Known for its negative environmental impact, nitric oxide (NO) causes acid rain and photochemical smog. As a molecule produced in the respiratory system, however, it's vital for the dilation of airways and blood vessels, and the beating of cilia to clear secretions from the lung. Nitric oxide is produced by the enzyme nitric oxide synthase. This enzyme is up-regulated under inflammatory conditions and down-regulated when an anti-inflammatory (i.e. corticosteroids) is taken. When nitric oxide is produced, it spreads readily into the airways, where it can be collected and measured upon exhalation. Screening individuals with an exhaled nitric oxide test is an effective means to diagnose asthma and can help tailor treatment and dosing, particularly in patients with chronic disease.
What's the current inflammatory model of asthma?
Are there drawbacks to using spirometry alone?
Asthma has been described as a "nocturnal" disease. The main problem that many people with asthma have is that they wake up at night due to cough and shortness of breath, despite feeling fine during the day. Of course, when they visit their physician about these nighttime complaints, their spirometry will be normal if it's measured in the day-time. This can be confusing for the doctor who may not suspect asthma if the FEV 1 is normal.
There's also a well-described "learning effect" where patients who take spirometry tests repeatedly discover how to improve their results by performing the test better. But in reality, their asthma isn't better. This can lead to a false sense of reassurance for clinicians if they rely on spirometry values to gauge if an individual with asthma is properly controlled.
Physicians who treat young children are at a particular disadvantage — spirometry is rarely done until at least the age of six. Under this age, spirometric testing doesn't consistently produce accurate results.
Good studies show that asthma control isn't necessarily reflected well by self-reported symptoms and spirometry. Clearly, there's a need for objective tests that correlate with asthma control and airway inflammation, remain constant at different times of the day and night, and don't show a learning effect.
So, how does eNO work?
The standard flow rate is achieved by having patients exhale at a slow steady rate, and a gauge on the analyzer will tell the patient whether to blow harder or softer. If the patient can't maintain exhalation at the right rate for the required length of time, the analyzer will not accept the measurement. That said, it usually only takes a few tries to get the right flow rate. The patients with poorer control will be reflected by more inflammation in the airways, therefore higher eNO levels.
The patient sits comfortably without nose clips and exhales at a steady level for 4-6 seconds. The test is repeated three times to ensure accurate values. Exhalation against resistance creates pressure in the oral cavity, which closes the nasal velum and prevents contamination with nasal air. Nasal nitric oxide levels can be measured separately with a nose attachment on the eNO analyzer. A normal adult will have nitric oxide levels exhaled from the mouth between 5 and 20 ppb; a steroid-naòve asthmatic will have much higher results — around 50 ppb.
How does eNO compare to other tests?
Recent studies have shown that asthma outcomes, like the number of exacerbations and symptom control, improved when management of medications was based on biologic markers like sputum eosinophils compared with standard symptom/spirometry-based guidelines. These trials highlight the potential to use airway inflammation markers to improve treatment, though the inconvenience and discomfort associated with methacholine challenge and induced sputum collection have limited the use of these tests in a daily setting.
There is a close relationship between sputum eosinophils and eNO levels — the advantages of eNO over induced sputum testing are the immediate availability of the test results and the ability to produce good results in young children.
Are there any limits to the eNO test?
A few patients may fall in the grey range between normal and positive for eosinophilic airway inflammation (20-35 ppb). In such a case, further clinical correlation is required.
How can eNO be used to manage asthma?
The higher the eNO level, the greater the amount of eosinophilic airway inflammation present. With anti-inflammatory treatment (i.e. ICs, systemic steroids, leukotriene receptor antagonists), the elevated eNO levels will return to the normal range. This correlates well with improvement in inflammation, respiratory symptoms and overall asthma control. An increase of 4% or 10 ppb over baseline represents a real increase in the patient's airway inflammation. A significant increase in eNO may be the result of worsening disease, poor adherence to medications or a recent trigger exposure (i.e. respiratory tract infection). Adjusting the doses of anti-inflammatory medications by following either eNO levels or sputum eosinophils has been shown to reduce exacerbations, generally at lower total doses of the drugs. Recent studies suggest that there is an increase in eNO days to weeks prior to a symptomatic asthma exacerbation.