Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care

Inhaled anti-inflammatory (corticosteroid, ICS) therapy is the cornerstone of asthma management with the ultimate goal of maintaining control of the clinical manifestations of the disease for prolonged periods [1]. Initiation of maintenance therapy as either low-dose ICS or as a leukotriene receptor antagonist (LTRA) is recommended for patients who remain symptomatic despite as-needed short-acting bronchodilator therapy [2, 3]. In patients who remain sub-optimally controlled on low-dose ICS, an increase in ICS dose (to medium- or high-dose), or the addition of a long-acting bronchodilator (LABA) or LTRA is recommended. For those who continue to be uncontrolled, further management options include higher doses of ICS, maintenance oral corticosteroids and anti-IgE therapy [2, 3].

Achieving optimum asthma control requires an understanding of the nature and extent of the airway inflammation present. In the Gaining Optimum Asthma controL (GOAL) study, for example, over 30% of patients failed to achieve totally controlled asthma despite receiving maximum doses of fluticasone propionate. While drug delivery and/or treatment adherence may have played a part in their failure to achieve control, it may also have been partially attributable to the presence of steroid unresponsive asthma in these patients [4, 5].

ICS dosing decisions (starting dose and subsequent dose adjustments) are typically symptom-driven and reliant on patient or carer/parental reports [6]. Yet respiratory symptoms can be non-specific and are not necessarily related to the extent or severity of the inflammation present [7]. Moreover, lung function and symptom scores have only a modest correlation with airway inflammation [8]. Indeed, although eosinophilic airway inflammation has been shown to be closely linked to steroid response [9‐14], it has only a weak correlation to airway dysfunction and to symptoms [15, 16]. Thus, a standard clinical assessment that relies on symptom assessment and simple lung-function tests alone provides limited information about the presence, or absence, of airway inflammation, or the extent to which a patient is at risk of future asthma exacerbations.

The results of this real-life evaluation of FeNO monitoring in UK primary care practice suggest FeNO is being used (by the subgroup of practices included in the study) as a complementary diagnostic tool to aid diagnosis in patients in whom traditional assessment tools may have been inconclusive. It appears to be being used to guide decisions around ICS initiation or step up.

While FeNO can provide useful information about the nature and presence (or absence) of eosinophilic airway inflammation and about the likelihood (or not) of ICS responsiveness, it can also be used to identify poor adherence. These data suggest that a high FeNO level appears to drive improved ICS adherence in routine care. Using FeNO in this way has the potential to optimize existing therapy and minimize inappropriate use of ICS in patients unlikely to respond.

This real-life study adds to a rather limited evidence base on the role of FeNO monitoring in asthma management. At one point, the combined findings of a Cochrane systematic review of FeNO-based asthma management and a meta-analysis of studies evaluating the role of FeNO or sputum eosinophils in asthma management of patients concluded FeNO-guided asthma management could not be recommended (for adults or children) and that further studies were needed [28, 29]. This conclusion was subsequently challenged on the basis that both the Cochrane review and the meta-analysis used the number of participants who had asthma exacerbations during follow-up as the primary endpoint, which does not take into consideration the fact that some patients may have multiple exacerbations during the course of a study. Indeed, the National Institute for Health (NIH) considers time to first asthma exacerbation and/or asthma exacerbation rates to be the most meaningful outcomes for assessing asthma exacerbations [30]. A re-analysis of the data from the Cochrane review and the meta-analysis [28‐30] using asthma exacerbation rates as the endpoint (and using the standard Cochrane meta-analysis approach) found the rate of exacerbations was significantly lower in patients receiving a FeNO-based asthma management strategy, in both adults and children [31‐35].

Pooling the evidence from the existing literature and the results of this real-life study together with our own experience of using FeNO in clinical practice, we have devised two clinical practice algorithms to aid primary care practitioners in the practical use of FeNO monitoring. The first algorithm is an “Initial Evaluation Algorithm”, which aims to provide guidance on the use of FeNO at the time of initial asthma diagnosis where traditional tools are inadequate (Figure 4). The second is an “On-going Monitoring and Decision Support Algorithm” to guide use of FeNO within longer-term asthma management and to inform prescribing decisions post diagnosis (Figure 5).

In conclusion, FeNO monitoring should be viewed as a complementary assessment and monitoring tool when traditional assessment techniques prove inadequate or inconclusive. It can offer added advantages for clinicians (and patients) in terms of: (1) detecting the presence of eosinophilic airway inflammation, (2) determining the likelihood of ICS responsive (and lack thereof), (3) monitoring of airway inflammation to determine the potential need for a corticosteroid, and (4) unmasking (otherwise unsuspected) non-adherence to corticosteroid therapy.

Using FeNO to guide asthma management may not only benefit patients and reduce pressures on healthcare professionals, but could also reduce asthma-related healthcare costs [52‐54]. FeNO-related cost savings could be realized through a variety of mechanisms, such as: reducing the use of inappropriately high doses of ICS (where ICS response has plateaued, or in patients who are stable and eligible for ICS dose reduction or cessation), and by reducing the cost of managing the effects of sub-optimal control (e.g. hospitalizations, exacerbations) in patients in whom guided step-up, or add-on therapy may be more beneficial. A UK cost-effectiveness study evaluated the relative comparative cost of using FeNO against other diagnostic and monitoring tools. For diagnosis, FeNO costs were compared against those for lung function and reversibility testing, bronchial provocation and sputum eosinophil count. For asthma management, the impact of FeNO monitoring on asthma control over one year (including ICS use, exacerbations and hospitalizations) was compared to symptoms and lung function (as in standard care). FeNO was measured using a hand-held monitor (NIOX MINO) at a reimbursement price of 23 pound sterling (£). The study found that an asthma diagnosis using FeNO cost £43 less per patient as compared with standard diagnostic tests. Asthma management using FeNO measurement (instead of lung function testing) resulted in annual cost-savings of £341 pound sterling for patients with mild to severe asthma and savings of £554 pound sterling for those with moderate to severe asthma [54]. While these data are of interest, further studies are required to explore the potential benefits and cost implications of FeNO-guided asthma management across a spectrum of asthma severities.

While some studies based in academic medical centres have found that physician-based treatment decisions are non-inferior to biomarker- or symptom-based ICS adjustments in mild-moderate asthma, [55] we believe that FeNO monitoring (use as discussed in our proposed clinical pathways) can assist primary care physicians who are not experts in respiratory disease to achieve improved diagnostic accuracy in patients with non-specific respiratory symptoms and to achieve more tailored and targeted treatment regimens for on-going asthma management.