Summary of: Khatri SB, Iaccarino JM, Barochia A, Soghier I, Akuthota P, Brady A, et al. Use of fractional exhaled nitric oxide to guide the treatment of asthma: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2021;204(10):e97–e109 (1).
Asthma is a heterogeneous disease characterized by variable airflow obstruction, features of airway hyperresponsiveness, and chronic airway inflammation. Management is aimed at reducing symptom burden, maximizing lung function, and preventing acute exacerbations (2, 3). However, response to daily controller therapies such as inhaled corticosteroids (ICS) is variable, and selecting the optimal therapeutic dose for an individual patient is challenging (4). Thus, clinicians need complementary tools to guide decision-making regarding appropriate daily controller therapy.
Nitric oxide (NO) can be measured in exhaled breath and is principally derived from the actions of inducible NO synthase 2, an epithelial-derived enzyme induced by airway inflammation (5–7). The fraction of NO during steady-state exhalation is known as the fractional exhaled NO (FeNO), which correlates well with eosinophilic airway inflammation and provides a noninvasive assessment of type-2 (T2) airway inflammation in asthma (8–12). Identifying patients with T2 inflammation is crucial in the current era of asthma management, not only to assess candidacy for T2-directed biologic therapies for patients with severe disease but also because patients with elevated T2 biomarkers are more likely to respond to ICS (13, 14).
A clinical practice guideline was developed by the American Thoracic Society (ATS) in 2011 regarding the interpretation of FeNO concentrations for clinical applications, but several key questions remained, including the use of this test in establishing a diagnosis of asthma, monitoring response to therapy, and for making individual treatment decisions in patients with known asthma (15). Because of these knowledge gaps, the ATS convened a multidisciplinary panel of experts to identify a single most pressing question regarding the use of FeNO in clinical practice and develop an evidence-based guideline after a systematic review of the literature and meta-analysis or narrative review of relevant outcomes (1). Specifically, the committee members determined by consensus to address the highest priority question: should patients with asthma in whom treatment is being contemplated undergo FeNO testing? This summary is intended to provide clinicians with the key take-home points from the clinical practice guideline, which have different implications for individual stakeholders (Table 1).
|Strong Recommendation (“We recommend…”)||Conditional Recommendation (“We suggest…”)|
|For patients||The overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not.||The majority of individuals in this situation would want the suggested course of action, but a sizable minority would not.|
|For clinicians||The overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.||Different choices will be appropriate for different patients, and each patient must be helped to arrive at a management decision consistent with her or his values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working toward a decision.|
|For policymakers||The recommendation can be adopted as policy in most situations, including for use as a performance indicator.||Policymaking will require substantial debates and the involvement of many stakeholders. Policies are also more likely to vary between regions. Performance indicators would have to focus on the fact that adequate deliberation about the management options has taken place.|
Recommendation: In patients with asthma in whom treatment is being considered, we suggest the use of FeNO testing in addition to usual care over usual care alone (conditional recommendation, low confidence in estimates of effect).
Before the analysis, the committee identified and ranked the importance of outcome measures relevant to asthma. These specific outcome measures were then assessed on whether the measurement of FeNO concentrations during the evaluation of an individual with asthma led to a significant change in these measures. The panel prioritized outcomes indicative of uncontrolled asthma, placing the highest value on the number and frequency of acute exacerbations and oral corticosteroid use (OCS). However, several of the selected outcome measures may not have had adequate power to detect a difference with FeNO-based care because of a relative paucity of data available from randomized control trials. The results of the panel’s systematic review are summarized below (Table 2).
|Question: Should patients with asthma in whom treatment is being contemplated undergo FeNO testing?|
|Recommendation: we suggest the use of FeNO testing in addition to usual care over usual care alone (conditional recommendation, low confidence in estimates of effect).|
|Summary of Evidence|
|Highest Priority Outcome Measures||Favors FeNO-based Care?||Level of Certainty?|
|Reduction in acute exacerbations|
|Frequency of acute exacerbations||Yes||Low|
|Number of acute exacerbations||Yes||Moderate|
|Reduction in oral corticosteroid use||Yes||Moderate|
|Validated questionnaires assessing asthma control||No difference||Low–Moderate|
|Emergency room and unscheduled healthcare visits||No difference||Low–Moderate|
The meta-analysis identified that FeNO-based care was associated with decreased asthma exacerbations when compared with usual care: for every 1,000 patients receiving FeNO-based care, 111 fewer individuals had exacerbations (95% confidence interval [CI], 175 fewer to 28 fewer; moderate certainty of evidence); similarly, the number of exacerbations per patient per year was reduced (mean difference, −0.15; 95% CI, −0.28 to −0.03; low certainty of evidence). Of note, the reported effect size was larger in studies with pediatric populations than those in adult populations.
