Does exhaled nitric oxide measurement have a role in asthma care

Recent guidelines have highlighted the importance of attaining and maintaining control in asthma, yet there currently is no perfect measure of control.1–3 One issue that is clearly gleaned from the literature is that although correlation exists among various measures of asthma control, no single variable can provide the complete picture. A composite of several indicators of control is required.4 These components include patient history, such as nocturnal awakening, 2-agonist rescue use, limitations in daily activity (and/or validated tools such as the Asthma Control Test or Asthma Therapy Assessment Questionnaire), and objective measures of lung function. It is hoped that in the future we will have a generally agreed on validated tool to better evaluate asthma control. Future evaluation of asthma control will likely include measures beyond medical history and lung function, such as indicators of airway inflammation.3 Because asthma is predominantly an inflammatory disorder, it is intuitive that a noninvasive biomarker evaluation of inflammation needs to be an integral component of diagnosis and management strategies. A study by Sont et al5 catalyzed interest in measures of inflammation as a tool for titrating maintenance therapy. These investigators examined adjustment of controller medicine using a standard guidelines approach compared with controller medicine adjustment directed to minimize airway hyperresponsiveness (AHR) via methacholine challenge. Their hypothesis was that control of AHR would correlate with improved asthma outcomes. This premise proved true; a 1.8-fold reduction in mild exacerbations and a greater reduction in thickness of the subepithelial reticular layer (obtained via bronchial biopsy) were achieved in the AHR-directed group. Similarly, in a study by Green and colleagues,6 normalizing sputum eosinophil counts also resulted in a reduction in asthma exacerbations. Unfortunately, both of these procedures are cumbersome and thus impractical in standard clinical practice. For this reason, efforts are ongoing in the search for a surrogate measure of inflammation that is reproducible and practical in “real-world” asthma care. Many had hoped that measurement of exhaled nitric oxide (eNO) would fill this role. With an initial positive study and several Food and Drug Administration–approved devices that are not cost prohibitive, many specialists have added this measure to their evaluation of patients with asthma. A great deal of enthusiasm followed the positive study by Smith and colleagues,7 who demonstrated that when comparing standard guidelines– directed care to the addition of eNO, the latter group demonstrated a statistical reduction in maintenance therapy required, while simultaneously achieving a trend toward decrease in asthma exacerbations. The results of this study supported the hypothesis that control of a surrogate of inflammation translated to improved asthma control. However, several more recent studies have questioned the utility of eNO. In the first, Shaw and colleagues8 examined the addition of eNO to standard care in a primary care setting and found no significant improvement in asthma control or medicine titration. The most recent study by Szefler and colleagues9 further questions the contribution of eNO measures. In this multicenter trial, which compared guidelines based care alone with a strategy directed toward a decrease in eNO, the authors examined a large cohort of inner-city residents with asthma. Like Shaw et al, they were unable to demonstrate added benefit with the use of eNO measures. In their 46-week study, they demonstrated no difference in number of days with asthma symptoms, pulmonary function, or asthma exacerbations, despite the fact that the eNO group received approximately 80 g more of inhaled corticosteroids (ICSs) daily. Thus, physicians are left to question whether eNO provides any added benefit to the present measures of asthma control. Potential concerns come to mind when considering the present use of eNO in the care of patients with asthma. The first issue is that we may be using the wrong protocol for interpreting eNO. Currently, we rely on an eNO cutoff level (generally between 20 and 30).10 It is well known that eNO is sensitive to the use of ICSs and that significant variation in levels occur in the population with asthma.11,12 Thus, possibly a change in the level of eNO vs a specific cutoff would provide a more useful measure. This premise is demonstrated in a study by Jones et al13 that evaluated the usefulness of eNO in diagnosing and predicting loss of control in asthma after ICS withdrawal. These investigators found that analysis Affiliations: * Pulmonary and Allergy Associates, New Jersey Medical School, Cedar Knolls, New Jersey; † Department of Pharmacy and Medicine, University of Wisconsin, School of Pharmacy, Madison, Wisconsin. Disclosures: Authors have nothing to disclose. Received for publication December 17, 2008; Received in revised form January 6, 2009; Accepted for publication January 7, 2009.