Identification of acid reflux cough using serial assays of exhaled breath condensate pH

Abstract

Background: Chronic cough is a common problem, frequently caused or exacerbated by acid reflux. Diagnosis of acid reflux cough is haphazard currently, often relying on long therapeutic trials of expensive medications. We tested the hypothesis that the most relevant mechanistic component of acid reflux in chronic cough is when it rises to the level of the airway where acid can potentially be aspirated. We further wished to determine if multi-sample exhaled breath condensate (EBC) pH profiles can identify chronic cough patients likely to respond to proton pump inhibitor therapy.

Methods: 59 subjects were recruited for this study. Initially we examined EBC pH (gas-standardized with Argon) in the setting of 15 experimental pharyngeal acid challenges to determine duration of EBC acidification. Subsequently, we enrolled 22 healthy subjects to determine a normal multi-sample exhaled breath condensate pH profile over 1-3 days. We additionally obtained multi-sample EBC pH profiles in 22 patients with chronic cough. These samples were timed to occur after coughing episodes. Exhaled breath condensate pH was measured after gas standardization.

Results: We found that exhaled breath condensate pH is substantially reduced for approximately 15 minutes after pharyngeal acid load. Healthy subjects rarely have any low EBC pH values (defined as < 7.4 based on a normative reference range from 404 healthy subjects). Patients with chronic cough who subsequently responded well to proton pump inhibition (n = 8) invariably had one or more cough episodes associated with EBC acidification. No patient who had normal EBC pH with each of their cough episodes reported a clinically relevant response to proton-pump inhibition.

Conclusion: Patients whose cough responds to proton pump inhibition have transient exhaled breath condensate acidification with coughing episodes, supporting the role of airway acidification in reflux-triggered cough. Multi-sample EBC pH profiles, involving samples collected immediately subsequent to a coughing episode, may be useful appropriately to direct therapy to those patients with cough who have relevant acid reflux.

Figure 1

Repeated exhaled breath condensate pH (after gas standardization) before and after pharyngeal challenge by means of an acidic drink (Figure 1A) and after a water control (Figure 1B). EBC pH is transiently low after acid challenge, lasting approximately 10 to 15 minutes. * indicates significant differences from baseline (ANOVA on Ranks with Dunn's test, at p = 0.05).

Figure 2

A. Individual isolated exhaled breath condensate pH values immediately after coughing episodes in patients grouped by the response of their cough to a subsequent 1 month trial of proton pump inhibition. There are multiple samples collected from each subject. EBC acidification is significantly more common during cough in patients who subsequently respond to proton pump inhibition. B. Individual EBC pH data points plotted from 22 control subjects, for comparison.

Figure 3

Multi-sample EBC pH profiles of controls and patients. Chronic cough patients are separated into three groups: those who subsequently showed minimal or no response to proton pump inhibition (PPI Non-responders); those who had substantial clinical response to proton pump inhibition (PPI responders), and those who elected to not take the prescribed proton pump inhibitor but who nonetheless had substantial improvement in cough (Spontaneous Resolver). EBC pH profiles are noted as positive if a cough was associated with a low EBC pH value on 1 or more occasions and one or more other EBC pH values was normal. Note the high predictive values of positive and negative EBC pH profiles for response to proton pump inhibition.