Unravelling the mysteries of COVID-19
In early 2020, with news about COVID-19 spreading around the globe, Dr. Douglas Fraser began immediately preparing for research. Within five months of a pandemic being declared, Dr. Fraser and his colleagues published multiple research papers that have significantly advanced the world’s understanding of the virus.
The research team analyzed blood samples from critically ill patients at London Health Sciences Centre (LHSC). Their studies included COVID-19 patients and patients with other infections admitted to LHSC’s intensive care unit (ICU), as well as healthy control participants. Blood was drawn regularly during ICU admission, processed in a lab, and then analyzed using conventional statistical methods and artificial intelligence (AI).
The goal was to better understand COVID-19 and how to treat it by uncovering concrete evidence for changes occurring in the body as the infection progresses.
“When we began seeing patients with COVID-19, we knew very little about the disease and how to treat it,” explains Dr. Fraser, lead researcher from Lawson Health Research Institute and Western University’s Schulich School of Medicine & Dentistry. “We’ve now begun answering some of the biggest questions asked about COVID-19. While further research is needed, our findings could have important implications for treating and studying this disease.”
Predicting which COVID-19 patients will get worse
With no proven therapies, many COVID-19 patients admitted to ICU do not survive.
“When a patient is admitted to ICU, we normally wait to see if they are going to get worse before we consider experimental or higher risk interventions. To improve outcomes, we need not only new therapies bu ways to predict which patients are going to get worse,” explains Dr. Fraser, who is also a Critical Care Physician at LHSC.
In one study, the team measured 1,161 plasma proteins from the blood of research participants. They identified six molecules (CLM-1, IL12RB1, CD83, FAM3B, IGFR1R and OPTC) that can be used as biomarkers to predict how severely ill a patient will become.
They found these immune-related molecules were elevated in COVID-19 patients who would become even more severely ill and that when measured on the first day of ICU admission, the molecules could be used to predict which COVID-19 patients will survive following standard ICU treatment.
“While further research is needed, we’re confident in these biomarkers and suspect these patterns may be present even before ICU admission, such as when a patient first presents to the emergency department,” notes Dr. Fraser. “These findings could be incredibly important in determining how severely ill a patient will become.”
The team notes that predicting a patient’s disease severity can help in a number of ways. It could allow for medical teams to have important conversations with family members, setting goals of care based on the patient’s health and personal wishes. Medical teams could use the knowledge to mobilize resources more quickly. If they know a patient is at higher risk of death, they may consider intervening sooner despite associated risks. The team also hopes the findings can be used to better design COVID-19 clinical trials by grouping patients based on their risk. This could allow for stronger results when examining potential treatments.
Profiling the body’s immune response
In order to discover effective treatments, researchers need to understand the changes occurring in the body and how to target them. Since the pandemic’s start there have been reports that the immune system can overreact to the virus and cause a cytokine storm – elevated levels of inflammatory molecules that damage healthy cells.
“Clinicians have been trying to address this hyperinflammation but without evidence of what to target,” notes Dr. Fraser. “We wanted to take away the guessing by identifying therapeutic targets.”
In another study, Dr. Fraser and his team were first in the world to profile the body’s immune response to COVID-19. By studying the blood samples from critically ill patients, the team identified a unique pattern of six molecules that could be used as therapeutic targets to treat the virus.
The researchers studied 57 inflammatory molecules in total. They found six molecules were uniquely elevated in COVID-19 ICU patients (tumor necrosis factor, granzyme B, heat shock protein 70, interleukin-18, interferon-gamma-inducible protein 10 and elastase 2).
The team then used AI to validate their results. They found inflammation profiling was able to predict the presence of COVID-19 in critically ill patients with 98 per cent accuracy.
“Understanding the immune response is paramount to finding the best treatments,” says Dr. Fraser “Our next step is to test drugs that block the harmful effects of several of these molecules while still allowing the immune system to fight the virus.”
Understanding why blood clots occur and how to treat them
Another complication occurring in critically ill COVID-19 patients is clotting in the lung’s small blood vessels, which leads to low oxygen levels in the body.
“The reason for this clotting has been unclear. Most suspect the clotting mechanisms in our blood are put into overdrive and so many clinicians have been treating with anticoagulant therapies like the drug heparin,” says Dr. Fraser. “But we’ve uncovered an entirely different mechanism.”
The team further analyzed participant blood samples and found that the inner linings of small blood vessels are becoming damaged and inflamed, making them a welcoming environment for platelets (small blood cells) to stick.
They discovered that COVID-19 patients had elevated levels of three molecules (hyaluronic acid, syndecan-1 and P-selectin). The first two molecules are products broken down from small hair-like structures (the glycocalyx) which line the inside of blood vessels.
Their presence suggests the inner linings of blood vessels are being damaged. The presence of P-selectin is also significant as this molecule helps to make both platelets and the inner lining of blood vessels adhere to one another.
“The glycocalyx keeps platelets from touching the inside wall of the blood vessel and helps facilitate the production of nitric oxide, which has an important role in preventing platelets from sticking,” explains Dr. Fraser. “We suspect the body’s immune response is producing enzymes that shear off these little hair-like structures, inflaming blood vessels and making them a welcoming environment for platelets to form clots.”
The team suggests that two therapies may hold promise for treating blood clots in COVID-19 patients: platelet inhibitors that stop platelets from sticking and molecules to protect and restore the inner lining of blood vessels.
“By exploring these therapies, we may be able to improve patient outcomes,” says Dr. Fraser.
Improving outcomes is the primary goal of the research team which includes a large collaborative group of clinicians and scientists and enthusiastic support from frontline health care workers, including nurses, respiratory therapists, ICU managers and research assistants.
“This research was a team effort driven by dedication from all involved,” states Dr. Fraser. “Through our combined findings, we hope to provide clinical tools to predict which COVID-19 patients will become the most severely ill and treatments for both hyperinflammation and blood clots.”
This research was made possible through generous donor support to London Health Sciences Foundation.