Chronic cough is a common troublesome symptom which has a global prevalence of approximately 10%, but with wide variations across continents. Patients with refractory and unexplained chronic cough (RCC/UCC) often exhibit dysregulated vagal pathways, necessitating a neuronal biomarker for targeted treatment. ATP, involved in the ATP/P2X3 pathway, may serve as a potential biomarker due to its role in the cough reflex. The study aims to discover if ATP production by the airway epithelium is greater in RCC/UCC patients compared with healthy controls, if the epithelium is a source of ATP, whether gene and protein expression related to ATP production differs between these groups and whether ATP release is triggered by mechanical and chemical stimulation. Additionally, the study seeks to determine if biomarker gene expression signatures can differentiate RCC/UCC patients from healthy controls.
Patients with a history of RCC/UCC.
Normal Chest X-ray in the last 5 years.
No Evidence of Airflow Obstruction (FEV1/FVC ratio above LLN)
Cough Severity VAS ≥ 40 mm at screening.
Participants who are currently established on treatment and their chronic cough is well controlled.
Unable to perform acceptable and reproducible spirometry.
Participants with a positive covid-19 test within 2 weeks of screening.
Current smoker or ex-smoker with ≥20 pack year smoking history and abstinence of ≤6 months
Healthy controls will be recruited through local advertising, existing study databases or participation in previous studies where they have given permission to be contacted. Participants with RCC/UCC will be recruited by the investigators from existing study databases, clinics at either of the following sites: McMaster University Medical Centre, Department of Respiratory Medicine, 1200 Main St. West, Hamilton, Ontario, Canada, L8N 3Z5 Firestone Institute for Respiratory Health, St Joseph's Healthcare, 50 Charlton Ave E, Hamilton, ON L8N 4A6
Case-control
Cross-sectional
Bronchoscopy
Diagnostic testBronchoscopy will be performed in patients with refractory or unexplained chronic cough and healthy controls.
Difference in expressed genes
Expression of genes involved in intracellular ATP production, transport, extracellular metabolism in the airway epithelium will be compared in both RCC/UCC and healthy controls.
Difference Immune Cells and Cytokines
Investigate differences in the levels of neuroinflammatory mediators and immune cells from the respiratory airways and distal alveoli.
Gene Expression
To compare the differences in RCC/UCC and healthy control in gene expression profiling in bronchial biopsies (sub-epithelial dominant).
Difference in Nerve Morphology
Investigate differences in nerve length, nerve branch points, nerves expressive P2X3 receptors on airway sensory nerves expressing P2X3 receptor in RCC/UCC compared with healthy controls.
Difference in ATP release
ATP release from the cultured bronchial epithelial cells (BEC) taken from RCC/UCC and healthy controls after exposure to dynamic mechanical stretch and environmental exposures (cigarette smoke and NO2).
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