MIS-C Risk Factors and Genetic Susceptibility in Children

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• MIS-C Susceptibility Overview
• Contrasting COVID and MIS-C Risk
• Genetic Factors in MIS-C
• HLH Gene Mutations Role
• Research and Future Directions
• Full Transcript

MIS-C Susceptibility Overview

Dr. Randy Cron, MD, addresses the critical question of why only a minority of children develop multisystem inflammatory syndrome after a COVID-19 infection. He acknowledges that this is a key area of ongoing investigation for pediatric specialists. Dr. Randy Cron, MD, explains that the underlying susceptibility factors are not yet fully understood. Dr. Randy Cron, MD, emphasizes the need for further research to identify which children are most at risk for this acute inflammatory condition.

Contrasting COVID and MIS-C Risk

Dr. Randy Cron, MD, highlights a stark contrast in risk profiles between severe acute COVID-19 and MIS-C in children. He notes that children hospitalized with severe COVID-19 pneumonia or acute respiratory distress syndrome (ARDS) often have pre-existing comorbidities. These co morbid conditions mirror those in adults and include obesity, diabetes, hypertension, chronic lung disease, and chronic kidney disease.

In direct opposition, Dr. Randy Cron, MD, states that the vast majority of children with MIS-C were previously healthy. These children were not on medications for chronic conditions and had no underlying chronic diagnoses. This reversal makes identifying clear risk factors challenging, as noted by Dr. Randy Cron, MD.

Genetic Factors in MIS-C

Emerging genetic research provides clues to MIS-C susceptibility. Dr. Randy Cron, MD, discusses collaborative work with colleagues in New York who studied a cohort of children from the early pandemic. Their research focused on genes known to be risk factors for macrophage activation syndrome, a severe cytokine storm disorder.

The initial findings from this genetic analysis are significant. They point toward a potential hereditary component that predisposes certain children to an exaggerated inflammatory response post-COVID-19. Dr. Randy Cron, MD, explains this research is crucial for understanding the immunology behind MIS-C.

HLH Gene Mutations Role

A key discovery involves mutations in genes associated with hemophagocytic lymphohistiocytosis (HLH). Dr. Randy Cron, MD, reports that approximately a quarter of the children in the New York MIS-C cohort had a single copy mutation in these HLH-related genes. Typically, HLH is an autosomal recessive disorder requiring two mutated gene copies for full disease presentation, which usually occurs in infancy.

Dr. Randy Cron, MD, explains that having just one bad copy of these genes may confer a slight risk for developing a cytokine storm syndrome like MIS-C. This finding aligns with pre-pandemic observations that other cytokine storm syndromes can also be influenced by single copy mutations. Dr. Randy Cron, MD, clarifies that this genetic susceptibility is different from classic HLH.

Research and Future Directions

The research into MIS-C susceptibility is ongoing and complex. Dr. Randy Cron, MD, is part of the effort to get this important genetic data from the cohort of nearly 40 children published. He cautions that it is still very hard to know the full picture of genetic risk factors at this point.

This research direction is vital for future pandemic preparedness and understanding post-viral inflammatory syndromes. The work of Dr. Randy Cron, MD, and his colleagues helps build a foundation for identifying children at highest risk for severe complications like MIS-C after viral infections.

Full Transcript

Dr. Anton Titov, MD: Since the minority of children get multisystem inflammatory syndrome after COVID-19, what are the susceptibility factors? Is that a question of genetics? Is it a question of having certain background medical conditions? What makes a minority of children so susceptible to this very acute onset disease?

Dr. Randy Cron, MD: That's the question that I think a lot of us would like to know, and we don't really know at this point. Unlike COVID, as I said before, for the most part, kids are spared of COVID. There are a lot of potential reasons for that that are still being explored.

Dr. Randy Cron, MD: But despite that, we've had almost a roughly equal number of kids who have been hospitalized specifically for COVID infection itself as we have with MIS-C. So although it's much rarer than in adults, for example, kids do get hospitalized.

Dr. Randy Cron, MD: The interesting thing is, much like the adults, the children who get hospitalized with active COVID infection and bad lung disease and can develop something called ARDS or acute respiratory distress syndrome—like in adults—often have comorbid conditions. That may be obesity, diabetes, hypertension, chronic lung disease, chronic kidney disease, just like the adults. So very similar in that sense.

Dr. Randy Cron, MD: The exact opposite is what we saw with MIS-C. These kids, for the most part, were essentially all previously healthy. They weren't on other medicines for chronic conditions; they didn't have other underlying chronic diagnoses. Now, there were a few kids who had some of these, but for the most part, not so much. These were for the large part previously healthy kids.

Dr. Randy Cron, MD: So that's hard to make a risk factor out of that, other than saying that if you don't have a chronic illness, you're at slightly higher risk than those who did. Maybe I don't know.

Dr. Randy Cron, MD: But my colleagues in New York that I've personally collaborated with did some genetic studies on their cohort of children that they saw early during the pandemic. We're in the process of trying to get this data published.

Dr. Randy Cron, MD: What they did—my colleagues looked at genes that we know are risk factors for what we'll probably talk about a little bit: macrophage activation syndrome. It turns out that about a quarter of the kids they diagnosed with MIS-C in their hospital early during the pandemic in New York had a single copy mutation in genes that, if you have both copies mutated, you would present with something called HLH or hemophagocytic lymphohistiocytosis.

Dr. Randy Cron, MD: That is a severe cytokine storm that appears usually within days, weeks, or months of life, but almost for the most part within the first year of life. So that's where you have two copies for mostly autosomal recessive disorders, where you need both genes mutated, and it's almost 100% penetrance, particularly early in life.

Dr. Randy Cron, MD: The surprising thing that we saw, even prior to this pandemic, is that other forms of cytokine storm syndromes can have single copy mutations in these genes. Normally, you think the good copy would outweigh having just one bad copy. That's true for diseases, for example, like cystic fibrosis or sickle cell anemia, where one bad copy is not going to give you the disease.

Dr. Randy Cron, MD: But in these diseases, having one bad copy may put you at slight risk for developing the cytokine storm syndrome. So in our cohort of about 40 kids, in collaboration with our colleagues in New York, that suggests that maybe some of those genes may be risk factors too.

Dr. Randy Cron, MD: But it's very hard to know at this point.