COVID-19 Breathes New Life into Sepsis Research

Developing Ontario-made cell therapies at the intersection of critical care and stem cell science

As the third wave of COVID-19 pandemic rages on, researchers worldwide and right here in Ontario are stepping up research activities to identify efficacious therapies for severe infections. OIRM caught up with Dr. Claudia dos Santos, Robert and Dorothy Pitts Research Chair in Acute Care and Emergency Medicine – University-Hospital Endowed Chair at St. Michael’s Hospital and the University of Toronto, to learn about the potential role stem cells may play in COVID treatment.

How are sepsis and COVID-19 related?

Dr. dos Santos: Sepsis was redefined in 2016 as a life-threatening dysregulated response to infection, and so by that definition fatal COVID is, in fact, a form of sepsis.

The function of the lung is to exchange carbon dioxide for oxygen. This exchange depends to the integrity of the alveolar-capillary membrane, where epithelial and endothelial work together to oxygenate the blood. Approximately five to six litres of blood are oxygenated in the lungs with every heartbeat! COVID disrupts the delicate balance by injuring cells that make up this membrane, causing gap formation. When that happens, the lung fills with inflammatory fluid and cells. An alveolus that is occupied cannot be filled with air – resulting in severe low oxygen. Life-support in the form of mechanical ventilation helps to support gas exchange by providing the lungs with a high concentration of oxygen and pressure to make sure lungs don’t collapse because they are so “boggy” with inflammatory fluid. However, mechanical ventilation is not a treatment for COVID, so unless we can stop and/or reverse this process, the lung injury may ultimately be fatal.

Why is sepsis so difficult to treat?

Dr. dos Santos: The complexity of sepsis is multifactorial. First, there is a lot of variability involved – variability in the host, variability in the virus, and variability in the interaction between them. Multiple cells play a highly active role, including the epithelial and endothelial cells as well as macrophages, T- and B-cells, platelets, and fibrocytes, which increases the complexity. The genetic and epigenetic makeup of the patient adds another layer of complexity, as COVID-19 has illustrated. This may in part explain why some people become very ill, while others are asymptomatic.

An important limitation is the fact that, traditionally, sepsis and acute respiratory distress syndrome (ARDS) have been defined syndromically – a group of symptoms that together characterize a specific disorder. This is very different from a disease with a clear mechanism, such as diabetes. Moreover, in the absence of detailed molecular data, treatment has been based on a one-size fits all approach. This has been the nucleus of my research: stepping away from a syndromic definition and trying to understand individual patient-specific mechanisms, to advance precision medicine.

What do we know about the potential role for stem cells in treating sepsis?

Dr. dos Santos: Mesenchymal stem cells (MSCs) are interesting as a potential treatment for sepsis because several landmark studies have demonstrated that they both synthesize and cause recipient cells to synthesize various molecules and proteins that have anti-inflammatory and antibacterial effects. Their beneficial effects are pleotropic, which means they work via multiple mechanisms, hitting various aspects of the sepsis response simultaneously. For example, they produce anti-bacterial and anti-inflammatory factors and encourage the production of resolvins, molecules that can promotes resolution of ARDS by reducing the leakage of fluids in the lungs, allowing those gaps I mentioned earlier to close and heal.

Importantly, when patients come to the hospital acutely ill with life-threatening difficulty in breathing and low blood pressure – this is called septic shock – we don’t have time to use autologous cells (a patient’s own cells) to treat sepsis. The good news is that MSCs have a very low number of cell markers that would allow the body to recognize them as foreign, so when MSCs from one person are transfused in another person (allogenic), they don’t cause a major immune reaction. This means we can benefit from their beneficial effects without worrying about causing severe side-effects. Many studies have shown over the years that they are quite safe in humans. Also, they don’t linger in the body. Once administered, they hang-around for about 96hrs to exert the therapeutic effect, after which they can no longer be detected. Also, they can tailor  their activity depending on the microenvironment in which they are introduced, generating those anti-inflammatory, antibacterial and bioenergetic responses that best suits the environment. So, they are almost a “smart” therapy that will adapt to the situation in hand. Plus, MSCs are amenable to genetic and pharmacological modifications that might make them to be modified so as to make them even more effective for the treatment of sepsis and ARDS.

These are just a few examples of why MSCs are so interesting for COVID and sepsis research right now – there are more than 80 clinical trials under way looking at MSCs and COVID alone. Researchers all over the world are watching very carefully results from these Phase 1 and 2 trials using cell therapy for COVID.

So COVID-19 has put new emphasis on sepsis research?

Dr. dos Santos: There is no real silver lining to COVID, but it has shone a light on the need for more sepsis research. It’s pitiful, given that we’ve known the awful reality of sepsis for years, that more resources have not gone into developing new treatments – especially after the SARS and H1N1 pandemics. Generally speaking, people don’t link sepsis and COVID-19 in their minds, but it’s such an important link because fatal COVID is a form of sepsis-induced ARDS. It’s not the virus, but the response to the virus that is killing people. This has presented an unprecedented opportunity  to fast-track this kind of research here in Ontario and worldwide.

Why is Toronto/Ontario/Canada the place to do critical care and stem cell research?

Dr. dos Santos: Canada is an exceptionally strong country in both areas. The University of Toronto is probably one of the top five centres in the world for critical care research; Saint Michael’s Hospital is quite unique in that we are one of the few hospitals that has an interest in mechanistic research and basic science work in critical illness. The work coming out of the Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group is pioneering. Of course, we have a great regenerative medicine ecosystem, including research and commercialization. What’s obvious is that we require more funding to make these potential therapies a reality.