Is Exhaled Nitric Oxide Useful: Yes or eNO?

Vol. 20 • Issue 10 • Page 22

Pediatric Asthma

Asthma is a giant among health care concerns. It affects an estimated 20 million Americans, 300 million people worldwide, and 10 percent of all children.1 The most common chronic lung disease of childhood, asthma’s prevalence and morbidity are on the rise; the death rate for asthmatic children under 19 years old has increased by nearly 80 percent since 1980.2

The importance of diagnosing and treating asthma is paramount, though not always straightforward. Diagnosis is based on clinical history and presentation, and while objective measurements such as spirometry, bronchodilator reversibility testing, peak expiratory flow recording, and bronchial challenge tests may be used, these all have limitations.

It’s no wonder exhaled nitric oxide (eNO) would seem to crack the door to diagnostic relief. Measuring the fraction of nitric oxide in exhaled air (FeNO) is a convenient, noninvasive, point-of-service office test for airway inflammation that is helpful in the diagnosis of atopic asthma, especially in the pediatric population. It can be a predictor of response to inhaled corticosteroids and useful in monitoring asthma control.

How eNO is put to use

Since the key feature in the pathogenesis of asthma is chronic airway inflammation, eNO, a biomarker for airway inflammation, is useful in asthma diagnosis and monitoring. Nitric oxide was first detected in exhaled breath samples in 1991.3 In 1993, researchers from the Karolinska Institute in Sweden were the first to report increased exhaled nitric oxide in people with asthma.4 Since that time, FeNO has been increasingly utilized in diagnostic and disease management processes.

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Nitric oxide, a reactive, free radical gas, forms in the airways when L-arginine is oxidized to L-citrulline by nitric oxide-synthase.5 Nitric oxide in the lung acts as a vasodilator, bronchodilator, and non-adrenergic, non-cholinergic neurotransmitter and is an important mediator of the inflammatory response.6 Proinflammatory cytokines like TNF-alpha and IL-1beta increase expression of inducible nitric oxide synthase, which is used by several cells like eosinophils to produce nitric oxide.6,7

In patients with asthma, the level of FeNO correlates with markers of blood and airway inflammation, such as blood eosinophilia, sputum eosinophils, mucosal eosinophilia, and bronchoalveolar lavage eosinophilia.8 Reduction of FeNO levels using treatment with inhaled or oral steroids is dose dependent.9,10 The leukotriene receptor antagonist, montelukast, also reduces FeNO, although to a lesser extent than low dose inhaled corticosteroids.11 Studies have shown an influence of atopy on FeNO with total IgE and specific IgE to house dust mite and a moderate correlation to the number of positive skin prick tests.12,13

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A tool for diagnosis

As evidenced by these correlations, FeNO can aid in the diagnosis of asthma by adding another practical tool.7,14 This is especially true in preschool age children, a population in whom other test modalities, such as spirometry, may be unproductive.7,14 FeNO also can be helpful in predicting exacerbations, and monitoring successful steroid reduction or withdrawal in atopic asthmatics. (See Table, page 26.) Measuring FeNO is noninvasive, repeatable and reproducible, so it is a viable addition for use in the pediatric population.7

Generally, nitric oxide is measured by chemiluminescence assay, based on detection of photons when nitric oxide reacts with ozone. Another measurement is by electrochemical detection.7

Several methods to collect exhaled air and measure FeNO are available. Online methods use a nitric oxide analyzer to directly sample exhaled air, while offline methods analyze exhaled gas that is first collected in a reservoir.15,16 There are many techniques used when performing nitric oxide measurements, including specific variations for the young child. One such variation is exhaling via a mouthpiece, against a resistance, into a reservoir. Another is tidal breathing via a mouthpiece or mask covering the mouth or mouth and nose, with or without expiratory resistance.15 Standardized guidelines for the measurement of FeNO in adults and children are available.7

Interpetation of FeNO levels

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There have been many proposals on how to interpret FeNO levels since there can be inter-patient variability. Upon review of the literature, the following levels are indicative in the pediatric population. A low FeNO is considered <5 parts per billion (ppb). A normal FeNO value is 5 to 25 ppb and implies the absence of eosinophilic airway inflammation. Intermediate FeNO levels are 25 to 35 ppb. This may reflect inadequate treatment or noncompliance with inhaled corticosteroids. Intermediate levels can also reflect allergen exposure or infections.7 Elevated FeNO levels of >35 ppb, indicate uncontrolled eosinophilic airway inflammation. Asthma is then a very likely diagnosis.17

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Several factors influence FeNO values (See Figure, page 24.) 15, 16 First, FeNO is highly dependent on exhalation flow rate. For example, FeNO levels will drop with a higher flow.8 An expiratory flow of 50 mL/s is recommended by an American Thoracic Society/European Respiratory Society task force.16 Secondly, higher concentrations of nitric oxide relative to the lower airways are found in the nose and paranasal sinuses, so it is important to avoid contamination of exhaled air with nasal air when measuring FeNO.18 Thirdly, environmental nitric oxide can increase during peak traffic hours or in poorly ventilated areas, so contamination with ambient air should also be avoided.7 Food and beverages also can alter FeNO levels, so patients should refrain from eating or drinking at least one hour before testing. Finally, in the adult population, smoking will notoriously lower FeNO values.16

The hurdle of reimbursement

There are still hurdles in practically performing FeNO in the clinical setting. An American Medical Association current procedural terminology (CPT) category 1 code has been assigned to eNO (95012 for nitric oxide expired gas determination). Despite the granting of a CPT code, gaining reimbursement from commercial insurers is difficult. Many carriers still classify the test as investigational, experimental, or unproven, and not reimbursable. However, the Centers for Medicare and Medicaid Services will reimburse for eNO testing at approximately $19, with fees ranging from $16 (Maryland Department of Health and Mental Hygiene and South Dakota) to $26.88 (North Carolina Industrial Commission).8

Because of eNO reimbursement issues and disparities, cost, and the many other factors that can influence its measurement, evidence for the overall diagnostic utility of FeNO in young children remains mixed at this time. Still, the evidence for its usefulness to clinicians continues to grow. n

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Jennifer Shih, MD, is a fellow in Allergy and Immunology at Emory University, Atlanta, Ga. Stanley M. Fineman, MD, MB, is clinical associate professor, department of pediatrics, allergy division, at Emory University School of Medicine. He is a fellow in the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology and the American Academy of Pediatrics.