The Best in Pulmonary Medicine

Nicholas J. Gross, MD, PhD


January 19, 2011

In This Article

Exhaled Nitric Oxide Predicts Control in Patients With Difficult-to-Treat Asthma

Pérez-de-Llano LA, Carballada F, Castro Añón O, et al.
Eur Respir J. 2010;35:1221-1227

Study Summary

The goal of this study was to determine whether measurement of exhaled breath nitrogen oxide, (also known as nitric oxide [NO]) could identify patients with poorly controlled asthma who would respond to intensification of anti-inflammatory therapy. Pérez-de-Llano and colleagues enrolled 102 patients with poorly controlled asthma, measured the fraction of NO in their exhaled breath (FeNO), and intensified their management in accordance with the Global Initiative for Asthma (GINA) Guidelines.[9] In summary, this entailed a stepwise approach, first placing the patient on the highest strength of a fluticasone-salmeterol combination inhaler (Advair®) for 1 month. If asthma was still not controlled, the patient would receive an oral corticosteroid, deflazacort 30 mg daily (approximately equivalent to 25 mg prednisone) for 1 month. The patient's level of control was reassessed 1 month later by the Asthma Control Test (ACT). A score of ≤ 20 was considered suboptimal (possible range: 5 = worst asthma, 25 = perfect control). The aim was to determine whether the FeNO at enrollment was predictive of achieving control of asthma by the above stepwise treatment program; and if so, to establish a threshold level of FeNO that best separated those who would reach an ACT score of 20 or above from those who would not.

By design, all 102 enrolled patients had poorly controlled asthma at entry, with mean ACT scores of 14 ± 1 unit. By the end of the incremental escalation of therapy, control had been achieved in 53 patients; 49 patients were still not optimally controlled. The mean FeNO at baseline was 43.1 ppb, (range 4-222); however, in the patients whose asthma was successfully controlled, the mean FeNO at baseline was 68 ppb, whereas in patients whose asthma was not controlled, mean baseline FeNO was 28 ppb, and the difference was significant (P < .0001). In addition, the FeNO level that optimally discriminated between the 2 groups was 30 ppb. By the criterion of a baseline FeNO level of > 30 ppb or < 30 ppb, the baseline FeNO was predictive of subsequently achieving control with a sensitivity of 87.5% and a specificity of 94.5%. Of interest was that serial measurements of FeNO during the sequence of treatment showed that the FeNO declined most in patients who achieved control.

The investigators concluded that the exhaled breath FeNO level could identify which patients with poorly controlled asthma would respond to the guideline approach to management of asthma.


The nitric oxide concentration in exhaled breath has been a test looking for an established role in asthma for some years now. Strong evidence suggests that exhalation of NO increases with asthmatic inflammation of the airways, particularly eosinophilic inflammation.[41] Biopsy evidence suggests that exhaled breath FeNO is a surrogate for the severity of airway inflammation.[42] However, there are conflicting reports about whether FeNO level is quantitatively indicative of the level of asthma control.[43,44,45] Much NO research has been conducted in children in whom asthma severity may be quite difficult to assess and where a non-invasive test would be invaluable.[46] A problem that may confront the healthcare provider who wishes to explore the utility of NO measurement is that exhaled NO levels are not specific for lower airways inflammation; they are also elevated in allergic sinusitis.

The present report is summarized here to draw attention to the potential that FeNO may find a useful role in the management of asthma. If FeNO is not a good surrogate for asthma control,[45] perhaps it would be useful as a predictor of the need for and responsiveness to more intensive anti-inflammatory therapy, as the present report suggests. Alternatively, it might find a role as a diagnostic test in patients with undiagnosed respiratory symptoms.

Nitric oxide meters are in the market; however, they tend to be somewhat bulky, which reduces their utility in the field. They also cost about $4000 each. The FDA approved the first NO monitoring device, NIOX (Aerocrine, New Providence, New Jersey), in 2003. Some guidance with respect to its significance and use is provided.[47] The purchase and clinical use of an NO monitor are not currently reimbursed by managed care.



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