PATHOGENESIS OF CHRONIC PERSISTENT COUGH ASSOCIATED WITH GASTROESOPHAGEAL REFLUX

It was previously shown that unexplained chronic cough is associated with asymptomatic gastroesophageal reflux. The aim of this study was to determine if distal esophageal acid is important in the pathogenesis of this cough. In 22 patients with cough and reflux as determined by 24-h ambulatory esophageal pH monitoring, distal esophageal acid perfusion was performed in a double-blind controlled fashion. Patients received both 0.1 N HCl and 0.9% saline for 15 min, in random order. Cough was recorded with a microphone and then computer analyzed. In 12 matched control subjects, 24-h ambulatory esophageal pH monitoring and distal esophageal acid perfusion studies were also performed. In patients, there was a significant increase in cough frequency, median (range): 36.5 (6 to 111) versus 8.3 (0 to 46)/15 min, p < 0.001, and amplitude, geometric mean (range): 85.2 (78.1 to 92.3) versus 73.1 (0.0 to 87.1) dB, p < 0.01, with HCl compared with saline. During HCl infusion, compared with control subjects, patients had more cough episodes, 36.5 (6 to 111) versus 0.0 (0 to 11)/15 min, p < 0.0001, with greater amplitude, 85.2 (78.1 to 92.3) versus 0.0 (0.0 to 79.6) dB, p < 0.001, but there was no difference in cough duration. We subsequently investigated whether inhibition of the induced cough was possible. In seven patients repeat esophageal acid perfusion was performed 15 min after the esophageal instillation of 4 ml of 4% lignocaine. Another six patients had repeat esophageal acid perfusion 15 min after inhalation of 4 ml of 0.025% ipratropium bromide, as well as repeat acid perfusion on another day after the esophageal instillation of 4 ml ipratropium bromide. Inhaled ipratropium bromide reduced cough frequency, median (range): 1.0 (0 to 7) versus 53.5 (12 to 89)/15 min, p < 0.02, as did esophageal lignocaine, 9.0 (3 to 23) versus 41.0 (13 to 111)/15 min, p < 0.05. However, there was no significant change in any cough parameter with esophageal ipratropium bromide. This suggests that inhaled ipratropium bromide acts on efferent tracheobronchial pathways rather than on the esophagus after swallowing of some of the inhaled dose. The afferent pathway is antagonized by lignocaine. We conclude that acid in the distal esophagus precipitates cough and that there is evidence for an esophageal-tracheobronchial cough reflex mechanism in patients with chronic cough associated with gastroesophageal reflux.