Clinical patterns in asthma based on proximal and distal airway nitric oxide categories

Background: The exhaled nitric oxide (eNO) signal is a marker of inflammation, and can be partitioned into proximal [J'aw(NO) (nl/s), maximum airway flux] and distal contributions [CA(NO)(ppb), distal airway/alveolar NO concentration]. We hypothesized that J'awNO and CANO are selectively elevated in asthmatics, permitting identification of four inflammatory categories with distinct clinical features. Methods: In 200 consecutive children with asthma, and 21 non-asthmatic, non-atopic controls, we measured baseline spirometry, bronchodilator response, asthma control and morbidity, atopic status, use of inhaled corticosteroids, and eNO at multiple flows (50, 100, and 200 ml/s) in a cross-sectional study design. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'awNO and CANO. Results: J'awNO was not correlated with CANO, and thus asthmatic subjects were grouped into four eNO categories based on upper limit thresholds of non-asthmatics for J'aw(NO) (>= 1.5 nl/s) and CA(NO) (>= 2.3 ppb): Type I (normal J'aw(NO) and CA(NO)), Type II (elevated J'aw(NO) and normal CA(NO)), Type III (elevated J'aw(NO) and CA(NO)) and Type IV (normal J'aw(NO) and elevated CA(NO)). The rate of inhaled corticosteroid use (lowest in Type III) and atopy (highest in Type II) varied significantly amongst the categories influencing J'aw(NO), but was not related to CA(NO), asthma control or morbidity. All categories demonstrated normal to near-normal baseline spirometry; however, only eNO categories with increased CA(NO) (III and IV) had significantly worse asthma control and morbidity when compared to categories I and II. Conclusions: J'aw(NO) and CA(NO) reveal inflammatory categories in children with asthma that have distinct clinical features including sensitivity to inhaled corticosteroids and atopy. Only categories with increase CANO were related to poor asthma control and morbidity independent of baseline spirometry, bronchodilator response, atopic status, or use of inhaled corticosteroids