The Development of Novel Clinical Tests to Diagnose and Monitor Asthma in Preschool Children

Study Overview
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Brief Summary
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The study will ascertain the ability of preschool lung function tests to distinguish healthy children from those with wheeze, and to differentiate phenotypes of wheezy children (high and low risk for asthma as defined by API) in order to predict response to therapy, and to explore the correlation between preschool lung function test results and symptoms, in order to develop objective methods for monitoring asthma.

Detailed Description
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In Canada, the most common chronic disease of childhood is asthma. Childhood asthma places a significant burden on the health care system (refn). No objective preschool asthma diagnostic tools exist, and the current gold-standard, the Asthma Predictive Index, does not provide information about lung function and symptom management. In this study, it is hypothesized that the lung clearance index (LCI), a value derived from the multiple breath washout test, will be the most sensitive, responsive discriminative test for preschool asthma. If it proves useful in the monitoring and diagnosis of preschool asthma, LCI has the potential to improve the clinical management and thus potentially significantly reduce hospitalization rates for preschool children suffering with asthma. In this unique data set, the investigators will also compare the relative utility of the forced oscillation technique (FOT) and preschool spirometry with the LCI in order to detect abnormalities amongst those children at high risk for preschool asthma. In addition, the impact of sleep apnea as a risk factor for and modifier of asthma will be investigated in this study. Furthermore, changes to the composition of the nasal microbiome during and after a wheezing episodes and the role of viral infections in wheezing exacerbations will be explored. Finally, the utility of new methods of diagnosing food allergy, such as the basophil activation test, will be examined in this Canadian cohort.

Official Title
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The Development of Novel Clinical Tests to Diagnose and Monitor Asthma in Preschool Children

Conditions
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Asthma, Wheeze, Obstructive Sleep Apnea, Food Allergy, Virus

Intervention / Treatment
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* Procedure: Bronchodilator response
* Procedure: Allergy Skin Test
* Procedure: Multiple-Breath Washout
* Procedure: Forced Oscillation Technique
* Procedure: Spirometry
* Drug: salbutamol
* Procedure: Nasal Brush
* Procedure: Blood sample
* Procedure: Basophil activation test
* Procedure: Nasal swab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Wheezing Subjects): 3 to 5 years of age (36 to 71 months) Diagnosis of Asthma made by a physician in the emergency department History of at least two other wheezing episode within the previous 12 months Received salbutamol within 4hrs before emergency department visit, during current emergency department visit, or was prescribed salbutamol at discharge from emergency department. Inclusion Criteria (Healthy Controls): 3 to 5 years of age (36 to 71 months) Free of a respiratory infection for a minimum of 4 weeks prior to the testing visit Exclusion Criteria (both subjects and controls): History or coexistence of renal, chronic pulmonary, cardiac, neurological or systemic disease Born pre-term (< 35 weeks GA) Insufficient command of the English language

