Role of alveolar nitric oxide in gastroesophageal reflux-associated cough: prospective observational study

Background: Fractional exhaled nitric oxide (FeNO) measured at multiple exhalation flow rates can be used as a biomarker to differentiate central and peripheral airway inflammation. However, the role of alveolar nitric oxide (CaNO) indicating peripheral airway inflammation remains unclear in gastroesophageal reflux-associated cough (GERC). Objectives: We aimed to characterize the changes in alveolar nitric oxide (CaNO) and determine its clinical implication in GERC. Design: This is a single-center prospective observational study. Methods: FeNOs at exhalation flow rates of 50 and 200 ml/s were measured in 102 patients with GERC and 134 patients with other causes of chronic cough (non-GERC). CaNO was calculated based on a two-compartment model and the factors associated with CaNO were analyzed. The effect of anti-reflux therapy on CaNO was examined in 26 GERC patients with elevated CaNO. Results: CaNO was significantly elevated in GERC compared with that in non-GERC (4.6 +/- 4.4 ppb versus 2.8 +/- 2.3 ppb, p < 0.001). GERC patients with high CaNO (>5 ppb) had more proximal reflux events (24 +/- 15 versus 9 +/- 9 episodes, p = 0.001) and a higher level of pepsin (984.8 +/- 492.5 versus 634.5 +/- 626.4 pg/ml, p = 0.002) in sputum supernatant than those with normal CaNO. More GERC patients with high CaNO required intensified anti-reflux therapy (chi(2) = 3.963, p = 0.046), as predicted by a sensitivity of 41.7% and specificity of 83.3%. Cough relief paralleled a significant improvement in CaNO (8.3 +/- 3.0 versus 4.8 +/- 2.6 ppb, p < 0.001). Conclusion: Peripheral airway inflammation can be assessed by CaNO measurement in GERC. High CaNO indicates potential micro-aspiration and may predict a necessity for intensified anti-reflux therapy.