Our Asthma Research

What does it take to outwit lung disease? Bold, brave research! Our investigators are involved in projects that cover all the bases, from studying how diseases work to developing real-world therapies. 

Below, you’ll learn more about the asthma research projects we are currently funding. Interested in applying for a research grant? Learn about our opportunities here

Asthma Research Projects

2019

Dr. Dhenuka Radhakrishnan

Derivation of clinical score to predict risk of future emergency department visits and hospitalizations among children with Asthma

Amount Awarded: $50,000

Asthma is one of the most common chronic diseases in childhood and is a leading cause of emergency department (ED) visits and hospitalizations. Despite improvements in available treatments, ED visit and hospitalization rates for asthma remain high. Currently, children who leave the ED following an asthma exacerbation do not always receive comprehensive asthma education or get started on asthma controller medications, even though these strategies are known to prevent repeat asthma visits. This may be due to physician discomfort in prescribing these treatments or lack of asthma educators. However, these treatments are likely only needed for children who are at high risk for repeat ED visits or asthma hospitalizations. There are currently no guidelines to direct clinicians how to practically identify these high-risk children before discharge from the ED.

Our aim is to derive an ED-based clinical risk score to identify children at highest risk for a repeat asthma ED visit or future hospitalization within 12 months following an initial ED visit for asthma. We will analyze data that was collected as part of a previous study that included all children with an asthma exacerbation who came to the ED at one of five specialized paediatric hospitals. Information on characteristics of children who participated in this previous study will be linked with provincial health administrative date in Ontario and Quebec to provide information on health care outcomes one year after their initial ED visit, and specifically whether the children were hospitalized or had repeat ED visits for asthma. This information will be used to develop a clinical score to identify high-risk asthma patients.

This study fills the current knowledge gap, and has the potential to significantly change the way we target and manage children at the time of discharge from the ED in order to reduce future repeat acute health care visits. We have identified a creative way to perform this study quickly and cost-effectively as it will utilize patient-level data that has already been accurately collected at multiple Canadian centres in a previously funded study. Since we will be linking this previously collected data to high quality provincial health administrative data to identify the study outcomes, our study findings will be relevant to all children across Ontario and Quebec and can even be applied across Canada.

It is estimated that 25% of children who visit the ED for an asthma exacerbation will have a (preventable) repeat asthma ED visit or hospitalization within one year. We propose that development of a clinical score that can be practically used in the ED setting to identify these high-risk children would allow efficient targeting of proven preventative interventions to the right patients. Having a method to identify this target group would also help in the design of future research studies aiming to test the effectiveness of new strategies to prevent repeat asthma acute health care visits. In short, developing a clinical risk score to identify high-risk children is the first step in our aim to ultimately prevent up to 20% of childhood ED visits, as well as the breathing problems, anxiety and life/work disruption experienced by this group of children and their families.

Dr. Roma Sehmi

Role of TL1A/Death Domain Receptor 3 (DR3) axis in the activation of ILC2 in Asthma

Amount Awarded: $50,000

Asthma is a chronic disease of the airways that affects more that 3 million people in Canada and it’s incidence is increasing. 1 in 3 individuals in Ontario will receive a physician diagnosis of asthma during their lifetime. Despite the development of anti-asthma drugs, many asthmatics continue to have worsening breathlessness as they age. Investigating biological processes that cause the symptoms of asthma may reveal new drug targets to treat uncontrolled breathlessness that worsens over time in asthmatics.

After asthmatics inhale particles to which they are allergic, their lungs become inflamed and their asthma worsens. During this process, recruitment to the lung of mature cells such as eosinophils and basophils and their precursor cells occurs. These cells, when activated release cell-derived products which damage the lung tissue and symptoms of asthma develop such as airway narrowing and mucus over production. Identifying factors/cells that promote and expand eosinophil numbers in the airways may provide a valuable target for treatment of asthma. In the last decade, a novel group of cells termed “Group 2 innate lymphoid cells (ILC2s)” have been discovered as a major tissue source of factors that promote eosinophil growth, recruitment and activation in the lung tissue. In asthma our group has found that ILC2 producing pro-eosinophilic cytokines are increased in the airways in patients with uncontrolled symptoms despite high doses of steroids. As well, we reported that ILC2 provide the initiation signal for allergic asthmatic responses. Little however is known about all the factors that recruit and activate ILC2 in asthmatic airways. This project will investigate the role of a factor known as tumor necrosis like factor 1A (TL1A) and changes in its receptor (death receptor 3; DR3) expression on ILC2 in the airways in asthmatic responses. We will test the effect of corticosteroids, the gold-standard for treatment of asthma, on DR3 expression on ILC2.

