AMO – Academic Medical Organization of Southwestern Ontario
AMO-20-029 – Rapid Identification of Therapeutic Targets to Optimize Care of Critically Ill COVID-19 Patients
Despite widespread vaccination, the threat of COVID-19 has not ended. Indeed, new variants continue to emerge and localized outbreaks are common. Once infected, therapeutic interventions are often supportive in nature and without specific therapeutic targets, demanding further studies. The rapidity and intensity of the COVID-19 pandemic has also left little time and/or resources to study the chronic symptoms exhibited by acute infection survivors, or to analyze the surge response with regards to optimizing healthcare delivery by reducing gaps in care. At the start of the pandemic in March, 2020, we mobilized our local resources and created a COVID-19 STUDY TEAM. Our objectives were ambitious, as we were determined to better understand how the human body reacts to COVID-19 and to identify potential therapeutic targets to improve outcomes. Our initial approach relied on collection of biological samples from human subjects, followed by proteomic, metabolomic and transcriptome investigations. Our studies were the first in the World to profile COVID19 inflammatory, thrombotic and serological changes in critically ill patients, and revealed several novel therapeutic targets. In fact, our results have provided extraordinary new insight into COVID-19 with 4 provisional patents, 16 publications (12 published, 4 in review), 22 collaborations, 6 industry contracts and over 40 media stories. Remarkably, we currently have over 25,000 aliquoted patient plasma samples currently stored within our freezers, which are uniquely available to us and our collaborators to continue our ground breaking studies. Data from our laboratories has implicated SARS-CoV-2 microvascular injury (or endotheliopathy), secondary to immune thrombotic events, in COVID-19 pathophysiology. The immunothrombotic mechanisms have been largely elucidated by us via plasma characterization; however, defining specific cellular mechanisms of endotheliopathy requires an in vitro approach with human based materials. Intercellular interactions that exacerbate COVID-19 severity, including both human leukocyte and platelet adhesion to endothelium, can only be investigated in vitro employing microperfusion systems. Our current studies will delineate key mechanisms of COVID-19 endotheliopathy in specific microvascular organ systems using only human tissues; with our plasma samples arguably the best characterized in the COVID-19 literature. COVID-19 instigates systemic inflammation, associated with a triad of fever, cytopenia, and hyperferritinemia. We were the first to profile the inflammatory response in COVID-19 ICU patients and to identify immune mediators and therapeutic targets. Our published evidence suggests that COVID-19 results in persistently elevated tumor necrosis factor (TNF) and instigates a “protease storm” secondary to early activation of lymphocytes leading to release of Granzyme B, followed by neutrophil activation and release of Elastase 2. Serine proteases can cause endothelial cell activation and dysfunction, which would increase leukocyte and platelet adhesion, as well as dysregulate local blood flow and tissue oxygen delivery. Our studies are now focused on inhibition of serine proteases, as novel therapeutic targets, in COVID-19. The COVID-19 pandemic has revealed a new clinical syndrome referred to as “Long COVID”. As many as 10% of individuals infected with SARS-CoV-2, and 90% of patients with severe disease, will have long term symptoms lasting at least 4 months. The lungs, heart and brain are the main organs affected, resulting in a constellation of symptoms that may include severe fatigue, shortness of breath and cognitive dysfunction. Our research, supported by the work of others, conclusively showed that acute COVID-19 is primarily a small blood vessel disease. The mechanisms of microvascular activation and injury are still under investigation, but may be secondary to a “Protease Storm”. To gain firm insight into endothelial cell pathology, multiple biomarkers are being measured simultaneously, but require a large number of assays and operator time. To circumvent these practical issues, diagnostic assays of endothelial cell activation/injury, as well as chronic remodeling, need to measure multiple and diverse biomarkers in a single assay with ease of use, as we are now pursuing. Given the impact of our studies on COVID-19 patients and frontline healthcare, and to ensure optimal knowledge translation (KT), we are leveraging our existing Healthcare Advisory Teams in collaboration with the Patient Advisory Councils. This team meets regularly and provides unique insight into the feasibility and validity of ongoing studies. Appropriate health units, medical councils and legislative representatives are actively engaged to produce meaningful changes to COVID-19 health care delivery.
Prevention and Treatment
Primary Project Lead for Contact
Dr. Douglas Fraser