Regarding the role of F_ENO in predicting failure after ICS reduction in mild-to-moderate asthma patients

To the Editor:

Although exhaled nitric oxide fraction (F_ENO) is one of most widely used type-2 biomarkers, there remains some controversy about its role in diagnosing asthma, assessing adherence, predicting steroid responsiveness and preventing exacerbations by adjusting medication dosage. Thus, we read with great interest the well-conducted individual patient data meta-analysis by Wang et al. [1]. The study showed that the use of F_ENO can potentially assist clinicians in deciding whether to reduce inhaled corticosteroid (ICS) dose in well-controlled asthmatics. We appreciate the authors' efforts in illuminating this important topic, but there is an essential methodological consideration that must be taken into account, which has already been outlined by Dinh-Xuan and Brusselle [2] in their editorial and by the authors themselves: the study did not evaluate the impact of other potential risk factors for exacerbations.

In a prospective, multicentre study that included 218 patients with well-controlled moderate asthma, followed-up for 12 months, with the aim of developing and externally validating a tool to predict failure when stepping down treatment, we assessed the impact of several prognostic variables (a documented history of previous bronchial obstruction, a history of severe exacerbations, forced expiratory volume in 1 s <80%, peak expiratory flow variability, the presence of a significant bronchodilator response, F_ENO values >50 ppb, an Asthma Control Test score <25, and adherence) on loss of control [3]. We found that, on multivariate analysis, high F_ENO levels were not significantly associated with loss of control, in line with the conclusions of a systematic review [4].

The discordance between the results found by Wang et al. [1] and those we have previously reported could have several explanations.

1) F_ENO primarily reflects the activity of the interleukin (IL)-4/IL-13 pathway, and an additional mechanism, related to airway eosinophilia and independent of F_ENO, could be responsible for some severe exacerbations [5]. Therefore, an ongoing inflammatory process may persist in asthmatics with low F_ENO values, leading to a “false sense of security”.

2) It is well known that F_ENO levels can remain elevated in some asthmatics with eosinophilic chronic rhinosinusitis, even after adequate treatment [6]. Thus, if we decide not to reduce the ICS dose based only on a high F_ENO value, these patients would never benefit from step-down treatment despite having controlled bronchial inflammation.

3) It has been reported that absolute exhaled nitric oxide measurements may differ to a clinically relevant extent, depending on which device is used, with individual differences as great as 150 ppb in a single patient [7]. Thus, an exact cut-off point cannot be established if different analysers were used in the studies that went into the meta-analysis. Although the same device is normally employed to repeatedly quantify F_ENO in a given patient, clinicians must ensure the reproducibility of F_ENO results between multiple measurements.

In conclusion, we must be cautious in deciding whether or not to reduce the ICS dose based only on the F_ENO measurement. As Wang et al. [1] acknowledge, we need further evidence.

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