Using an allergen exposure model that is well established in our laboratory, we will study subjects who are induced to have an asthmatic response as a result of a controlled inhalation of a compound to which they are allergic. By taking sputum samples coughed up from the airways, level of expression of DR3 on ILC2 cells and amount of TL1A in sputum will be assessed. The time points chosen to sample sputum before and after allergen challenge are well defined as time points at which maximum increases in airway eosinophil numbers occur. We will investigate expression levels of DR3 on ILC2 from sputum (a) before and after an allergic asthmatic response, (b) compare these changes with cell types that produce eosinophil growth factors such as T cells, and (c) by isolating ILC2s from blood (as these are too rare to isolate from sputum), we will investigate what effect this receptor has on ILC function and the ability of corticosteroids to interfere with this effect. Effects on ILC2s will be compared to T cells, as the latter are known to be steroid sensitive cells.

Animal studies show that ILC2 are an important local source of growth factors that promote expansion of cells that cause many of the symptoms of asthma. Understanding the role of ILC2 in human eosinophilic asthma is a new and important field. By comparing activation of ILC2s and T cells, and investigating the effect of known drugs on modulating this activation, this study will provide unique drug targets that may be beneficial in asthmatics who continue to have uncontrolled symptoms despite being treated with high doses of corticosteroids.

Increased numbers of eosinophils is a prominent feature of the asthmatic lung and studies have shown that this feature increases as the symptoms of this disease worsen. By understanding the role of cells that promote the persistence of eosinophils in the lung, we aim to better treat this condition. 

Dr. Azadeh Yadollahi

Investigating whether Bronchodilator Medications can Prevent Effects of Rostral Fluid Shift on Airway Narrowing in Asthma

Amount Awarded: $50,000

Asthma affects 8% of Canadians and its health related costs are $600M annually. Nocturnal exacerbation of asthma is a clinically important phenotype of asthma and is common in two-thirds of asthma patients. Nocturnal asthma is associated with increased use of asthma medication, more severe asthma symptoms, and greater asthma related morbidity and mortality. The recumbent posture and sleep increase lower airways narrowing and nocturnal asthma.

Emergency visits due to asthma exacerbation, calls to physicians, and death due to asthma are more common during the night. Despite optimum treatments, nocturnal symptoms remain a major concern and mechanisms accounting for nocturnal asthma remain unclear. We propose that lying down during sleep causes shifts of body fluids from the legs to the chest and neck, and this rostral fluid shift exacerbates narrowing of small airways in lungs in patients with asthma. Fluid accumulation in the chest can increase bronchial blood volume, narrow the airway lumen, and thus contributes to asthma severity and fatality.

Our objective is to demonstrate that in patients with nocturnal asthma, bronchodilating medications do not prevent the airway narrowing due to fluid shift. Asthmatics with and without nocturnal asthma will be randomized to receive placebo or bronchodilator. Then, they will lie supine for 30 minutes and their legs will be squeezed for 25 minutes (from 5 mins to 30 mins) to increase fluid shift out of the legs and simulate the amount of fluid shift that occurs at night. A week later they will be crossed over to the other study arm. In both study arms, we will measure fluid volumes in the leg and chest, and airway resistance at 0 min and 30 min. We expect that in patients with nocturnal asthma, even with bronchodilator treatment, increased fluid shift into the chest will increase airway resistance.

Post-mortem analysis of the lungs show that airway walls are thicker in asthmatics who died from fatal asthma attacks than from other causes. Acute changes in airway wall thickness can occur from local edema due to vascular leakage in the airway wall. One of the principal mechanisms by which increased excess airway fluid can increase airway resistance is through entering the airway adventitia, swelling the airway wall and decreasing the airway lumen. As this mechanism is independent of contraction of the airway smooth muscle, it would not be expected that it would be prevented by bronchodilating medication. Demonstrating this is of clinical relevance, as long acting bronchodilating medication in combination with inhaled steroids is the principle component of current guidelines for the prevention of nocturnal asthma. With this proposal, we intend to demonstrate that bronchodilating treatment does not address all mechanisms of nocturnal airway narrowing in asthma.

This research addresses physiological mechanisms that apply to an important clinical problem. Understanding the mechanisms of lower airway narrowing due to fluid shift will facilitate development of new treatments for nocturnal asthma by reducing fluid shifts and their pernicious effects. These treatments can be as simple and practical as use of compression stockings during the day, exercise, diuretics, or head elevation during sleep. If supported by the data, this practicality, together with their translational impact, would comprise the greatest strengths of this research.