Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma

Abstract

Rationale: Exhaled nitric oxide (FE NO ) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FE NO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FE NO levels would identify a more reactive, at-risk asthma phenotype. Methods: FE NO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program. Measurements and Main Results: FE NO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FE NO levels (.35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FE NO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FE NO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care. Conclusions: Grouping of asthma by FE NO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

“…Finally, exhaled nitric oxide fraction (FeNO) has been extensively evaluated in mild-to-moderate asthma and the ATS has recently published specific guidelines for FeNO use in these patients [74]. Cross-sectional studies of severe asthma have indicated some potential usefulness of FeNO as a measure of symptom frequency [75] and as an index of the most obstructed and frequent users of emergency care [76].…”

“…Higher FeNO values, perhaps due to the higher reported inducible nitric oxide synthase expression in severe asthmatic epithelial cells, have been associated with a more exacerbation prone phenotype in severe asthma, as well as more rapid decline in FEV1 [76,[91][92][93]. In addition, higher levels of oxidative stress have been associated with a reduction in superoxide dismutase and s-nitrosothiol depletion [94,95].…”

Usefulness of Fractional Exhaled Nitric Oxide-Guided Treatment in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap

“…We detected IL-13-or IL-4-related eosinophilic airway inflammation using FeNO measurements in patients with COPD. We selected 35 ppb as a cutoff point for high and low FeNO levels in accordance with s previously reported research on severe asthma [16]. Based on these criteria, we diagnosed 24 out of 83 patients with COPD (28.9%) as having ACO.…”

Significant Increase of IL-8 Sputum Levels in Treatment Resistant Severe Asthma Compared with Difficult to Treat Severe Asthma Patients

“…The SARP study showed that a high Fraction of Exhaled Nitric Oxide (FeNO) was associated with severe asthma patients [21].…”