In this program of research, the investigators aim to answer the question: In patients with asthma aged 18-80, how do the lung airways and vessels respond to biologic therapy and what role does age and asthma duration have in this response? While about 4.6 million Canadians live with asthma, \~5-10% of patients have severe asthma meaning that multiple inhaled and systemic oral corticosteroid treatments have failed to improve symptoms and exacerbations, leading to lost work and school days and substantially diminished ability to participate in normal life. For such people, the vast majority of whom are middle aged and remember asthma as part of their entire lifespan, biologic immunomodulator therapies, which block the function of asthma inflammatory pathways, provide a final step-up therapy option. There is emerging evidence that prescribed in the right patient at the right time, the right biologic can result in clinical remission of asthma. While spontaneous clinical remission of asthma is rare, it has been documented in children in whom lung growth and remodeling is still possible. It remains unknown whether clinical remission in adults is accompanied by the reversal of pathologic remodeling, at the level of the airways and pulmonary vessels. This is critical to elucidate as investigators and physicians move forward with currently proposed criteria for "complete asthma remission". The inconvenient truth about asthma and age is that in older adult lungs, exposed to years of infection, exacerbations, smooth muscle remodeling and pulmonary vascular shunt, the mechanisms by which complete pathologic remission may be achieved are complex and poorly understood. To address this knowledge gap, the investigators will evaluate 150 patients (Vancouver, Ottawa, Hamilton, London) (in three age tertiles 18-29; 30-59; 60-80) with severe asthma and 50 age- and sex matched healthy volunteers over 2-years using chest CT, MRI and pulmonary function tests. The investigators will use the pulmonary imaging measurements to generate an imaging-index of normal airway structure and function which will be compared with and significantly correlate with MR-guided bronchoscopic sample measurements made before and after 1-/2-years of treatment. The investigators will reveal the pathobiologic relationship between age, asthma duration, clinical remission and imaging normalization with direct comparison to histology-based airway measurements.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
200
Participants with severe asthma (GINA 5) who are eligible to begin biologic therapy. Participants will undergo serial assessment with pulmonary imaging (CT, MRI), lung function testing, sputum collection, and symptom questionnaires. A subset of participants (\~15%) will be randomized to undergo MRI-guided bronchoscopy with airway sampling at baseline and 2 years.
Robarts Research Institute; The University of Western Ontario
London, Ontario, Canada
Determine extent of imaging-based remission in patients with severe asthma following 1 and 2 years of biologic therapy
Measured using 129Xe ventilation defect percent (VDP)
Time frame: from baseline to year 1 and year 2
Measure the extent and timing of clinical remission in patients with severe asthma as measured by changes in spirometry measurements of FEV1 and FVC
Measured using forced expiratory volume in 1 second and forced vital capacity
Time frame: from baseline to 1 year and 2 years
To determine the extent and timing of clinical remission in patients with severe asthma using symptoms scores of ACQ-5 and ACT
Measured using changes in asthma control questionnaire and asthma control test
Time frame: From baseline to 1 year and 2 years
Determine the extent and timing of imaging-based remission in patients with severe asthma using CT airway and vessel morphology
Measured using computed tomography (CT) airway and vessel metrics
Time frame: From baseline to 1 year and 2 years
To determine the extent and timing of clinical remission using the clinical outcome of frequency of asthma exacerbations in patients with severe asthma
Measured using the number of asthma exacerbations
Time frame: from baseline to 1 year and 2 years
To determine the extent and timing of clinical remission of patients with severe asthma using the clinical outcome of OCS use
Measured by the frequency of oral corticosteroid usage
Time frame: From baseline to 1 year and 2 years
Determine the extent and timing of clinical remission in patients with severe asthma as measured by sputum and blood eosinophil counts
Measured using blood and sputum eosinophil counts
Time frame: From baseline to 1 year and 2 years
Timing and proportion of patients achieving clinical remission after biologic treatment as measured by FEV1 and FVC.
Measured using forced expiratory volume at 1 second and forced vital capacity.
Time frame: From baseline to 1 year and 2 years
To determine the timing and proportion of patients achieving clinical remission as measured by ACQ-5 and ACT questionnaires.
Measured by asthma control questionnaire and asthma control test questionnaire scores.
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving clinical remission after biologic treatment using FeNO.
Measured using fractional exhaled nitric oxide (FeNO)
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving clinical remission using DLco.
Measured using diffusing capacity of the lung for carbon monoxide (DLco)
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving clinical remission after biologic treatment using SGRQ score.
Measured using St. George's Respiratory Questionnaire (SGRQ) score.
Time frame: From baseline to 1 year and 2 years.
Determine the timing and proportion of patients with severe asthma achieving clinical remission on biologic treatment using AQLQ scores.
Measured using the Asthma Quality of Life Questionnaire (AQLQ) score.
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using 129-Xe MRI VDP
Measured using the changes in 129-xenon MRI ventilation defect percent (VDP)
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Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using CT metrics
Measured using computed tomography (CT) mucus-score, airway dimensions and vascular pruning
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using DLco.
Measured using diffusing capacity of the lung for carbon monoxide (DLco)
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using RV/TLC
Measured using the ratio of residual volume to total lung capacity (RV/TLC)
Time frame: From baseline to 1 year and 2 years
Determine the timing and proportion of patients with severe asthma achieving imaging normalization after biologic treatment using FRC.
Measured using functional residual capacity (FRC).
Time frame: From baseline to 1 year and 2 years
Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using changes in VDP
Measured using ventilation defect percent (VDP)
Time frame: from baseline to 12-weeks and 2-years
Determine the relationship between clinical and imaging remission and generate predictive models for their achievement using changes in CT.
Measured using computed tomography (CT) airway wall thickness, mucus metrics
Time frame: From baseline to 12-weeks and 2-years
Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using FeNO.
Measured using forced exhaled nitric oxide (FeNO).
Time frame: From baseline to 12-weeks and 2-years
Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using ACQ-5 and ACT scores.
Measured using asthma control questionnaire and asthma control test scores.
Time frame: From baseline to 12-weeks and 2-years.
Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using sputum biomarkers.
Measured using sputum eosinophil and cell count values
Time frame: From baseline to 12-weeks and 2-years
Determine the relationships between clinical and imaging remission and generate predictive models for their achievement using exacerbation history.
Measured using patient's reported exacerbation history.
Time frame: From baseline to 12-weeks and 2-years.