doi: 10.1111/j.1365-2222.2011.03945.x Clinical & Experimental Allergy, 42, 775–781 ORIGINAL ARTICLE Clinical Allergy © 2011 Blackwell Publishing Ltd Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics K. Matsunaga 1 , S. Yanagisawa 1 , T. Hirano 1 , T. Ichikawa 1 , A. Koarai 1 , K. Akamatsu 1 , H. Sugiura 1 , Y. Minakata 1 , K. Matsunaga 2 , T. Kawayama 2 and M. Ichinose 1 1 Third Department of Internal Medicine, School of Medicine, Wakayama Medical University, Wakayama and 2 Department of Medicine, Kurume University, Fukuoka, Japan Clinical & Experimental Allergy Correspondence: Masakazu Ichinose, Third Department of Internal Medicine, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. E-mail: masakazu@wakayama-med. ac.jp Cite this as: K. Matsunaga, S. Yanagisawa, T. Hirano, T. Ichikawa, A. Koarai, K. Akamatsu, H. Sugiura, Y. Minakata, K. Matsunaga, T. Kawayama and M. Ichinose, Clinical & Experimental Allergy, 2012 (42) 775–781. Summary Background The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demograph- ics and there is considerable variation among clinically stable patients. Objective We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. Methods This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expi- ratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were exam- ined (Study 2). Results A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identi- fying the patients with poorly controlled asthma. The persistent high FENO group (40 p. p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. Conclusions and Clinical Relevance These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma. Keywords airflow obstruction, airway lability, allergic rhinitis, chronic rhinosinusitis, eosinophil, gastro-esophageal reflux disease, immunoglobulin E, inhaled corticosteroids, smoking Abbreviations ACT, asthma control test; CRS, chronic rhinosinusitis; FENO, exhaled nitric oxide fraction; GERD, gastro-esophageal reflux disease; ICS, inhaled corticosteroids; NOS, nitric oxide synthases. Submitted 06 September 2011; revised 08 November 2011; accepted 13 December 2011 Introduction Airway inflammation is a central features of asthma, and inhaled corticosteroids (ICS) are widely used for the long-term management of the disease [1]. Nitric oxide (NO) is a gaseous signalling molecule that is generated by NO synthases (NOS). The expression of inducible NOS is enhanced by inflammatory stimuli producing large amounts of NO independently of calcium ion flux [2]. Indeed, the exhaled nitric oxide fraction (FENO) is