Physiology of Cough in Asthma: Comparison of Sensory-Mechanical Responses to Mannitol and Methacholine Challenge Tests

Cough is a common, disruptive and at times disabling symptom which often prompts patients to seek medical attention. Determining the cause(s) of chronic cough can be challenging, and costly. Asthma and other airway disorders are among the most common causes of chronic cough; and cough can be the sole symptom of asthma. Little is known about why some patients with asthma primarily cough and do not develop the other symptoms of asthma such as shortness of breath or wheeze. Improved understanding of the reasons for these different manifestations may lead to new and more effective treatment strategies. We have notices differences in pressure measurements inside the chest in patients who mostly cough during induced bronchoconstriction, which might be part of the explanation for varying symptoms. This study will compare lung mechanical responses during methacholine and mannitol-induced induced airway narrowing between typical asthma, cough variant asthma (CVA) and an airway inflammatory disorder that is not asthma.The purpose of this research is to explore the pathophysiology and sensory-mechanics of cough in individuals with asthma, CVA and methacholine-induced cough but normal airway sensitivity using mannitol and high-dose methacholine bronchoprovocation testing.

Study Overview

• Status: Completed
• Conditions: Asthma; Cough Variant Asthma
• Intervention / Treatment: Drug: high-dose methacholine challenge test; Other: mannitol challenge test

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L2V7
      • Kingston General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects with asthma or suspected CVA who have previously participated in or who have expressed interest in participating in studies will be invited to participate in the study. Previous treatment with inhaled or systemic corticosteroids is not an exclusion criterion, but medication use will be recorded and examined in the analysis.

Exclusion Criteria:

1. An exacerbation necessitating any alteration in medication, emergency department visit or hospitalizations within the previous 4 weeks;
2. Inability to perform acceptable quality spirometry;

3. Medical contraindications to methacholine challenge testing 35, including:

   1. Severe airflow limitation (FEV1 <50% predicted or <1.0 L);
   2. Heart attack or stroke in last 3 months;
   3. Uncontrolled hypertension, systolic BP > 200 or diastolic BP > 100;
   4. Known aortic aneurysm;
   5. Moderate airflow limitation < 60% predicted or <1.5 L);
   6. Inability to perform acceptable quality spirometry;
   7. Current use of cholinesterase inhibitor medication (for myasthenia gravis); and
   8. Pregnant or nursing mothers.
4. Smoking history in excess of 10 pack years;

5. Medical contraindications to mannitol challenge testing, including:

   1. Aortic or cerebral aneurysm;
   2. Uncontrolled hypertension; and
   3. Myocardial infarction or a cerebral vascular accident in the previous six months).
6. Women who are pregnant or breastfeeding because the effects of a possible hyperresponsiveness reaction to mannitol in mothers and/or fetuses are unknown and many compounds are excreted in human milk therefore caution should be taken.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cough Variant Asthma; Those diagnosed with cough variant asthma.	Drug: high-dose methacholine challenge test; nebulized liquid inhalation, 0.0625 - 256 mg/mL, doubling doses; Other Names: Provocholine; Other: mannitol challenge test; inhaled powder, 0 - 635 mg, increments of 5,10, 20 and 40 mg; Other Names: Aridol
Experimental: Asthma; Those with diagnosed asthma.	Drug: high-dose methacholine challenge test; nebulized liquid inhalation, 0.0625 - 256 mg/mL, doubling doses; Other Names: Provocholine; Other: mannitol challenge test; inhaled powder, 0 - 635 mg, increments of 5,10, 20 and 40 mg; Other Names: Aridol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
PD15 (15% fall in forced expiratory volume in one second (FEV1) from baseline during challenge test visits)	baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test)

Secondary Outcome Measures

Outcome Measure	Time Frame
%ΔFEV1 (percentage change in forced expiratory volume in one second)	baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test)
Plateau response	baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test)
Dose-response slope	baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test)
Expiratory Flow Limitation (EFL)	baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test)

Collaborators and Investigators

• Sponsor: Dr. Diane Lougheed
• Collaborators: The Ontario Thoracic Society of the Ontario Lung Association; Queen's University (William M Spear / Start Memorial Fund)
• Investigators: Principal Investigator: Scott Turcotte, Queen's University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2010
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: February 1, 2010
• First Submitted That Met QC Criteria: February 5, 2010
• First Posted (Estimate): February 8, 2010

Study Record Updates

• Last Update Posted (Actual): February 28, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Asthma; Hypersensitivity; Cough; Methacholine; Mannitol; Cough Variant Asthma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Respiration Disorders; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Cough; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Cholinergic Agonists; Respiratory System Agents; Miotics; Parasympathomimetics; Bronchoconstrictor Agents; Muscarinic Agonists; Mannitol; Methacholine Chloride
• Other Study ID Numbers: 2010-01 (internal number)