An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications

Abstract

Background: Measurement of fractional nitric oxide (NO) concentration in exhaled breath (Fe(NO)) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. While Fe(NO) measurement has been standardized, there is currently no reference guideline for practicing health care providers to guide them in the appropriate use and interpretation of Fe(NO) in clinical practice.

Purpose: To develop evidence-based guidelines for the interpretation of Fe(NO) measurements that incorporate evidence that has accumulated over the past decade.

Methods: We created a multidisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway disease and/or NO. The committee identified important clinical questions, synthesized the evidence, and formulated recommendations. Recommendations were developed using pragmatic systematic reviews of the literature and the GRADE approach.

Results: The evidence related to the use of Fe(NO) measurements is reviewed and clinical practice recommendations are provided.

Conclusions: In the setting of chronic inflammatory airway disease including asthma, conventional tests such as FEV(1) reversibility or provocation tests are only indirectly associated with airway inflammation. Fe(NO) offers added advantages for patient care including, but not limited to (1) detecting of eosinophilic airway inflammation, (2) determining the likelihood of corticosteroid responsiveness, (3) monitoring of airway inflammation to determine the potential need for corticosteroid, and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy.

Figure 1.

Schematic representation of the distribution of Fe_NO levels in an unselected population of 2,200 male and female subjects. The median value was 16.0 ppb with a range of 2.4 to 199 ppb. The cut point of 26 ppb is the optimum cut point for significant sputum eosinophilia, indicating that up to 20% of individuals with an Fe_NO greater than 25 ppb may not necessarily have sputum eosinophilia, and that the clinical context requires to be taken into account. The data used to prepare this composite figure were obtained from Shaw and colleagues (51) and Olin and colleagues (73) after consultation with the authors.

Figure 2.

An amplification of Figure 1 in which the distribution of Fe_NO in stable asthma is depicted as a dotted line. Taken from Olin and colleagues (73). In that study, the 95% confidence intervals for Fe_NO in stable asthma was reported to be 22 to 44 ppb. The cut point of 47 ppb is the optimum cut point for steroid responsiveness in patients with nonspecific respiratory symptoms. The other data used to prepare this composite figure were obtained from Smith and colleagues (56) after consultation with the authors.