The meta-analysis identified that FeNO-based care was associated with a reduction in OCS use (a surrogate measure of asthma control and severity) when compared with usual care: for every 1,000 patients receiving FeNO-based care, 69 fewer individuals used OCS (95% CI, 115 fewer to 16 fewer; moderate certainty of evidence). Notably, four out of the six studies included in the pooled analysis were conducted solely in pediatric populations (16–19).
The meta-analysis did not demonstrate a difference between FeNO-based care and usual care in asthma control as assessed by either Asthma Control Test (mean difference, 0.40; 95% CI, −0.49 to 1.28) or Asthma Control Questionnaire (mean difference, −0.01; 95% CI, −0.19 to 0.16). However, only a small number of studies were eligible for analysis, and the pooled sample size may have been statistically underpowered.
Similarly, in comparison with usual care, FeNO-based care was not significantly associated with reductions in unscheduled healthcare or emergency room visits (relative risk (RR), 0.67; 95% CI, 0.37–1.22) or asthma-related hospitalizations (RR, 0.78; 95% CI, 0.36–1.70). However, this analysis was potentially underpowered because of the limited number of studies available for emergency room visits and the overall low event rate for asthma-related hospitalizations.
With the notable exceptions of changes in lung function and ICS use, analysis of outcomes that received a lower priority ranking from the committee were limited because of a paucity of eligible studies and were therefore likely underpowered.
There was an overall improvement in lung function seen in patients receiving FeNO-based care compared with those receiving usual care, but the effect size was small. For example, the percentage of predicted forced expiratory volume in the first second was 1.11% (95% CI, 0.02–2.21%) higher in patients receiving FeNO-based care.
Multiple studies reported ICS usage, but most of them did not report differences in ICS use between patients receiving FeNO-based care and usual care. However, these studies were inappropriate for meta-analysis because of differences in specific ICS medications and dosage across studies. As a result, no conclusion could be drawn on this outcome on the basis of currently available data.
A limited number of studies were available for analysis of the following outcomes, none of which were significantly different with FeNO-based care versus usual care: quality of life on the basis of the Asthma Quality of Life Questionnaire, days of missed school or work, symptom-free days, rescue inhaler use, patient satisfaction with care, medication adherence, adverse events, and the percentage of blood eosinophils. No eligible study was identified for the following outcomes: asthma medication ratio (the ratio of ICS to rescue inhaler use), inhaler technique, physical activities (daily activities, exercise, sports), or mortality.
Most studies have identified that FeNO measurement is cost-effective, but it has been studied primarily to monitor disease rather than address its overall utility in guiding asthma management. FeNO-based care may be particularly cost-effective in those who experience exacerbations (20), for monitoring disease activity (21), and in identifying potential responders to T2 biologics (22). Despite limited data, the panel concluded the available evidence probably favors FeNO-based care from a cost-effectiveness standpoint.
The committee provided a conditional recommendation for the use of FeNO testing in individuals with asthma in whom treatment is being considered. The panel’s consensus was that FeNO testing provides clinicians with a simple and noninvasive test that complements standard asthma care. This recommendation placed a high value on meta-analysis results identifying reduced number and frequency of acute exacerbations as well as a reduction in OCS use with FeNO-based care. However, the panel acknowledged overall modest effect sizes and statistical significance of individual outcome measures with FeNO-based care.
Importantly, this clinical practice guideline was intended to address the single question of whether FeNO testing should be performed in individuals with asthma but does not precisely define “FeNO-based care”, including the timing of initial FeNO testing, accuracy of FeNO testing in establishing a diagnosis of asthma, the utility of serial FeNO testing to monitor disease, FeNO testing in specific patient subgroups of asthma (i.e., T2-high vs. non-T2 asthma), and establishment of FeNO concentration cutpoints that should dictate clinical action. The panel’s inability to make specific recommendations regarding these topics was driven primarily by the variability of FeNO use within currently available studies as well as the overall limited number of randomized control trials in this area. The committee acknowledged the limited scope of this single-question clinical practice guideline and encouraged future research to include larger, pragmatic trials that address these individual applications of FeNO testing.
Despite these limitations, the committee did provide a conceptual framework for the use of FeNO testing to guide treatment decisions within the context of pretest probability for an individual patient (Figure 1). For instance, lower and more sensitive cut points for patients with high pretest probability and higher and more specific cut points for patients with low pretest probability. This framework is similar to other diagnostic tests, such as bronchoprovocation testing, in which both the decision to perform testing and interpretation of testing is predicated on specific characteristics of an individual and discussions between that individual and their provider. The panel’s consensus was to give clinicians latitude to use this suggested framework in making individual treatment decisions.
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