Hypotonic Saline Effectively Discriminates Refractory/Unexplained Chronic Cough from Healthy Volunteers

Background: P2X3 antagonism effectively reduces cough frequency in patients with refractory/unexplained chronic cough (RCC/UCC), but the exact mode of this action is unknown. One possible mechanism is ATP release via TRPV4 receptors on AꝽ fibres (activated by hypotonic saline and low pH). Aims: To compare cough responses, measured by maximum evoked cough response (Emax) to descending osmolarities of hypotonic saline in RCC/UCC patients and HVs. Methods: Adult RCC/UCC patients and HVs (pooled from two studies) underwent cough challenge, with 4 single breath inhalations of descending concentrations of buffered hypotonic saline (300,250,200,150 and 100 mOsm/kg). Number of coughs within the first 15 seconds of each inhalation was recorded. The highest total number of coughs evoked at any dose (Emax) was measured. Results: 24 RCC/UCC patients and 24 gender matched HVs were recruited (18F/6M per group). Age was lower in HVs (median 53 vs 67 in RCC/UCC p<0.001), but otherwise the groups were comparable (median BMI 26 vs 26, HV predicted FVC 113% and FEV1% 103% vs CC predicted FVC 115% and FEV1 101%. There were no current smokers. In the CC group, median (IQR) for duration of cough was 702 weeks (221-1040), CQLS 55.5 (42-67) and day VAS 48 mm (32- 68). RCC/UCC group mean (IQR) cough frequency was 34.4/hr (13.7-53.0) over 24hrs (wake mean cough 50.1/hr and asleep 6.9/hr). There was a significant difference in Emax, median (SD) in HV 0.00 (2.56) vs CC 21.00 (13.04) p<0.001. ROC curve analysis showed hypotonic saline Emax discriminated the groups well (AUC 0.917). Conclusions: Buffered hypotonic saline, a novel cough challenge, effectively discriminates RCC/UCC from healthy volunteers.