Quantifying test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings

The citric acid cough reflex test (CRT) is used to quantify cough sensitivity and evaluate the effects of cough therapies and antitussive medications. This study quantifies the test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings in healthy individuals.

Healthy adults (n = 16) inhaled increasing concentrations of citric acid (0.01-3.2 mol/L) on three alternate days (1, 3, 5) until C₂ cough thresholds (i.e. two consecutive coughs within 3 s) or the highest concentrations of citric acid was reached. Participants were instructed to "cough if you need to" in the natural cough condition, and "try not to cough" in the suppressed cough condition. Following each inhalation, participants were asked to rate their urge to cough (UTC) using a modified Borg Scale.

Natural cough thresholds (NCTs) increased across days 1-3 (0.87 doubling concentrations, 95% CI, 0.28, 1.44, p = 0.004) and 1-5 (0.87 doubling concentrations, 95% CI, 0.33, 1.41, p = 0.004). Suppressed cough thresholds (SCTs) increased across days 1-5 (0.64 doubling concentrations per day, 95% CI, 0.03, 1.22, p = 0.04). After taking the effect of day into account, NCTs and SCTs varied within-participants by 0.75 (95% CI, 0.53, 0.93) and 0.78 (95% CI, 0.55,0.98) doubling concentrations respectively. UTC ratings at NCT, or SCT did not significantly increase across days 1-3 or 1-5. Sub-threshold (0.05 mol/L) UTC ratings increased across days 1-3 (-1.43 ratings per day, 95% CI, -2.31, -0.5, p = 0.005) and 1-5 (-1.71 ratings per day, 95% CI, -2.59, -0.79, p = 0.001). UTC ratings at NCT, SCT, and sub-threshold varied within-participants after taking into account the effect of day by 1.34 (95% CI, 1.03, 1.71), 1.47 (95% CI, 1.10, 1.91) and 1.20 (95% CI, 0.91, 1.50) ratings.

Natural and suppressed cough thresholds and UTC ratings are subject to test-retest variability. These data are important for the use of citric acid CRT as an outcome measure in longitudinal cough research, as they facilitate interpretation of whether changes in citric acid cough thresholds across days reflect true changes in cough sensitivity, rather than an artefact of repeating the test.