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

• %ΔFEV1 (percentage change in forced expiratory volume in one second) [ Time Frame: baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test) ] [ Designated as safety issue: No ]
• Plateau response [ Time Frame: baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test) ] [ Designated as safety issue: No ]
• Dose-response slope [ Time Frame: baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test) ] [ Designated as safety issue: No ]
• Expiratory Flow Limitation (EFL) [ Time Frame: baseline and several time points collected throughout test (high-dose methacholine challenge test or mannitol challenge test) ] [ Designated as safety issue: No ]

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.

• Asthma
• Cough Variant Asthma

• Drug: high-dose methacholine challenge test
  nebulized liquid inhalation, 0.0625 - 256 mg/mL, doubling doses
  Other Name: Provocholine
• Other: mannitol challenge test
  inhaled powder, 0 - 635 mg, increments of 5,10, 20 and 40 mg
  Other Name: Aridol

• Experimental: Cough Variant Asthma
  Those diagnosed with cough variant asthma.
  Interventions:

  • Drug: high-dose methacholine challenge test
  • Other: mannitol challenge test
• Experimental: Asthma
  Those with diagnosed asthma.
  Interventions:

  • Drug: high-dose methacholine challenge test
  • Other: mannitol challenge test

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.

• The Ontario Thoracic Society of the Ontario Lung Association
• Queen's University (William M Spear / Start Memorial Fund)