Our results suggest that FeNO had a modest ability to identify either atopy alone or asthma alone in our study population; however, our data suggest that it may be a useful aid in differentiating between atopic and non-atopic phenotypes among asthmatic children. We found that a FeNO>20 ppb may have sufficient discriminatory power to identify the asthmatic atopic phenotype.
Our results showed that FeNO had limited accuracy in identifying atopy in the general population. These findings contrast with those reported by Yao et al., who reported a better discrimination of FeNO for allergic sensitization in the general population than that reported by our group (AUC of 80%, 95% CI 77% to 82%). Differences between the study conducted by Yao et al. and our current study could be attributed to the target population and assessment of atopy. Previous studies have described that age contributes to the variability of FeNO
[4, 5, 8, 18, 20, 25]. Our study had an older but narrower age range than the study by Yao et al. (5–18 years). Other studies suggest that FeNO may be more useful in young children, who often have no correlation with spirometric assessments or the manifestation of symptoms, but in whom a screening, early diagnosis, and preventive measures would be useful
[19, 20]. Other differences included the method of atopic assessment. Yao et al. conducted atopic assessment using the multi-allergen screen for serum specific IgE (e.g. Phadiatop), whereas we used allergy skin testing. Because allergy skin prick testing does not always identify atopy accurately, measurement of a panel of serum specific IgE is the best method to assess atopy. Some studies report a concordance between 85% and 95%, depending on the allergen being tested, between allergy skin testing and measurement of serum specific IgE
; however, it is still unclear if these two tests can be used interchangeably to determine atopic sensitization or if both should be used for the diagnosis of atopy
[29–31]. Finally, another difference between both studies were that the study by Yao et al. and ours used different chemiluminescence analyzers for FeNO.
Variables such as sex, current asthma, allergic rhinitis, personal history of tobacco use, current use of inhaled corticosteroids, atopy and seasonality have all been previously identified as important explanatory factors that influence FeNO levels
[17, 20, 24, 32]. While our study corroborates the importance of these variables in our study setting, we also found that rural dwelling (i.e., living in Tumbes vs. Lima) was additional important explanatory factor associated with FeNO levels. Indeed, few studies have considered the rural versus urban setting in their analysis or study design, despite well-recognized differences in the prevalence of asthma and allergic disease between these two environments
[26, 33, 34]. This is particularly relevant to investigations in low- and middle-income countries, as two recent studies conducted in South America, one in Ecuador
 and another conducted by our team in Peru
 have shown that urbanization increases the risk of both asthma and allergic diseases. The differences in FeNO levels are explained by the higher prevalence and increased severity of both asthma and atopy in Lima compared to Tumbes
. Use of tobacco could impact assessment of FeNO, and if under-reported, could have affected our results. We found an overall low prevalence of daily smokers in previous surveys of tobacco use in our study population. Using a previously-validated, Spanish questionnaires of tobacco smoke in the region, our group reported a low prevalence of daily smoking in adults
Our findings may help to explain previous inconsistences that other studies have reported when using FeNO levels as a criterion in the diagnosis or management of asthma
[6, 8, 12, 15, 22, 23]. We found that FeNO>35 ppb predicted asthma with better accuracy than cutoffs of 20 ppb or 25 ppb. This points to the importance of proper characterization of the atopic phenotype when interpreting the relationship between FeNO and asthma, and also the proper consideration of particular cut-off FeNO values by atopic status, age and sex. Another explanation for previous inconsistences with other studies using FeNO levels could be related to methodology mostly related to flow dependence and the type of device used to measure FeNO. Recently, Malinovschi et al. compared several methods of measuring FeNO and found a better association between asthma control using exhaled breath condensate nitrates rather than with chemiluminescence analyzers for FeNO, which is currently considered the gold standard
[25, 36, 37].
Our study has some potential shortcomings. First, our findings are cross-sectional and we do not evaluate longitudinal changes in FeNO values within individuals. Studies have reported different coefficient of variations from 10% (about 4ppb) in healthy individuals to 40% in asthmatics
[10–12]. Second, we assessed only at a narrow age range, and predictive cut-offs may change with age. Future investigations should include younger children or cover a broad age range, consider within-individual changes in FeNO levels and assessment of environmental allergenic exposures
[10, 21, 25, 34, 37]. Third, we measured atopic sensitization to indoor aeroallergens only and did not include pollen or food allergens.
We chose not to measure pollens because Lima is located in a semi-arid, tropical region where there are few tree and grass allergens. While it is possible that food allergy may affect our overall prevalence of atopy and potentially the values of fractional exhaled nitric oxide
; however, the incidence of food allergies in our study population is unknown and understudied. Fourth, we did not conduct an evaluation of parasitic infections in our study children; however, previous population-based evaluations by our team on the burden of soil-based helminths in our study areas have been previously found to be low
. Finally, another aspect to consider is that potential genetic differences may exist between our study sites, which were settled by different ethnic groups; despite that phenotypically, these populations are similar (i.e., mestizo).