The value of FeNO measurement in childhood asthma: uncertainties and perspectives.

Asthma is considered an heterogeneous disease, requiring multiple biomarkers for diagnosis and management. Fractional exhaled nitric oxide in exhaled breath (FeNO) was the first useful non-invasive marker of airway inflammation in asthma and still is the most widely used. The non-invasive nature and the relatively easy use of FeNO technique make it an interesting tool to monitor airway inflammation and rationalize corticosteroid therapy in asthmatic patients, together with the traditional clinical tools (history, physical examination and lung function tests), even if some controversies have been published regarding the use of FeNO to support the management of asthma in children. The problem of multiple confounding factors and overlap between healthy and asthmatic populations preclude the routine application of FeNO reference values in clinical practice and suggest that it would be better to consider an individual "best", taking into account the context in which the measurement is obtained and the clinical history of the patient. Besides, there is still disagreement about the role of FeNO as a marker of asthma control, due to the complexity of balance among the different items involved in its determination and the lack of homogeneity in the population groups studied in the few studies conducted so far. Heterogeneity of problematic severe asthma greatly limits utility of FeNO alone as a biomarker of inflammation to optimize the disease management on an individual basis. None of the studies conducted so far demonstrated that the use of FeNO was better than current asthma guidelines in controlling asthma exacerbations. In summary, there is a large variation in FeNO levels between individuals, which may reflect the natural heterogeneity in baseline epithelial nitric oxide synthase activity and/or the contribution of other noneosinophilic factors to epithelial nitric oxide synthase activity. FeNO is a promising biomarker, but at present some limits are highlighted. We would recommend that further research can be carried out by organizing studies aimed to obtain reliable reference values of FeNO and in order to better interpret FeNO measurements in clinical settings, taking also into account the influence of genetic and environmental factors.