Review

Measuring exhaled nitric oxide when diagnosing and managing asthma

Payal Sen, MD, Sumita B. Khatri, MD and Vickram Tejwani, MD
Cleveland Clinic Journal of Medicine June 2023, 90 (6) 363-370; DOI: https://doi.org/10.3949/ccjm.90a.22072

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Inflammatory cytokines interleukin (IL)-13, IL-1-beta, and tumor necrosis factor alpha (TNF-alpha) are upregulated in response to tissue damage and induce expression of the inducible nitric oxide synthase (iNOS) gene, leading to a more sustained release of nitric oxide (NO).

    NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; NO2 = nitrite; NO3 = nitrate; ONOO = peroxynitrite; Th2 = T helper cell type 2

  • Figure 2
    Figure 2

    Algorithm for clinical use of measurements of the fractional concentration of exhaled nitric oxide (FeNO).

    Adapted from reference 11.

Tables

  • TABLE 1

    Factors other than asthma that raise or lower the fractional concentration of exhaled nitric oxide (FeNO)

    Factors that increase FeNOFactors that decrease FeNO
    Chronic rhinosinusitis, nasal polyposis, or both: FeNO is increased in patients with allergic rhinitis or nasal polyposis even in the absence of a concomitant asthma diagnosis. Patients with allergic rhinitis have higher FeNO levels than patients with nonallergic rhinitis. Perennial sensitization leads to higher FeNO than seasonal allergens.
    Atopy: Acute exposure to allergens can increase FeNO by up to 50%.
    Rhinovirus respiratory infections can increase FeNO by 50% to 150% through inducible nitric oxide synthase upregulation. However, not all viral infections increase FeNO—respiratory syncytial virus and influenza reduce FeNO, and bacterial infections of the respiratory tract do not affect FeNO.
    Nitrate-containing foods such as beetroot can increase FeNO levels by 20% to 60%.
    Air pollution (particulate matter and ozone), possibly because of oxidative potential, even in the absence of asthma.
    Male sex: association is consistent after adjustment for height.
    HIV infection is associated independently with raised FeNO after adjusting for use of airway medication, blood eosinophil counts, and immunoglobulin E.
    Increasing age: Effect is greater in people over age 60 or 64, but data conflict in adults and are more consistent in children.
    Increased height, because of increases in airway mucosal surface area.    		Cigarette smoking decreases FeNO by 40% to 60%. Magnitude of reduction correlates with the cumulative lifetime cigarette consumption. The effect of cigarette smoking may be reversible, but has not been reported consistently. Smokers with asthma have higher FeNO levels than healthy smokers. In clinical practice, look for intraindividual changes.
    Inhaled steroid use. FeNO generally is sensitive to inhaled steroids and therefore will be low in most patients who are adherent to treatment.
    Alcohol ingestion—Avoid before testing.
    Spirometry may cause a marginal decrease. The effect is of minor importance in clinical practice, but one preferably should measure FeNO before spirometry.
    Certain drugs

    • Leukotriene receptor antagonists

    • Prostaglandins: inhaled prostaglandin E2 and iloprost downregulate inducible nitric oxide synthase expression.


    Physical exercise—Avoid strenuous exercise before testing.
    UNCERTAIN EFFECT
    Menstrual cycle
    FeNO levels may vary, but this is not a consistent finding.

    • Reprinted from Chest 2022; 161(4):906-917, Rupani H, Kent BD. Using fractional exhaled nitric oxide measurement in clinical asthma management, with permission from Elsevier.

  • TABLE 2

    How is measuring exhaled nitric oxide useful in asthma?

    Elevated fractional concentration of exhaled nitric oxide (FeNO) serves as an adjunct to history, physical examination, and spirometry testing to help with the diagnosis of asthma and is most reliable in patients who have never received steroids.
    Conversely, low FeNO can help exclude asthma in the setting of normal spirometry and no suggestive symptoms.
    High FeNO is an indicator of a T2-high phenotype and can predict response to inhaled corticosteroids and biologic therapies.
    High FeNO is a predictor of increased exacerbation risks and accelerated decline in lung function.
    FeNO can be used to monitor adherence and compliance with treatment.
    Low FeNO can help to step down asthma treatment with inhaled corticosteroids.
    Factors limiting the interpretation of FeNO
    FeNO should not be used in isolation, and clinical history, physical examination, and spirometry testing should be incorporated.
    Many factors other than asthma can raise or lower FeNO (See Table 1).
    FeNO is also lower during bronchoconstriction and in the early phases of allergic response.
    FeNO can be variable during viral respiratory infections.
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