Perspectives on exhaled nitric oxide

The history of nitric oxide (NO) in the respiratory field dates back to the beginning of the 1990s with the pioneering study by Lars Gustafsson et al describing the presence of endogenous NO in the exhaled breath of human beings. Soon after, independent studies showed that exhaled NO concentrations (F_ENO) is higher in asthmatics than in normal subjects. Not all asthmatics demonstrate a high F_ENO, reflecting the heterogeneity of asthma. High values of F_ENO are associated with over-expression of corticosteroid-sensitive iNOS isoform and allergic/eosinophilic inflammation. A major feature of elevated F_ENO in asthma is the prediction of inhaled corticosteroid (ICS) response, and F_ENO more than 50 ppb in adults is a strong indicator of likely ICS sensitivity. In addition, F_ENO values are elevated in asthma when asthma control deteriorates, identifying patients at risk of exacerbations, and, on the other hand, F_ENO reductions during ICS therapy precede improvement in respiratory symptoms and lung function, suggesting that F_ENO is a sensitive predictor of loss of asthma control. F_ENO also predicts the response to biological therapy (anti-IgE, -IL-5 and -IL-13 antibodies) in severe asthma but, interestingly, F_ENO values fall only after treatment with anti-IL-13 and -IL-4/IL-13 receptor antibodies. The use of F_ENO as a Type-2 inflammatory biomarker, in constellation with other Type-2 markers, could help to determine who might benefit from ICS and biological treatment. It remains to find out more precise cut-off values of F_ENO to identify potential ICS responders in specific phenotypes.