DENVER—Measuring exhaled nitric oxide (NO) has been proposed as a simple, noninvasive method of asthma diagnosis and monitoring for several reasons. The most notable of these is that exhaled NO levels are elevated in asthma patients and correlate closely with many surrogate markers of the disease, such as peak flow variability and sputum eosinophil count.

But does exhaled NO reflect asthma itself? “That is difficult to prove,” admitted Hans Bisgaard, MD, at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in Denver. Nonetheless, he said that exhaled NO is “a useful tool that should be taken into clinical practice side by side with spirometry for diagnosing and monitoring asthma.”[1]

In support of this statement, Dr. Bisgaard, a Professor of Pediatrics at Copenhagen University in Denmark, cited two recent studies. In one study, Dupont et al[2] found that at a cutoff of 16 parts per billion (ppb), exhaled NO measurement is an accurate way to diagnose asthma in adults. In the other study, Steerenberg et al[3] showed that in atopic children, exhaled NO levels correlate with bronchial hyperresponsiveness.

EVIDENCE OF DIRECT LINK

Proving that exhaled NO levels reflect asthma is difficult, said Dr. Bisgaard, for two reasons: There is no diagnostic gold standard to which those levels can be compared, and the correlations between other surrogate markers of asthma are not necessarily meaningful. For example, spirometric results do not always correlate with lung symptoms. “But, that does not mean FEV1 [forced expiratory volume in one second] does not reflect asthma,” he pointed out.

Exhaled NO’s high positive predictive value for subsequent exacerbations indicates a direct relationship with asthma pathophysiology. Even stronger proof of such a relationship comes from the fact that exhaled NO rises during both acute asthma attacks and allergen exposure in asthma patients and drops after corticosteroid therapy is given, noted Dr. Bisgaard.

Because exhaled NO measurements have been shown to correlate with asthma severity and corticosteroid dosing, they may have a role in monitoring patients’ responses to anti-inflammatory therapy. The technique used to measure exhaled NO is well standardized, requires about the same amount of time that spirometry takes, and is feasible to perform in children as young as 2.

Few assessment tools are flawless, however. In the case of exhaled NO, there is a small subgroup of asthma patients (10% to 15%) whose levels remain elevated even after they are given treatment with high-dose corticosteroids. Allergy appears to be an important factor in this phenomenon; the exhaled NO concentration is directly related to the number of specific allergens to which a patient reacts.

FINDING A CUTOFF

The study by Lieven J. Dupont, MD, PhD, and colleagues included 240 consecutive adults referred for symptoms suggesting obstructive airway disease. These patients were nonsmokers, had never used corticosteroids, and were believed to be free from other significant medical conditions. A diagnosis of asthma was given to 160 of the patients because their airway obstruction displayed significant reversibility or they had substantial airway hyperresponsiveness.

Each patient’s NO level in a single exhalation was measured with a chemiluminescence analyzer. The exhalation consisted of a slow expiratory vital capacity maneuver against a fixed resistance to maintain a constant 200-mL/s flow.

At a cutoff of 10 ppb—the mean level among the healthy adults in the study—exhaled NO had a sensitivity for asthma of 90% but a specificity of only 50%. Overall accuracy was greatest at the 13-ppb cutoff; at this level, sensitivity was 85% and specificity was 80%. However, the specificity and positive predictive value both reached 90% at the 16-ppb cutoff, making this the best level for diagnosis.

In an interview, Dr. Dupont, a Professor of Respiratory Medicine at the Catholic University of Leuven in Belgium, noted, “Our findings imply that exhaled NO might be used to discriminate asthma from other diseases with symptoms suggestive of obstructive airway disease.” In fact, said Dr. Dupont, exhaled NO measurements might replace some other forms of assessment. “Measuring exhaled NO might avoid the need for further, more complex tests in a significant number of patients with suspected asthma,” he suggested.

LINK TO HYPERRESPONSIVENESS

The 450 participants in the study by Steerenberg et al were 7- to 12-year-old children living in urban areas of the Netherlands. These children provided exhaled NO samples by blowing into balloons at a flow rate of 500 mL/min.

Regression analysis showed that among the children with atopy (but not the nonatopic children), there were positive associations between elevated exhaled NO levels and allergy symptoms (eg, wheezing and nasal discharge) within the past 12 months. In the atopic children, elevated levels were also positively linked with bronchial hyperresponsiveness and the number of blood eosinophils. Surprisingly, commonly used lung function indices, such as peak expiratory flow and FEV1, were not associated with elevated exhaled NO levels.

Measuring exhaled NO may therefore add another dimension to the determination of adverse respiratory effects because it allows detection of inflammatory responses in the absence of functional impairment, the investigators suggested. “[Exhaled] NO appears to be a reliable tool for confirming asthmatic, allergic, and bronchitis-like symptoms,” they added.

—Timothy Begany