Guideline and Statement
An official JRS statement: The principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice

https://doi.org/10.1016/j.resinv.2020.05.006Get rights and content

Abstract

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.

Section snippets

Mechanism of exhaled NO production

NO is produced by NO synthase (NOS) and l-arginine is its substrate. NOS is classified as constitutive and inducible. Constitutive NOS (cNOS) includes neuronal NOS (nNOS) and endothelial NOS (eNOS), which are mainly expressed in nerve cells and vascular endothelial cells, respectively. Inducible NOS (iNOS) is upregulated by various stimuli, such as inflammatory cytokines. iNOS is expressed mainly in epithelial cells in addition to several inflammatory cells, including macrophages and

Principles of measurement

Methods of analyzing FeNO concentrations include the chemiluminescence method, which uses stationary measuring equipment, and the electrochemical method (also termed the ion electrode method or electrode method; however, this statement will use the term “ion electrode method”), which uses portable measuring equipment. There are three stationary measuring devices that can be used in Japan. The NOA280i® (by Sievers, USA) and CLD88sp® (by ECO MEDICS, Switzerland) are commercially available;

Influence of various factors on exhaled NO values

FeNO measurement is influenced by various individual factors, such as food, medicines, smoking, rhinosinusitis, and atopy in addition to the measurement conditions. Previous studies have found sufficient evidence to show that current smoking and use of steroids can reduce FeNO values, while atopy and rhinosinusitis can elevate FeNO values. On the other hand, none of the other factors have been established to be critical confounding factors for the interpretation of the measurement results.

Exhaled NO in various respiratory diseases

FeNO is a useful biomarker of airway inflammation in asthma. In 1993, Alving et al. found two-to three-fold elevations in FeNO in patients with asthma in comparison with healthy individuals [50] and, in the following year, Kharitonov et al. showed that there was no difference in FeNO values for asthmatic patients treated with ICS compared to healthy individuals [3]. The role of FeNO in asthma management has been steadily revealed. In 2013, FeNO measurements became applicable for medical

Conflict of interest

Kazuto Matsunaga received consulting fees and lecture fees from Astra-Zeneca, Nippon Boehringer Ingelheim, Novartis Pharma, Kyorin Pharma, Meiji-Seika Pharma, Sanofi, GlaxoSmithKline, and Kyorin Pharma, and research grant from Nippon Boehringer Ingelheim and Novartis Pharma. Junpei Saito received consulting fees and lecture fees from AstraZeneca and GlaxoSmithKline, and research grant from AstraZeneca, Novartis Pharma, and Shionogi & Co.,Ltd. Koichi Fukunaga received consulting fees and

Acknowledgements

This official statement was approved by The Japanese Respiratory Society October 2019, and was prepared by an ad hoc committee of the JRS Assembly on Pulmonary Physiology.

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    This is a translated summary of a full handbook published as a book in Japanese (ISBN: 978-4-7792-2018-0) by The Japanese Respiratory Society, [The JRS official handbook for the measurement of fractional exhaled nitric oxide (FeNO)].

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