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Non-invasive asthma marker helps minimize the need for steroids

Posted Feb 03 2010 11:34pm

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?
It's now known that asthma isn't just an occasional narrowing of the air tubes causing shortness of breath, wheeze and cough. It's a complex relationship between airflow obstruction, hyper-responsiveness, inflammation and airway remodelling over a period of time. This interaction, along with exposure to triggers, determines the severity of asthma and the frequency of exacerbations. While a person with asthma may feel well between flare-ups, biopsy studies show that the destructive eosinophilic airway inflammation process continues even when the patient is asymptomatic. As a result, daily control of inflammation with anti-inflammatory inhaled corticosteroids (ICs) is the cornerstone of medical treatment for asthma.

Are there drawbacks to using spirometry alone?
Spirometry is vital as a readily available tool for the screening and initial diagnosis of asthma, and is useful for long-term follow-up. An improvement in forced expiratory volume in one second (FEV 1 ) can prove to the clinician whether a new medication is helping the patient. There are pitfalls, though, when relying on spirometry alone. Airway inflammation continues even when spirometry is normal; this can lead to under-treatment of asthma, with poor quality of life and frequent visits to the emergency department.

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?
When nitric oxide is exhaled into an exhaled nitric oxide (eNO) analyzer, it reacts with ozone and is measured by the process of chemiluminescence, accurate to one part per billion (ppb). Since NO is produced continuously in the airways, the concentration of NO depends on the flow rate. Consequently, a standard flow rate (50 mL/second) is mandated by international guidelines.

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?
There are other biologic markers available to diagnose and manage asthma long term. Some reflect airway inflammation (i.e. induced sputum eosinophils, bronchoscopy with lavage, biopsies), while others estimate the degree of airway hyper-responsiveness when exposed to a stimulus (i.e. methacholine challenge test). Most clinicians agree that bronchoscopy is much too invasive to diagnose asthma. Collecting sputum and quantifying the level of eosinophils is uncomfortable for the patient and requires a lengthy turnaround time from the lab for the results. Confirmation of a diagnosis with a methacholine challenge test is well validated, but it's time consuming and, because of the risk of severe bronchoconstriction, must be done in a monitored setting like a hospital.

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?
Confounders for the test include airway inflammation from respiratory tract infection (i.e. pneumonia); therefore, the test should be delayed until this has resolved. Recent spirometry or induced sputum collection will alter eNO levels, so the exhaled nitric oxide test should be done before these tests, or on an alternate day. Diet, caffeine use, recent exercise and other possible sources of error cause very little "noise" in the test, generally less than 1 or 2 ppb.

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?
Here's a common clinical scenario: your patient has typical asthma symptoms but only non-significant improvement in FEV 1 post-bronchodilator (not the 12% and 180 mL required to make a diagnosis of asthma). You have a choice of an empiric two- or three-month trial of steroid-based agents, or an asthma confirmation test like methacholine challenge or eNO. A trial of corticosteroids is especially unpopular among parents of small children due to the fear of adverse effects and concern surrounding medications containing steroids. Many patients and physicians opt for a confirmation test to make a firm diagnosis. The eNO test is as accurate as a methacholine challenge and has the advantage of producing immediate results in your office.

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.



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