Sensory-Mechanical Responses to Eucapneic Voluntary Hyperventilation and Mannitol

Study Overview
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Brief Summary
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The objectives of this study are to determine the sensory-mechanical responses to Eucapneic Voluntary Hyperventilation (EVH) and Mannitol in individuals with cough variant asthma (CVA) and methacholine-induced cough with normal airway sensitivity (COUGH) and compare these responses to a control group of healthy individuals without asthma or chronic cough. We hypothesize: EVH and Mannitol cause dyspnea, cough, small airway obstruction with resultant dynamic hyperinflation, gas trapping and autoPEEP in individuals with CVA and COUGH, but not healthy controls. The sensory-mechanical responses to both hyperosmolar challenges (EVH and Mannitol) are comparable within groups (CVA, COUGH and healthy controls).

Detailed Description
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Asthma is a chronic respiratory condition characterized by eosinophilic airway inflammation. Individuals with classic asthma experience paroxysmal symptoms including cough, wheeze, shortness of breath and chest tightness. Cough variant asthma (CVA) is asthma in which chronic cough (cough lasting eight weeks or more) is the sole or predominant symptom of asthma. The pathophysiologic mechanisms which differentiate asthma, CVA, and eosinophilic bronchitis without asthma are not fully understood. We have recently identified individuals with chronic cough who cough during methacholine but have normal airway sensitivity (ie. do not have asthma or CVA) (COUGH) and may or may not have eosinophilic bronchitis. The purpose of this research is to further explore the pathophysiologic basis for cough in these conditions using two 'indirect' inhalation challenge tests: eucapneic voluntary hyperventilation (EVH) and Mannitol), which induce osmotic and/or temperature changes in airway. Specifically, this study will collect preliminary data on the sensory-mechanical responses of individuals with CVA, COUGH and healthy controls to EVH and Mannitol Challenges.

Official Title
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Sensory-Mechanical Responses to Eucapneic Voluntary Hyperventilation and Mannitol in Individuals With Cough Variant Asthma and Chronic Cough

Conditions
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Cough, Asthma, Cough Variant Asthma

Intervention / Treatment
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* Drug: Methacholine (MCh) Challenge Testing
* Diagnostic Test: Eucapneic Voluntary Hyperventilation (EVH)
* Drug: Mannitol Inhalation Kit


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals aged 18-65 years of age with CVA and individuals with methacholine-induced cough but normal airway sensitivity. The following definitions will be used: CVA: chronic cough (≥8 weeks) is the sole or predominant symptom and positive methacholine challenge (PC20 ≤ 16 mg/mL) and history of cough responding to specific asthma treatment (such as inhaled steroid or 1 week trial of bronchodilator); Methacholine-induced cough but normal airway sensitivity: chronic cough (≥8 weeks) is the sole or predominant symptom and negative methacholine challenges (PC20 > 16 mg/mL). Individuals aged 18-65 years of age with no history of asthma or chronic cough. Exclusion Criteria: an exacerbation necessitating a change in medication, emergency department visit or hospitalizations within the previous 4 weeks inability to perform acceptable spirometry medical contraindications to methacholine challenge testing smoking history in excess of 10 pack years Note: Previous treatment with inhaled or systemic corticosteroids is not an exclusion criterion; medication use will be recorded and examined in the analysis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cough Variant Asthma<br>Individuals diagnosed with Cough variant asthma | Drug: Methacholine (MCh) Challenge Testing<br>* Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.<br>* Other names: Provocholine;Diagnostic Test: Eucapneic Voluntary Hyperventilation (EVH)<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>Drug: Mannitol Inhalation Kit<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>* Other names: Mannitol Challenge Test;|
| Experimental: Methacholine-induced cough<br>Individuals with chronic cough and negative methacholine challenge | Drug: Methacholine (MCh) Challenge Testing<br>* Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.<br>* Other names: Provocholine;Diagnostic Test: Eucapneic Voluntary Hyperventilation (EVH)<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>Drug: Mannitol Inhalation Kit<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>* Other names: Mannitol Challenge Test;|
| Experimental: Control<br>Individuals with no history of asthma or chronic cough | Drug: Methacholine (MCh) Challenge Testing<br>* Visit 1: Informed consent, Baseline screening and pulmonary function tests and Low-dose methacholine challenge testing using partial and full flow-volume loops.<br>* Other names: Provocholine;Diagnostic Test: Eucapneic Voluntary Hyperventilation (EVH)<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>Drug: Mannitol Inhalation Kit<br>* Visit 2 or 3: Will be conducted in random order and subjects will perform one of the two challenge tests at either visit.<br>* Other names: Mannitol Challenge Test;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mid expiratory flows | The bronchodilating effect of a DI will be examined using responses to the challenge testing (Visit 2/3) in these subgroups by comparing the mid-expiratory flow difference between the partial (PEF) and full maximal flow-volume (MEF) loops at 40% above Residual Volume (RV) from the forced vital capacity (FVC) (PEF40 and MEF40 respectively) at provocative dose of 4.5% saline causing a 20% decline in FEV1 (PD20 (HS)) and provocative minute ventilation causing a 20% decline in FEV1 (PC20 (EVH)) with that recorded at baseline. | Time frame of the methacholine challenge varies between individuals. At provocative dose/ventilation causing a 20% decline in FEV1 (PD20 and PC20 respectively). On average, these occur about 15-25 minutes into the challenge test | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory System Reactance (X5) | Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing. | After dose administration; will occur 2-5 minutes after dose | 
| Peripheral Resistance (R5-R20) | Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing. | After dose administration; will occur 2-5 minutes after dose | 
| Central Airway Resistance | Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing. | After dose administration; will occur 2-5 minutes after dose | 
| Forced Vital Capacity (FVC) | As an index of airway closure. | After dose administration; will occur 2-5 minutes after dose | 
| FEV1/FVC | As an index of airway obstruction. | After dose administration; will occur 2-5 minutes after dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Cough, Eucapneic Voluntary Hyperventilation, Hypertonic Saline