Expert Insight: A systems-level approach to understanding the immunology of COVID-19 in adults and children

---

Dr. Petter Brodin, Director of SciLifeLab Mass Cytometry Facility at the Karolinska Institute

A popular SelectScience webinar that provides important new insights into the immune system responses to SARS-CoV-2 infection is now available on demand. The studies, conducted by Dr. Petter Brodin's group at Karolinska Institute in Stockholm, took a systems-level approach to analyze both the cellular and protein components involved, using methodologies including mass cytometry, flow cytometry and high-multiplex proteomics.

A longitudinal study of severe COVID-19 patients identified distinct patterns of immune cell coregulation in four different stages of the disease and demonstrated a shared trajectory of immunological recovery that may provide future biomarkers of disease progression. In an investigation of multisystem inflammatory syndrome in children (MIS-C), a relatively rare complication of SARS-CoV-2 infection in children, important differences in inflammatory response were seen between MIS-C and severe COVID-19 in adults. Moreover, while some similarities were observed between inflammatory responses in MIS-C and Kawasaki disease, important differences were also apparent, particularly in the T cell subsets involved.

Read on for highlights from the live Q&A discussion with Dr. Brodin or register to watch the full webinar on demand >>

Q: What are the clinical differences in presentation between acute COVID and MIS-C, as well as MIS-C and Kawasaki disease?

PB: If we start with MIS-C and Kawasaki disease, then Kawasaki disease occurs in young children 2-4 years of age in the wintertime. It's a viral infection of a different kind and the thing about Kawasaki disease is that children present with a rash and sometimes heart involvement. Initially, when this MIS-C presentation started to occur, people mistook them for Kawasaki Disease. However, we've now learned that Kawasaki disease and MIS-C often involve different populations of children. MIS-C typically involves older kids, children of teenage years and often much more severe in presentation than the typical Kawasaki disease. They often have abdominal involvement with vomiting, stomach ache, and so on, which is not typical in Kawasaki disease. There are clearly clinical differences between MIS-C and Kawasaki disease.

When it comes to acute COVID and these other post-infectious conditions, they are quite distinct. Acute COVID typically begins with a respiratory infection, coughing, fever, and then, later on, might develop into a hyperinflammatory disease. At that time, during the hyperinflammatory later phases of the infection, then there can be similarities between MIS-C and acute COVID, but that is sort of in the later stages.

Q: Could you tell us about the current understanding of the determinants of severe COVID-19?

PB: This has been probably the most important issue to sort out since we started to learn about this new virus because what's pretty evident is that for the majority of patients and people infected with SARS-CoV-2, the infection is rather mild. A lot of people have fevers and a cough, and so on. Young children more frequently are asymptomatic, but then in all age groups, some individuals develop very severe disease. Most commonly, of course, men more than women, and older people more than young people. There is a very big variation in presentation with patients with COVID-19.

We've learned quite a bit over these past 10 months, with 30,000 papers published. There has been an extraordinary development in understanding both the virus, but also the immune response to the virus. We know now that men suffer often more severe disease than women when it comes to acute COVID, are more likely to end up in intensive care units and more likely to die. We think that this is related to differences in the immune system between men and women because the infection rate, the likelihood of being infected, is not different in men and women, as far as we know.

What are those immune system differences? There have been a couple of reports, and we know from other people's work that, for example, vaccine responses differ between men and women. We also know that many autoimmune diseases, particularly diseases such as lupus, which involves interferon responses, are much more prominent in women than in men, more common in women than in men. A lot of evidence points towards differences in men and women with respect to innate, initial antiviral immune responses, both before COVID-19 but also now.

I think that is probably the best determinant we have to date, to explain the differences in COVID-19 severity. It has to do with the ability to mount a robust early immune response to the virus, involving type 1 interferons but also other factors probably.

Q: Did you observe any genetic predisposition to the severity of COVID infection among the children studied?

PB: I think that relates to the MIS-C work, which was done in children. The question implies that there are genetic differences when it comes to the likelihood of getting the infection. That particular question we have not studied. It's very difficult to study whether people are resistant to a particular virus. Those people are very difficult to find. We are looking into genetic host factors that would explain both why some children develop MIS-C, while most children obviously don't, and also those factors, genetics and other things, that might determine why an individual develops severe COVID versus a milder COVID. There has been some progress made in that area by researchers such as Jean-Laurent Casanova’s Lab at the Rockefeller Institute, Helen Su at the NIH, leading a large consortium called Human Genetic Effort. Their patients with rare immunodeficiencies involving viral sensing and interferon responses have been reported and those are individuals that are very rare, but they presented with life-threatening COVID-19. That's related in general to the infection, not specifically children.

Q: What in your opinion is the reason COVID-19 has a milder course in the pediatric setting? Could that be previous coronavirus exposure, vaccine history, or better regulatory cell activity in children?

PB: My guess is that it might involve prior coronaviruses, but that remains to be determined. I believe, and I think quite a few people believe, that the coronaviruses are so abundant that not only children would carry immunity to such viruses but probably also quite a few adults. Therefore, it does not entirely, in my opinion, explain why children are so able to manage this infection without severe disease in general. I think probably this points more to differences in the immune system. If you think about it from an evolutionary point of view, or life history point of view, children are experts at responding to new pathogens because the younger a child is, the less experience that child would have, and the more able the child must be to respond to a new infection. While adult people, and especially older people, they can get by quite well by relying on their memory responses of prior exposures. Typically, older people might be less equipped to respond to new pathogens. This can be explained by many different factors, the lower number of naive cells in the adaptive immune system, thymic involution, and then lack of production of naive T cells, and so on. I think there are many different pieces to this puzzle, and we only know a little bit of that at the moment.

Q: What do you see are the biggest advantages of combining the two platforms used in your studies?

PB: Sometimes people say that immune responses don't occur in the blood, and so there's no point in looking in the blood. Instead, all the relevant responses occur in tissues. Obviously, it's true that the blood is not the main site of immune activity; it is definitely tissue, specific responses that we cannot see in the blood. Given the fact that we can sample the blood so easily and we can collect non-determinable samples, there is real potential in detecting important signals in the blood, even if the immune response is actually going on primarily in a distal tissue, like the lung.
What do we do to study the blood in the best possible way? My group has reasoned that by looking at the various components of blood and the immune cells and proteins that make up the blood immune system, and the circulating immune system, and doing that in the most comprehensive way that we can, we believe this gives us a very strong potential, sort of an ability to actually look at the immune response in younger children, or over time in a patient. This combination of technologies, the Olink platform for plasma protein measurements which gives very reproducible signals with very low background signal, and then the mass cytometry assay, which gives us very broad coverage of the immune cell components, we think it's a very strong combination of features.

Watch this on-demand webinar to find out more in-depth insights about the immune responses of COVID-19>>