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 5 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 |
| --- | --- |
| Wheezing subjects<br>Two study visits will be completed with wheezing subjects. The baseline visit will be completed within a 5 day window from the child's discharge from the emergency department. The follow-up visit will be completed 3 months after the baseline visit. At both visits, participants will provide a nasal swab and urine sample, complete three breathing tests: multiple-breath washout, forced oscillation technique, and Spirometry. In addition, at the follow-up visit, children will have an allergy skin test done, a nasal brush to collect epithelial cells and provide a blood sample. Whole blood will be used for basophil activation test (BAT). Children age 4+ will also complete post-bronchodilator testing using Salbutamol to capture information about bronchodilator response. | Procedure: Bronchodilator response<br>* Bronchodilator (Salbutamol - dose dependent on participant prescription) to wheezing subjects. 15 minutes after bronchodilator, spirometry and FOT repeated.<br>Procedure: Allergy Skin Test<br>* Child will be tested for allergies to 17 different allergens, and positive (histamine) and negative (glycerin) controls, for a total of 19 allergens.<br>Procedure: Multiple-Breath Washout<br>* Facemask in children 3-5 yrs, Wash-in phase: medical air inhaled during tidal breathing until steady state. Bias flow switched to 100% oxygen. Wash-out phase: patient breathes in 100% oxygen until nitrogen levels reach  2%. Each test in duplicate and average is calculated.<br>* Other names: MBW;Procedure: Forced Oscillation Technique<br>* Sterile mouthpiece attached to FOT device. Patient is tested seated with noseclips and mouthpiece. FOT device produces oscillations at different frequencies (from that flow into lungs. Device measures resistance and reactance in lungs.<br>* Other names: FOT;Procedure: Spirometry<br>* Forced exhale manoeuvre completed by participant into flow meter, measuring forced exhale volumes and speed.<br>Drug: salbutamol<br>* Given during bronchodilator response.<br>* Other names: ventolin;Procedure: Nasal Brush<br>* Nasal brush of 1 inferior turbinate to collect epithelial cells. Collected on either nare, choice dependent on how clear the nare is (i.e. no mucous, no nasal mucosal edema, no major structural impediments).<br>Procedure: Blood sample<br>* 8mLs of venous blood collected using a butterfly needle of appropriate gauge. Blood sample used to collect CBC values, total IgE, serum, DNA, plasma, and whole blood.<br>Procedure: Basophil activation test<br>* Collect basophils from whole blood sample, and expose cells to food allergens in flow cytometry machine to measure allergic response, if any.<br>* Other names: BAT;Procedure: Nasal swab<br>* Gentle swabbing of both nasal openings to collect mucous sample for analysis of microbial contents (i.e. bacteria, virus, fungi).<br>|
| Healthy cohort<br>One study visit will be completed with healthy participants. At this visit, three breathing tests will be performed: multiple-breath washout, forced oscillation technique, and spirometry. As well, an allergy skin test will be performed at the visit. | Procedure: Allergy Skin Test<br>* Child will be tested for allergies to 17 different allergens, and positive (histamine) and negative (glycerin) controls, for a total of 19 allergens.<br>Procedure: Multiple-Breath Washout<br>* Facemask in children 3-5 yrs, Wash-in phase: medical air inhaled during tidal breathing until steady state. Bias flow switched to 100% oxygen. Wash-out phase: patient breathes in 100% oxygen until nitrogen levels reach  2%. Each test in duplicate and average is calculated.<br>* Other names: MBW;Procedure: Forced Oscillation Technique<br>* Sterile mouthpiece attached to FOT device. Patient is tested seated with noseclips and mouthpiece. FOT device produces oscillations at different frequencies (from that flow into lungs. Device measures resistance and reactance in lungs.<br>* Other names: FOT;Procedure: Spirometry<br>* Forced exhale manoeuvre completed by participant into flow meter, measuring forced exhale volumes and speed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lung Clearance Index (LCI) in wheezing subjects. | Determine whether a change in LCI value captured over a 3 month period distinguishes two groups of wheezing children (high vs. low risk for asthma) as determined by the asthma predictive index (API). | baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Obstructive Sleep Apnea (OSA) | Obstructive sleep apnea symptoms in wheezing preschool aged children, captured using the Pediatric Sleep Questionnaire. | Day 1, and again 3 months later. | 
| Change in asthma symptoms | Changes in parental report of symptoms (using the TRACK questionnaire) and clinically assessed symptoms (PRAM scale, ISAAC modified questions) over 3 month time frame. | baseline and 3 months | 
| Change in Forced Oscillation Technique (FOT) values in wheezing subjects. | Determine whether a change in FOT values (lung impedence) over 3 month period distinguishes two groups of wheezing children (high vs. low risk for asthma) as determined by API. | baseline and 3 months | 
| Change in spirometry values in wheezing subjects. | Determine whether a change in spirometric indices (i.e. FEV1, FEV0.75, FVC, FEV1/FVC,PEF) over a 3 month period distinguishes two groups of wheezing children (high vs. low risk for asthma) as determined by API. | baseline and 3 months | 
| Comparison of LCI values between wheezy subjects and healthy controls. | Determine if LCI values in preschool children differ between children with no history of wheeze and those with recurrent wheeze. | Day 1 for wheezing subjects and healthy controls, and again 3 months later for wheezing subjects. | 
| Comparison of forced oscillation technique (FOT; lung impedence) values between wheezy subjects and healthy controls. | Determine if FOT values in preschool children differ between children with no history of wheeze and those with recurrent wheeze. | Day 1 for wheezing subjects and healthy controls, and again 3 months later for wheezing subjects. | 
| Comparison of spirometric values between wheezy subjects and healthy controls. | Determine if spirometric indices (i.e. FEV1, FEV0.75, FVC, FEV1/FVC,PEF) in preschool children differ between children with no history of wheeze and those with recurrent wheeze. | Day 1 for wheezing subjects and healthy controls, and again 3 months later for wheezing subjects. | 
| Change in nasal microbiome in wheezing subjects | A nasal swab collected at Day 1 and again 3 months later will allow us to categorize the change in bacterial and viral communities of the nasal microbiome in wheezing subjects during and post wheezing exacerbations. | Day 1 and 3 months | 
| Viral infections causing wheezing | A nasal swab collected at Day 1 will be used to determine which viruses are causing wheezing in wheezing subjects. | Day 1 | 
| Basophil activation test (BAT) | Determine the ability of the BAT to confirm food allergies in a wheezing cohort. | Day 1 and 3 months | 
| Lung epithelial cell immune response in wheezing subjects. | Epithelial lung cells collected from the inferior turbinate in wheezing subjects will be stimulated with viruses to categorize and differentiate immune cell response in wheezing subjects. | Day 1 and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, lung ventilation inhomogeneity, preschool, asthma, wheeze