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 (FNO) is higher in asthmatics than in normal subjects. Not all asthmatics demonstrate a high FNO, reflecting the heterogeneity of asthma. High values of FNO are associated with over-expression of corticosteroid-sensitive iNOS isoform and allergic/eosinophilic inflammation. A major feature of elevated FNO in asthma is the prediction of inhaled corticosteroid (ICS) response, and FNO more than 50 ppb in adults is a strong indicator of likely ICS sensitivity. In addition, FNO values are elevated in asthma when asthma control deteriorates, identifying patients at risk of exacerbations, and, on the other hand, FNO reductions during ICS therapy precede improvement in respiratory symptoms and lung function, suggesting that FNO is a sensitive predictor of loss of asthma control. FNO also predicts the response to biological therapy (anti-IgE, -IL-5 and -IL-13 antibodies) in severe asthma but, interestingly, FNO values fall only after treatment with anti-IL-13 and -IL-4/IL-13 receptor antibodies. The use of FNO 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 FNO to identify potential ICS responders in specific phenotypes.