ATP and P2X3 Receptor in Chronic Cough

Summary

This is a laboratory-based study that will be performed at the Clinical Research Centre at the Royal Brompton Hospital,London. The objectives are:

1. Determine whether adenosine triphosphate (ATP) is present or released in airways of idiopathic chronic cough patients
2. Determine whether there is an increase in cough sensitivity and laryngeal sensitivity to exogenous ATP
3. Examine the effects of exogenous ATP on the inflammatory response in the upper and lower airways.

The participants will be: (i) Healthy subjects: non-smoker (8 subjects) and (ii) Chronic cough subjects attending Chronic Cough clinic (12 subjects). Each will be involved in:

Study 1. Following recruitment, subjects will attend for a fiberoptic bronchoscopy.

Study 2: Subjects will take part in a study of the effect of inhaling nebulized ATP. Subjects will be studied on 2 days separated by at least 5 days. On each day, after measurements of lung function, FeNO and cough questionnaires, the subject will inhale either saline or ATP solution from a nebulizer, following which laryngeal hypersensitivity, capsaicin cough challenge and sputum induction will be performed.

Results will be expressed as mean ± standard error of the mean (SEM). Study data will be analysed by the Investigators at the completion of the study. Planned analyses will be done by comparing chronic cough patients to the healthy controls. The Spearman rank-correlation test will be used to determine correlations.

Conditions

• Cough

Interventions

DEVICE

Adenosine triphosphate (ATP) solution inhalation from nebuliser

ATP and 0.9% saline solution will be inhaled from a nebuliser on separate days, and their effects will be examined.

DIAGNOSTIC_TEST

Inhalational challenge with increasing concentrations of capsaicin solutions

Coughs are counted for one minute after single-breath inhalations of 0.9% sodium chloride and capsaicin solutions of increasing concentrations (0.98-500 μm) generated from a dosimeter (P.K. Morgan Ltd, Gillingham, UK) set at a dosing period of 1 s. The concentration that caused more than 2 or 5 coughs was recorded as C2 and C5, and the data is analysed as log10 C2 or C5.

DEVICE

Recording of Cough Count and frequency using the Hyfe Cough Monitor

All enrolled study participants will be provided with a dedicated Android phone or watch loaded with the Hyfe Research application to monitor and record their cough sounds. The participant will be provided with a carrying case to ensure the phone stays within five feet of their mouth. They will be asked to "wear" the phone for the duration of 3 weeks, and keep the phone within five feet of their mouth over nights - keeping it, i.e., on a bedside table. Hyfe is a research use only tool which does not provide clinical diagnosis. Cough collection within this study will not lead to specific medical interventions or differential clinical management. Hyfe records only short snippets (\<0.5 seconds). As such, the recordings will not be identifiable. Conversations or acoustic environments are not recorded. The informed consent form will explicitly describe exactly what is recorded.

PROCEDURE

Collection of exhaled breath condensate

EBC will be collected by asking the subject to breathe normally onto a handheld breath collection apparatus from Respire Diagnostics, Imperial College, that will cool the exhaled breath to allow for condensation of the exhaled air. The subject will breathe for 2 periods of 5 minutes each separated by a 3-4 min rest to allow the collection of up to 500 uL of liquid. The liquid will be stored for later analysis.

DIAGNOSTIC_TEST

Continuous laryngoscopic examination

Continuous laryngoscopy testing is performed based on previous methodology. Continuous laryngoscopy testing is performed by placing a fibreoptic nasendoscope in the posterior nasopharynx and securing it using specialist headgear. A small quantity of lubricating jelly is used to ease passage of the scope. Video images of the laryngeal inlet are, thereafter, continuously recorded whilst a subject performs various manoeuvres including respiratory movements and cough. These movements will be observed and recorded before and following the various aspects of the challenge protocol and thus allow us to evaluate laryngeal movement abnormalities and for example position of the vocal folds. The size and change in size of the glottic aperture will be evaluated.

DIAGNOSTIC_TEST

Sputum induction

Sputum is induced by inhalation of an aerosol of sterile 3% saline solution and subsequently increasing to 4% and 5% during 3 periods of 5 minutes each. Particular care is taken to avoid contamination with saliva and post-nasal drip by instructing subjects to rinse orally with water and to blow their nose after each inhalation. Sputum samples are collected into sterile pots. Peak flow measurements are made after each inhalation. If there is a fall in peak flow of 20% or more or if symptoms occurred during the procedure, the induction is stopped. Sputum plugs are selected and one portion is used to perform differential cell counts. To perform differential cell counts, dithiothreitol is added to the sputum plug and mixed vigorously on a plate shaker to solubilize the sputum. Cytospins are then prepared, and differential cell counts obtained.

DIAGNOSTIC_TEST

Spirometric measurements

Spirometry (FEV1 and forced vital capacity, FVC) is measured using a dry wedge spirometer (Vitalograph, Buckinghamshire, UK).

DIAGNOSTIC_TEST

Blood sample collection

Venous blood (30 cc) will be taken from a vein in the forearm. This test causes a transient discomfort as a needle is used to obtain the blood sample. The blood sample will be used for measuring various proteins and for getting white blood cells to obtain some types of stem cells.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC

  collaborator INDUSTRY

• Imperial College London

  lead OTHER

Principal Investigators

• Kian Fan Chung, MD · Imperial College London

Study Design

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

DOUBLE

Model

SINGLE_GROUP

Eligibility

Min Age

30 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-02-28

Primary Completion

2024-03-28

Completion

2024-08-31