in children with both rhinitis and demonstrable allergic sensitization.
Our overall rates of obtaining successful FeNO measurements at 6 years of age (64%) and 8 years of age (93%) by on-line measurement were similar to previously published data.(3
) Successful measurement in 2/3 of 6 year olds and more than 90% of 8 year olds confirms the appeal of FeNO measurement in this age group as a reliable, non-invasive test that yields real-time results.
Another important finding of this study is that FeNO measurements varied by season, with summer and fall yielding the highest FeNO measurements. This is similar to recent findings reported from another cohort in which FeNO was highest in fall.(25
) One potential explanation for this finding could be greater exposure to allergens, such as dust mites and viruses (rhinovirus in particular), during the summer and fall, respectively. Importantly, controlling for season of measurement did not alter any of the relationships seen between atopic status and FeNO; however, season of measurement still should be considered when interpreting FeNO measurements in a clinical or research setting.
While Buchvald & Bisgaard reported no association between FeNO and atopy as measured by RAST testing in 2-5 year old children,(17
) Brussee and colleagues, in a significantly larger cohort of 4 year old children, reported a small but statistically significant elevation of FeNO in atopic individuals as determined by RAST testing.(14
) In this manuscript, we report greater differences in FeNO in atopic vs. non-atopic children at age 8 years compared to age 6 years. A significantly more pronounced elevation of FeNO in older atopic children has been demonstrated by many researchers, (3
) which suggests that while normal FeNO values have previously been shown to increase with age, there also appears to be a larger discrepancy between “normal” and “abnormal” values as individuals progress through childhood. The small difference between “normal” and “abnormal” FeNO seen in early school age children makes it difficult to foresee widespread successful use of FeNO for diagnosis in this age group.
In this study, we found a significant relationship between FeNO and asthma only in those children with concomitant allergic sensitization. This is consistent with at least one pediatric(26
) and one adult study,(16
) but not with others.(14
) This discrepancy may be secondary to the use of many different methods for classification of history of wheezing and asthma throughout the studies, in addition to the various ages of the populations studied, as a greater percentage of teenagers and young adults, compared to early school age children, have atopic asthma. Whether a stronger relationship between asthma and elevated levels of FeNO will develop over time in our cohort remains to be seen.
While there is much agreement that there is a strong relationship between elevated FeNO and atopy, there have been mixed results when comparing measurements of lung function and FeNO. Several groups have demonstrated a correlation between spirometric evidence of airway obstruction and elevated FeNO in children;(4
) however, most studies have not shown any correlation between elevated FeNO and impairment of FEV1
) In this study, we found no significant correlation between FeNO and any measurement of lung function at 6 or 8 years of age. This confirms the notion that FeNO measures a different aspect of atopic airway disease than spirometry, and is potentially a more sensitive test for allergic airway disease in this age group,(6
) where the vast majority of asthmatic children have normal lung function.(31
There are several limitations to our study. First, COAST is a cohort of children at high risk for the development of asthma and other allergic diseases, which could limit the generalizability of our results. However, despite the high risk status of the COAST cohort, the geometric mean FeNO measurements were comparable to those previously published in an unselected population of early school age children.(3
) Second, due to the observational nature of COAST, treatment regimens varied amongst children. Some individuals with asthma were taking inhaled corticosteroids which are known to decrease FeNO. However, when adjusting for controller medication use, the relationship between asthma and FeNO did not change.
In summary, in this cohort of children at 6 and 8 years of age at high risk for the development of asthma and allergic disease, elevations of FeNO were strongly and significantly correlated with allergic sensitization. While this data adds to the growing evidence of a strong relationship between elevated FeNO and atopy in children, the relationship of FeNO and asthma in early school age is much less clear. These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.