Asthma and lower airway disease
Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children

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Background

Fraction of exhaled nitric oxide (Feno), a marker of airway inflammation, has been proposed to be useful for asthma management, but conclusions are inconsistent. This might be due to the failure of mean statistics to characterize individual variability in Feno values, which is possibly a better indicator of asthma control than single measurements.

Objective

We characterized fractal fluctuations in daily Feno values over time and the relationship between Feno values and symptom scores. We investigated whether these are associated with asthma severity, control, and exacerbation risk.

Methods

Daily Feno values and symptom scores over 192 days in 41 atopic asthmatic children from the Childhood Asthma Respiratory Inflammatory Status Monitoring study were analyzed. Two methods of time-series analysis were used: detrended fluctuation analysis to quantify fractal patterns in fluctuations in daily Feno values (α value) and cross-correlation to quantify the strength of the relationship between daily Feno values and symptom scores. The associations of α values and cross-correlation with markers of asthma severity and control were assessed by means of regression analysis.

Results

Daily fluctuations in Feno values exhibited fractal-type long-range correlations. Those subjects receiving higher doses of inhaled corticosteroids at study entry had a significantly lower α value, corresponding to more random fluctuations in Feno values in those with greater inhaled corticosteroid need. The cross-correlation between Feno values and symptom scores was significantly higher in those subjects who had exacerbations.

Conclusions

Fluctuation in Feno values and their cross-correlation to symptom scores contains information on asthma severity and control. Methods that quantify the complexity of asthma over time might assist in identifying asthmatic subjects with concordance between eosinophilic inflammation and symptoms and thus increased exacerbation risk.

Section snippets

Study population and design

We retrospectively analyzed data from the Childhood Asthma Respiratory Inflammatory Status Monitoring (CHARISM) study,12 a prospective, open-label, randomized, multicenter, parallel-group study in Italy and The Netherlands. Asthma was monitored daily over 30 weeks in 151 children aged 6 to 18 years with mild-to-moderate atopic asthma. The aim of the original study was to investigate whether ICS doses are better titrated based on Feno values and symptom scores rather than symptom scores only. We

Results

Forty-one children met the inclusion criterion of less than 10% data missing of daily Feno values and symptom scores of the first 192 days of the study, resulting in a total of 7820 measurements of Feno for analysis. Table I summarizes the subjects’ characteristics stratified by severe, moderate, or no asthma exacerbation during the study period. In the whole study group Feno values measured over 192 days displayed a considerable amount of fluctuation. Two examples of a Feno time series over

Discussion

In our study of Feno values recorded daily over 192 days in atopic asthmatic children,12 we found that fluctuations in Feno values were not random but were correlated over time scales of more than a month (long-range correlation). The long-range correlation exponent α was found to be lower in those subjects requiring higher ICS doses at study entry. Thus fluctuations in Feno values were more random in children requiring higher ICS doses. However, the α value was not related to mean asthma

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    Supported by Swiss National Foundation grant 3200-B0-1 12099 and a Swiss Federal Office of Public Health (Tobacco Prevention Fund) research grant. The data collection was financially supported by Aerocrine AB, Solna, Sweden. R.v.d.V. was supported by a travel grant from the Erasmus MC–Sophia Foundation for Scientific Research.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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