ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F_ENO50)

Background Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s⁻¹ (F_ENO50) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F_ENO50. Methods Available individual F_ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of “healthy” were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. Results Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F_ENO50 (R²=0.12). F_ENO device was neccessary as a predictor of F_ENO50, such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F_ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F_ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. Conclusion Available F_ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F_ENO devices and measurement are required before population reference values might be derived.