Cough Responses to Tussive Agents in Health and Disease

Study Overview
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Brief Summary
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The sensitivity of a persons cough reflex can be measured by getting them to breath in (inhale) irritant chemicals. The purpose of this clinical research study is to test the sensitivity of the cough reflex to a variety of chemicals that can be inhaled to see if coughing responses are different between healthy people and people with respiratory problems that make them cough.

Detailed Description
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Coughing is a distressing symptom which has a major impact on quality of life. It has been estimated that cough costs the UK economy £1 billion each year. Currently there are no effective anti-tussive agents to treat subjects with cough. Although drugs such as morphine may have some anti-tussive effect, side effects unacceptable. Currently our understanding of the mechanisms which lead to coughing in different diseases is poor. Many mechanistic studies rely on testing the sensitivity of the cough reflex by inhalation of capsaicin (chilli-pepper extract) or citric acid. These challenges do not differentiate well between health and disease or between different disease states. Other agents such as prostaglandins and bradykinin are known to stimulate a coughing but responses to these agents have rarely been used as a measure of cough reflex sensitivity and not been compared to standard challenges. It is clear that patients with common airway diseases such as COPD and asthma cough significantly more than healthy subjects. Moreover subjects presenting with chronic cough have cough rates an order of magnitude higher than most patients with airway disease. These differences are poorly represented by the differences in current cough challenge tests. The investigators hypothesize that patterns of cough responses to different tussive agent may better differentiate between health and different disease states. These patterns may also suggest the different mechanisms leading to cough in different diseases.

Official Title
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Cough Responses to Tussive Agents in Health and Disease

Conditions
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Chronic Obstructive Airway Disease, Asthma, Chronic Cough

Intervention / Treatment
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* Other: Cough Challenge Tests
* Other: ambulatory cough recording
* Other: Cough questionnaires


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Adult subjects aged 18 years and over Meet criteria for subject groups as outlined below (1) Healthy volunteers Non-smokers No history of respiratory disease (2) Healthy smokers Current smokers with smoking history of ≥10 pack years Spirometry within normal limits i.e. FEV1>80% predicted and FEV1/FVC ratio >75% predicted (3) Asthma Physician diagnosis of asthma Airways hyperresponsiveness to methacholine; PC20<16mg/ml (within last 2 years) Non-smokers or ex-smoker with smoking history of ≤10 pack years (4) COPD Physician diagnosis of COPD Ex-smokers with smoking history of ≥20 pack years Spirometry demonstrating airflow obstruction i.e. FEV1/FVC ratio <70% (5) Chronic Cough History of a dry cough for >8 weeks Normal CXR Non-smokers or ex-smoker with smoking history of ≤10 pack years Exclusion Criteria: 1) Symptoms of upper respiratory tract infection within the last 6 weeks 2) Participation in another clinical trial of an investigational drug within the last 4 weeks 3) Use of medication likely to alter cough reflex sensitivity i.e. ACE inhibitors, codeine phosphate, morphine sulphate, 4) Patients with severe respiratory disease i.e. FEV1 < 1 litre, 5) Significant medical co-morbidities likely to affect ability to participate in the trial or affect cough reflex sensitivity e.g. diabetes, stroke, Parkinson's disease, multiple sclerosis etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Asthma<br>Subjects with asthma more than 18 years old with minimal or no smoking history and evidence of bronchial hyperreactivity | Other: Cough Challenge Tests<br>* Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2<br>Other: ambulatory cough recording<br>* Cough recording with a portable device to capture cough sounds<br>Other: Cough questionnaires<br>* Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.<br>|
| Chronic obstructive pulmonary disease<br>Subjects with diagnosis of COPD who must be ex smokers and have evidence of airflow obstruction on breathing tests. | Other: Cough Challenge Tests<br>* Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2<br>Other: ambulatory cough recording<br>* Cough recording with a portable device to capture cough sounds<br>Other: Cough questionnaires<br>* Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.<br>|
| Healthy Volunteers<br>Healthy non smoking adults. | Other: Cough Challenge Tests<br>* Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2<br>Other: ambulatory cough recording<br>* Cough recording with a portable device to capture cough sounds<br>Other: Cough questionnaires<br>* Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.<br>|
| Healthy smokers<br>Current smokers with normal breath tests (spirometry) | Other: Cough Challenge Tests<br>* Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2<br>Other: ambulatory cough recording<br>* Cough recording with a portable device to capture cough sounds<br>Other: Cough questionnaires<br>* Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.<br>|
| Chronic cough<br>Subjects with idiopathic chronic cough. | Other: Cough Challenge Tests<br>* Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2<br>Other: ambulatory cough recording<br>* Cough recording with a portable device to capture cough sounds<br>Other: Cough questionnaires<br>* Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cough response to tussive agents | To measure cough responses to capsaicin, citric acid, prostaglandin E2 (PGE2) and Bradykinin (BK) in healthy volunteers, airway diseases (asthma and COPD) and chronic cough. To compare the ability of individual challenges and patterns of challenge response to discriminate between diagnostic groups. | 45 minutes | 
| Objective cough recording | To perform ambulatory cough recording over 24 hours to assess if there are any differences | 24 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C2 to inhaled tussive agents | C2 concentration difference between different diagnostic groups after inhalation of tussive agents | 45 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cough, Inhalational cough challenges, Cough reflex sensitivity, Chronic cough.