IOP PUBLISHING JOURNAL OF BREATH RESEARCH J. Breath Res. 2 (2008) 037001 (8pp) doi:10.1088/1752-7155/2/3/037001 History, technical and regulatory aspects of exhaled nitric oxide Philip Silkoff Drexel University, Philadelphia, PA, USA Received 31 May 2008 Accepted for publication 6 August 2008 Published 8 September 2008 Online at stacks.iop.org/JBR/2/037001 Abstract The history of nitric oxide (NO) in exhaled breath as a marker of inflammation is summarized, followed by measurement aspects of exhaled NO including NO excretion models of NO in the airway, the estimation of flow-independent NO exchange parameters and issues with the standardization of these methods. Regulatory considerations in the US are also presented. A brief summary of the state of the art for clinical application of exhaled NO is also included. (Some figures in this article are in colour only in the electronic version) Background Nitric oxide, a free radical, is a pro-inflammatory molecule produced by a family of NO synthases in certain types of inflammation, and can serve as a biomarker of that inflammation. In 1991, Lars Gustafsson from the Karolinska Institute published the first report of NO in exhaled breath [1]. Exhaled nitric oxide (FE NO ) levels are elevated in steroid- na¨ ıve asthma [2] and fall rapidly after the start of anti- inflammatory medications, e.g. inhaled steroids [3], oral steroids, antileukotrienes (less reduction compared to ICS) [4, 5] and anti-IgE (omalizumab). The reduction after ICS starts within hours and is complete by seven days. After cessation of ICS, FE NO rises almost equally rapidly [6]. FE NO has been shown to correlate with eosinophilic airway inflammation measured in induced sputum [7] and bronchoscopy (lavage and biopsy). Eosinophilic inflammation is most commonly seen in asthma but also in some patients with COPD, in subjects with allergic rhinitis without asthma and in eosinophilic bronchitis [8]. In COPD, one report indicated an elevation of exhaled NO during COPD exacerbations [9]. FE NO levels are also elevated temporarily in healthy subjects with a viral syndrome [10], but in general are within the normal range in COPD unless there is associated eosinophilia (possible COPD + asthma). In addition, FE NO correlates with bronchial reactivity to methacholine and histamine in steroid-na¨ ıve patients (higher FE NO associated with greater reactivity) [11], and rises during acute symptoms, but shows poor correlation to lung function and asthma severity as defined by guidelines [12]. The ATS/ERS have published guidelines for the standardized measurement of FE NO [13]. An additional ATS/ERS task force is developing clinical interpretation guidelines. Asthma guidelines have mentioned the potential utility of FE NO measurement without any firm recommendations. The US National Institutes of Health (NHANES) is performing the measurement of FE NO in healthy volunteers to describe normal ranges. History Since the discovery of NO in exhaled breath in 1991, the field has expanded remarkably with over 2000 peer-reviewed publications. Landmarks in this remarkable development are summarized in table 1. Origin of exhaled NO The healthy nasal cavity and sinuses have levels of NO up to 30 ppm, several orders higher than those in the lower respiratory tract (0–500 ppb) [14–16]. The measurement of nasal NO can be useful in the evaluation of nasal/sinus, e.g. conditions such as primary ciliary dyskinesia [17] and allergic rhinitis [18]. Modern measurement techniques exclude the nasal NO when measuring exhaled NO. Possible roles for these high background nasal NO levels include maintenance of sinus sterility, modulation of lung V/Q relationship and enhancement of ciliary motion. The NO measured at the mouth falls in the 1–500 ppb range and derives from NO synthases in the cells, e.g. epithelial cells, endothelial cells, neurons of the airway wall of the bronchial tree and inflammatory cells. Additionally, under acidic situations, there may be NO produced nonenzymatically by the reduction of 1752-7155/08/037001+08$30.00 1 © 2008 IOP Publishing Ltd Printed in the UK